J Neurooncol DOI 10.1007/s11060-016-2065-5
CLINICAL STUDY
Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial Carmen Balana1 • Ramon De Las Penas2 • Juan Manuel Sepu´lveda3 • Miguel J. Gil-Gil4 • Raquel Luque5 • Oscar Gallego6 • Cristina Carrato7 • Carolina Sanz7 • Gaspar Reynes8 • Ana Herrero9 • Jose Luis Ramirez10 • Pedro Pe´rez-Segura11 • Alfonso Berrocal12 • Jose Maria Vieitez13 • Almudena Garcia14 Sergio Vazquez-Estevez15 • Sergi Peralta16 • Isaura Fernandez17 • Ivan Henriquez18 • Maria Martinez-Garcia19 • Juan Jose De la Cruz20 • Jaume Capellades21 • Pilar Giner22 • Salvador Villa`23
•
Received: 23 September 2015 / Accepted: 22 January 2016 Ó Springer Science+Business Media New York 2016
Abstract We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ ? BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m2,
This study has previously been presented in part as an oral presentation at the 2014 ASCO Annual Meeting, May–June 2014 (included in ASCO Highlights), as an oral presentation at the 39th ESMO Congress, September 2014, as a poster with discussion at the ASTRO 56th Congress, April 2014, and as a poster at the 11th EANO Meeting, October 2014.
Electronic supplementary material The online version of this article (doi:10.1007/s11060-016-2065-5) contains supplementary material, which is available to authorized users. & Carmen Balana [email protected] 1
2
Medical Oncology Service, Institut Catala` d’Oncologia, Hospital Universitari Germans Trias i Pujol, Carretera Canyet, s/n, 08916 Badalona, Spain Medical Oncology Service, Hospital Provincial de Castello´n, Castello´n, Spain
3
Medical Oncology Service, Hospital Universitario, 12 de Octubre, Madrid, Spain
4
Medical Oncology Service, Institut Catala` d’OncologiaIDIBELL, Hospitalet de Llobregat, Barcelona, Spain
5
Medical Oncology Service, Hospital Universitario Virgen de las Nieves, Granada, Spain
6
Medical Oncology Service, Hospital de Sant Pau, Barcelona, Spain
days 1–21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ ? BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ ? BEV arm were evaluable for response. Results favored the TMZ ? BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ ? BEV arm, though the difference did not reach statistical significance. MGMT methylation 7
Pathology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
8
Medical Oncology Service, Hospital Universitario La Fe, Valencia, Spain
9
Medical Oncology Service, Hospital Miguel Servet, Zaragoza, Spain
10
Cancer Molecular Biology Laboratory, Institut Catala` d’Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
11
Medical Oncology Service, Hospital Universitario Clı´nico San Carlos, Madrid, Spain
12
Medical Oncology Service, Hospital General Universitario de Valencia, Valencia, Spain
13
Medical Oncology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
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in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ ? BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.
bevacizumab could be easily evaluated without the potential confounding effects of previous chemoradiotherapy. To test this hypothesis, we carried out a randomized phase II trial comparing temozolomide alone versus temozolomide plus bevacizumab as neoadjuvant and concurrent therapy in unresected glioblastoma patients (clinicaltrials.gov NCT01102595).
Keywords Bevacizumab Temozolomide Glioblastoma Neoadjuvant MGMT Serum MGMT
Patients and methods Introduction
Patients
The standard first-line treatment of glioblastoma is radiotherapy with concurrent and adjuvant temozolomide, based on the results of the EORTC-NCIC trial [1, 2]. However, patients with unresected tumors have a dismal prognosis, with no significant differences in overall survival (OS) between standard chemoradiotherapy and radiotherapy alone (9.4 vs. 7.8 months; hazard ratio [HR] 0.7) [1]. The absence of previous debulking surgery leads to greater neurological instability during treatment, indicating a clear need for alternative methods of reducing tumor size prior to chemoradiotherapy. Bevacizumab, a potent antiangiogenic agent, has demonstrated activity in recurrent glioblastoma [3–6]. In the first-line setting, however, three trials, including mainly resected patients, showed a benefit for bevacizumab in progression-free survival (PFS) but not in OS [7–9] . We hypothesized that in unresected patients, early administration of bevacizumab prior to standard radiotherapy plus temozolomide would shrink the tumor sufficiently to allow completion of the standard treatment. Moreover, in this neoadjuvant setting, the real activity of
Patients were eligible if they had unresected glioblastoma, diagnosed by biopsy, including stereotactic or open craniotomy, and had received no prior treatment. Candidates were required to have measurable disease (C2 cm) and stable or decreasing glucocorticoid doses within the 5 days before randomization. In patients undergoing craniotomy, post-operative magnetic resonance imaging (MRI) was mandatory within 72 h. Other inclusion criteria were as follows: age C 18 years, Eastern Cooperative Oncology Group (ECOG) PS 0–2, Barthel index C 50 %, adequate healing of craniotomy or cranial biopsy, normal baseline hematology and biochemistry and absence of proteinuria. Patients were excluded if they had a history of a prior malignant infiltrating disease during the last five years, uncontrolled arterial hypertension, inflammatory digestive disease, cardiac or vascular disease, or recent symptomatic intracranial hemorrhage on post-operative MRI or postbiopsy computerized tomography (CT). Written informed consent was obtained from all patients before registration, and the study was approved by the Ethics Committee of each participating hospital.
14
Medical Oncology Service, Hospital Marque´s de Valdecilla, Santander, Spain
15
Medical Oncology Service, Hospital Universitario Lucus Augusti, Lugo, Spain
16
Medical Oncology Service, Hospital Sant Joan de Reus, Reus, Spain
17
Medical Oncology Service, Hospital Xeral-Cies, Vigo, Spain
18
Radiation Oncology Service, Hospital Sant Joan de Reus, Reus, Spain
19
Medical Oncology Service, Hospital del Mar, Barcelona, Spain
20
Department of Preventive Medicine and Public Health, School of Medicine, Autonomous University of Madrid, Madrid, Spain
21
Radiology Service, Hospital del Mar, Barcelona, Spain
22
Pharmacy Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
23
Radiation Oncology Service, Institut Catala` d’Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
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Study design Patients were randomized 1:1 to either the temozolomide (TMZ) or the bevacizumab (TMZ ? BEV) arm. Treatment in both arms was initiated within 21 days after a stereotactic biopsy and within 28 days after a craniotomy and was administered in three stages: neoadjuvant, concurrent, and adjuvant (Fig. 1a). In the TMZ arm, neoadjuvant treatment consisted of temozolomide (85 mg/m2, days 1–21, for two 28-day cycles) and concurrent treatment consisted of radiation (60 Gy in 2 Gy fractions, for 42 days) plus temozolomide (75 mg/m2/d) for a maximum of 49 days. In the TMZ ? BEV arm, patients received the same regimens but with the addition of bevacizumab (10 mg/kg) on days 1 and 15 of each cycle in the neoadjuvant stage and on days 1, 15 and 30 of the concurrent stage. In both arms, the concurrent stage was followed by a 28-day break in
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NEOADJUVANT STAGE
CONCURRENT STAGE
TMZ 85 mg/m2/days 1-21 Two 28-day cycles
ADJUVANT STAGE
4-week rest
RT 60 Gy/2 Gy/6w TMZ 75 mg/m2/d
4-week rest
RANDOMISATION
Unresectable Glioblastoma
(a)
TMZ 85 mg/m2/days 1-21
RT 60 Gy/2 Gy/6w TMZ 75 mg/m2/d BEV 10 mg/kg/days 1, 15, 30
BEV 10 mg/kg/days 1&15 Two 28-day cycles
Centralized Review of Response (RANO) Investigator-Assessed Response (RANO)
(b)
TMZ 150-200 mg/m2/days 1-5 Six 28-day cycles
Week 9
Week 21
Week 25
Randomly assigned (n=102)
Allocated to TMZ+BEV Arm (n=49)
Allocated to TMZ Arm (n=53)
Excluded (n=8 ) GBM not confirmed (n=2) Declined to parcipate (n=3) Clinical decline (n=2), Inclusion criteria not met (n=1)
Received allocated intervention (n=45) Discontinued neoadjuvant treatment (n=16) Progression (n=10) Toxicity (n=6) Concurrent treatment per protocol (n=23) Received adjuvant TMZ 1 cycle (n=19) ≥ 3 cycles (n=8) Completed 6 cycles (n=3)
Salvage therapy Palliative care (n=10) Radiotherapy alone (n=2) Radiotherapy/TMZ off protocol (n=9) Other (n=1)
Evaluable Response to neoadjuvant therapy (n= 43) PFS, OS, toxicity (n=45)
Excluded (n=1) Hemorrhage on MRI (n=1)
Received allocated intervention (n=48) Discontinued neoadjuvant treatment (n=11) Progression (n=2) Toxicity (n=9) Concurrent treatment per protocol (n=33) Received adjuvant TMZ 1 cycle (n=33) ≥ 3 cycles (n=13) Completed 6 cycles (n=5)
Salvage therapy Palliative care (n=5) Radiotherapy (n=1) Radiotherapy/TMZ off protocol (n=6) Other (n=4)
Evaluable Response to neoadjuvant therapy (n= 44) PFS, OS, toxicity (n=48)
Fig. 1 a Study design and b flow chart showing disposition of patients through the study. Treatment could be withheld due to either progression, toxicity or both. Patient numbers shown in the flow chart correspond to the final treatment administered
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treatment and then by adjuvant treatment with temozolomide for six cycles. A preplanned interim safety analysis was performed after the first ten patients were included in the TMZ arm [10]. The primary endpoint was investigator-assessed response after the neoadjuvant stage according to the Response Assessment in Neuro-Oncology (RANO) Criteria [11] although response was not confirmed one month later since concurrent treatment had already started by that time. Investigator-assessed response was subsequently reviewed by an independent radiologist who was blinded to study arm. Secondary endpoints were toxicity, neurological deterioration before radiation, treatment compliance, PFS, OS, 1-year survival, quality of life, and the impact on outcome of MGMT methylation in tissue and serum. Dose modification and treatment interruption Treatment was not started unless the granulocyte count was [ 1500/L and platelet count was [100,000/L. During the neoadjuvant stage, treatment was postponed for a maximum of two weeks if grade C 2 toxicities were observed. In addition, if grade C 3 toxicities were observed, the temozolomide dose was reduced to 75 mg/m2/d. In the concurrent stage, biweekly blood analyses were performed and temozolomide (or temozolomide plus bevacizumab)— but not radiotherapy—was interrupted if hematological toxicity of any grade was observed, and weekly blood analyses were performed until recovery of normal levels. Bevacizumab treatment was stopped in case of a grade C 2 arterial or cardiac event or intestinal obstruction, grade C 3 venous thrombosis, hypertension adequately treated, hemorrhage, intestinal perforation, or proteinuria. If disease progression occurred during the neoadjuvant stage, patients were permitted to continue to the concurrent stage without having completed neoadjuvant therapy. In case of clinical decline at any time during the neoadjuvant stage, patients were treated off-protocol. Efficacy Disease assessment was planned at week 9 (after the neoadjuvant stage) or earlier if progression was suspected), at weeks 21 and 25 (after the concurrent stage), and every 12 weeks thereafter. Neurological progression was defined as irreversible neurological deterioration or a worsening of PS of 1 grade. Disease progression was defined as the need for dexamethasone use during [ 2 weeks without symptom remission. The centralized review of response and progression was performed by an independent radiologist. T2/FLAIR sequence changes were recorded as ‘‘?2’’ if the extension was obviously greater on visual examination, ‘‘?1’’ if the
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extension was greater than the previous assessment but required to be assessed in various sections, ‘‘0’’ without change, ‘‘-1’’ if the extension was reduced but required to be assessed in various sections, and ‘‘-2’’ if the extension was obviously improved on visual examination. Progression was also defined as the appearance of new hyperintense foci in T2/FLAIR or T1Gd sequences distinct from the initial lesion. Any progression observed at week 21 needed to be confirmed at week 25 to rule out pseudoprogression. If progression was confirmed at week 25, week 21 was considered the date of progression. Quality of life and adverse events Quality of life was measured with the validated core EORTC quality-of-life questionnaires QLQ-C30 and BN20 and will be reported in a separate paper. Adverse events were assessed throughout the study according to National Cancer Institute Common Terminology Criteria, version 3.0. MGMT methylation At the time of registration, paraffin-embedded tumor tissue blocks and serum samples were submitted for central pathological review and MGMT methylation analysis. MGMT methylation was analyzed in tumor and paired serum samples by investigators who were blinded both to treatment arm and to each other’s results, using methylation-specific PCR (MSP). Circulating DNA analysis and serum MGMT assessment were performed as previously described [12]. Statistical methods Patients were centrally randomized with a randomization list generated electronically in blocks of variable length without stratification. It was assumed that temozolomide induces 7 % of objective responses and 20 % of clinical benefit, defined as objective response or stable disease, in the neoadjuvant setting [13]. Assuming a statistical power of 80 % and accepting an alpha risk of 0.05 with a twosided test, we calculated that we would need 45 subjects in the TMZ Arm and 45 in the TMZ ? BEV arm to detect a 30 % difference in clinical benefit between the two arms. We estimated patient losses of 10 %. With 45 patients per arm, the study had only a statistical power of 80 % to detect an increase in 1-year survival of 37 % to 66 %, with an assumed 95 % confidence interval (CI). Categorical variables and response were compared with the v2 test or the Fisher’s exact test. Odds ratios (ORs) were calculated for response. All patients who began treatment were included in the analyses. PFS was defined
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as the time from inclusion to the first documented progression or death from any cause. OS was defined as the time from inclusion to death from any cause. Patients who were still progression-free or alive at the date of last contact were censored. Median PFS and OS were calculated with the Kaplan–Meier method and compared using the log-rank test. The Cox proportional hazards model was used to calculate HRs with their 95 % CIs. All statistical tests were two-sided and significance was set at 0.05. All analyses were performed with SPSS v21.0 (IBM).
Results From December 2009 to April 2013, 102 patients from 18 Spanish hospitals were registered. Only 93 started treatment—45 in the TMZ arm and 48 in the TMZ ? BEV arm (Fig. 1b). Baseline characteristics were well-balanced between the two arms (Table 1). Sixteen patients in the TMZ arm and 11 in the TMZ ? BEV arm discontinued neoadjuvant treatment before completion, mainly due to disease progression in the TMZ arm (ten patients) and toxicity in the TMZ ? BEV arm (nine patients). Twenty-three patients (51.1 %) in the TMZ arm and 32 (66.7 %) in the TMZ ? BEV arm completed concurrent treatment as per protocol (P = 0.21). Nineteen patients (42.2 %) in the TMZ arm and 33 (70.2 %) in the TMZ ? BEV arm received at least one cycle of adjuvant temozolomide (P = 0.007). Three patients (6.7 %) in the TMZ arm and five (10.4 %) in the TMZ ? BEV arm completed all treatment as per protocol (P = 0.39) (Fig. 1b, Online Resource Table A1). Patients progressing during neoadjuvant treatment received standard chemoradiotherapy or other treatment offprotocol (Fig. 1b). Bevacizumab was administered as second- or further-line therapy in 24.4 % of patients in the TMZ arm and in 33.3 % of patients in the TMZ ? BEV arm. Response to neoadjuvant therapy Forty-three patients in the TMZ arm and 44 in the TMZ ? BEV arm were evaluable for investigator-assessed response (Fig. 1b). Before the first disease assessment at nine weeks, three patients in the TMZ ? BEV arm had died due to toxicity, one patient in each arm had withdrawn due to toxicity, and one patient in the TMZ arm had withdrawn consent. Three patients (6.7 %) in the TMZ arm and 11 (22.9 %) in the TMZ ? BEV arm attained a partial response (OR 4.2, 95 % CI 1.1-16.1, P = 0.04). Eleven patients (24.5 %) in the TMZ arm and 29 (60.4 %) in the TMZ ? BEV arm attained clinical benefit, defined as partial response or stable disease (OR 4.7, 95 % CI 1.911.5, P \ 0.001) (Table 2). The centralized review of
response provided similar results (Online Resource text and Table A2). Progression-free and overall survival With a minimum follow up of 18 months after the last patient was included, investigator-assessed PFS was 2.2 months (95 % CI 2.0–2.5) for patients in the TMZ arm and 4.8 months (95 % CI 4.0–5.6) for patients in the TMZ ? BEV arm (HR 0.70, 95 % CI 0.46–1.07, P = 0.10) (Fig. 2a). Findings of the centralized review of PFS were similar (Online Resource text and Table A2). Median OS was 7.7 months (95 % CI 5.4–10.0) in the TMZ arm, compared to 10.6 months (95 % CI 6.9–14.3) in the TMZ ? BEV arm (HR 0.68, 95 % CI 0.44–1.04, P = 0.07) (Fig. 2b). One-, 2- and 3-year survival rates were 29.6, 8.9 and 4.4 % in the TMZ arm, compared to 48.9, 20.5 and 10.9 % in the TMZ ? BEV arm. Multivariate analyses identified only TMZ ? BEV as an independent marker of longer PFS and OS (PFS: HR 1.58, 95 % CI 1.0–2.51, P = 0.05; OS: HR 1.68, 95 % CI 1.07–2.63, P = 0.02) (Online Resource Table A3). Toxicities During the neoadjuvant stage, more patients overall experienced toxicities in the TMZ ? BEV arm than in the TMZ arm (81.3 % vs. 64.4 %; P = 0.06). Patients in the TMZ ? BEV arm also experienced more grade 1–2 stomatitis. Clinically meaningful intracranial hemorrhage occurred in four patients in the TMZ ? BEV arm, including two deaths. A third patient in the TMZ ? BEV arm died from intestinal perforation. There was no other significant difference in frequency of toxicities between the two arms (Table 3). In spite of the higher toxicity profile in the TMZ ? BEV arm, fewer patients experienced neurological decline during the neoadjuvant stage than in the TMZ arm (12 [25 %] vs. 24 [53.3 %]; P = 0.005). Four patients in each arm died during the neoadjuvant stage. The most frequent cause of death was progression (8.9 %) in the TMZ arm and toxicity (8.3 %) in the TMZ ? BEV arm. In the concurrent stage, there was a higher frequency of grade 3–4 asthenia and grade 3–4 thrombosis in the TMZ arm. MGMT methylation Ninety tumor samples and 80 serum samples were available. MGMT methylation was successfully analyzed in tumor in 67 patients, in serum in 71, and in both tumor and serum in 50. There was only a fair concordance between tumor and serum (Kappa index = 0.259, P = 0.02) (Online Resource Table A4).
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J Neurooncol Table 1 Patient characteristics
Characteristic
TMZ arm (N = 45) N (%)
TMZ ? BEV arm (N = 48) N (%)
P
Age (years) Median
62
62.9
0.73
Range
36–75
43–75
0.19
\50
4 (8.9)
1 (2.1)
C50
41 (91.1)
47 (97.9)
Male
25 (55.6)
31 (64.6)
Female
20 (44.4)
17 (35.4)
25 (55.6)
30 (62.5)
20 (44.4)
18 (37.2)
0
8 (17.8)
10 (20.8)
1
24 (53.3)
25 (52.1)
C2
13 (28.9)
13 (27.1)
Gender 0.37
Number of brain lesions 1 [1 ECOG PS
0.35
0.93
Barthel index 100 %
15 (34.1)
20 (43.5)
95–80 %
16 (36.4)
16 (34.8)
\80 %
13 (29.5)
10 (21.7)
0.62
MMS score \27
20 (47.6)
13 (28.9)
C27
22 (52.4)
32 (71.1)
Yes
28 (62.2)
28 (58.3)
No
17 (37.8)
20 (41.7)
14.1 5.1–52.8
14.7 3.6–50.0
0.59
0.21
0.07
Neurological deficit 0.70
Tumor surface (cm2)a Median Range Surgery Biopsy
35 (77.8)
42 (87.5)
Craniotomy
10 (22.2)
6 (12.5)
Yes
34 (75.6)
39 (81.3)
No
11 (24.4)
9 (18.8)
Successfully analyzedb
30 (66.7)
37 (77.1)
Methylated
12 (40.0)
20 (54.1)
Unmethylated
18 (60.0)
17 (45.9)
Successfully analyzedb
33 (73.3)
38 (79.1)
Methylated
3 (9.1)
8 (21.1)
Unmethylated
30 (90.9)
30 (78.9)
Baseline dexamethasone 0.37
MGMT in tumor tissue 0.18
MGMT in serum 0.25
ECOG Eastern Cooperative Oncology Group; PS performance status; MMS mini-mental status a b
Tumor surface is expressed as the product of the two diameters in T1Gd imaging axial plane
Although 96 % of tumor samples and 86 % of serum samples were processed for MGMT methylation analysis, not all results were informative. Percentages of methylated and unmethylated are given over number of samples successfully analyzed
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J Neurooncol Table 2 Investigator-assessed response TMZ arm (N = 45) N (%)
TMZ ? BEV arm (N = 48) N (%)
Odds ratio (95 % CI)
P
Complete response
–
–
–
–
Partial response
3 (6.7)
11 (22.9)
4.2 (1.1–16.1)
0.04
Stable disease
8 (17.8)
18 (37.5)
2.8 (1.1–7.1)
0.03
Clinical benefit (PR ? SD)
11 (24.5)
29 (60.4)
4.7 (1.9–11.5)
\0.001
Progressive disease
32 (71.1)
15 (31.3)
5.4 (2.2–13.2)
\0.001
Not evaluablea
2 (4.4)
4 (8.3)
–
–
PR partial response; SD stable disease a
Three patients in the TMZ ? BEV arm had died due to toxicity; one patient in each arm had been withdrawn due to toxicity; one patient in the TMZ arm had withdrawn consent before the first disease assessment at nine weeks
Fig. 2 a Progression-free survival and b overall survival by treatment arm
Both PFS and OS were longer in patients with MGMT methylation in tumor (PFS: 5.8 vs. 2.2 months; HR 0.31, 95 % CI 0.18–0.55, P \ 0.001; OS: 13.3 vs. 5.3 months; HR 0.40, 95 % CI 0.24–0.68, P = 0.001) (Online Resource Fig. 1a, b). This difference in outcome between patients with and without MGMT methylation in tumor held true when each of the two arms was analyzed separately (Online Resource Fig. 2a, b, Online Resource Table A4). MGMT methylation in serum was not associated with PFS or OS.
Discussion We have performed a randomized phase II trial to compare response to temozolomide alone versus temozolomide plus bevacizumab as neoadjuvant therapy in unresected glioblastoma patients. The addition of bevacizumab conferred a higher response rate (22.9 vs. 6.7 %; P \ 0.001) and greater clinical benefit (60.4 vs. 24.5 %; P \ 0.001). These results were confirmed upon centralized blinded review. PFS (4.8 vs. 2.2 months) and OS (10.6 vs. 7.7 months) were also longer in patients treated with the
combination of bevacizumab plus temozolomide, though the difference did not reach statistical significance. Neurological deterioration was significantly lower among patients treated with bevacizumab plus temozolomide (25 vs. 53.3 %; P = 0.005), and treatment completion rates were slightly higher (77.1 vs. 64.4 %; P = 0.18). Glioblastoma is frequently left unresected [14–16] and unresected patients have a dismal prognosis [1]. Attempts to reduce the tumor by means other than surgery have been explored in multiple non-randomized [13, 17–19] but few randomized [20–22] trials, with varying results. The neoadjuvant setting, with response evaluation performed prior to starting concurrent therapy, seemed optimal for the comparison of response to temozolomide alone versus temozolomide plus bevacizumab, since any potential confounding factors arising from prior administration of temozolomide or radiotherapy [11, 23] would easily be ruled out. The TEMAVIR trial [21] also evaluated bevacizumab as first-line treatment in unresected patients, comparing standard temozolomide plus radiotherapy with four cycles of bevacizumab and irinotecan administered prior to and after standard concurrent therapy. Although PFS was longer in
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J Neurooncol Table 3 Adverse events during the neoadjuvant and the concurrent stages of the trial Neoadjuvant stage TMZ arm N = 45 (%)
Concurrent stage TMZ ? BEV arm N = 48 (%)
P
TMZ arm N = 45 (%)
TMZ ? BEV arm N = 48 (%)
P
15 (33.3)
23 (47.9)
0.15
Any toxicity
29 (64.4)
39 (81.3)
0.06
Death during treatmenta
4 (8.9)
4 (8.3)
1
Grade 3–4
Grade 5
Grade 3–4
Grade 5
Grade 3–4
Grade 5
Grade 3–4
Grade 5
Non-bevacizumab related toxicities (%) Hematologic Anemia
1 (2.2)
–
1 (2.1)
–
–
–
–
–
Leucopenia
2 (4.4)
–
1 (2.1)
–
–
–
1 (2.1)
–
Neutropenia
3 (6.7)
–
1 (2.1)
–
–
–
2 (4.2)
–
Febrile neutropenia
2 (4.4)
–
1 (2.1)
–
–
–
–
–
Lymphopenia
1 (2.2)
–
1 (2.1)
–
3 (6.7)
–
8 (16.7)
–
Thrombocytopenia
5 (11.1)
–
1 (2.1)
-
–
–
3 (6.1)
–
Medullar aplasiab
–
–
–
1 (2.1)
–
–
–
–
Nausea & vomiting
–
–
1 (2.1)
–
–
–
–
–
Stomatitis Constipation
– –
– –
– –
– –
– –
– –
– –
– –
Asthenia
1 (2.2)
–
2 (4.2)
–
3 (6.7)
–
–
–
Infection
3 (6.6)
–
5 (10.4)
–
–
–
–
–
Liver
3 (6.6)
–
1 (2.1)
–
–
–
1 (2.1)
–
Non-hematologic
Bevacizumab-related toxicities (%) Hypertension
–
–
2 (4.2)
–
–
1 (2.1)
–
Proteinuria
–
–
–
–
–
–
–
Hemorrhage
–
–
1 (2.1)
Intracranial hemorrhagec
–
–
2 (4.2)
Thrombotic event
3 (6.6)
–
2 (4.2)
–
–
1 (2.1)
Intestinal perforation
d
a
Four patients in the TMZ arm died due to disease progression
b
One patient died due to medullar aplasia
2 (4.2) 1 (2.1)
–
–
–
–
–
–
–
–
3 (6.7)
–
–
–
–
–
–
–
c
In the TMZ ? BEV arm, four patients had intracranial hemorrhages, one grade 3, one grade 4, and two grade 5. Differences in frequency of grade C 3 hemorrhages between arms were not significant (0.24) d
One patient had grade 3 intestinal perforation and one had grade 5
the experimental arm, the trial did not reach its primary endpoint of an increase from 50 to 66 % in 6-month PFS. In contrast, the present study reached its main endpoint of higher response, although it was not powered to detect differences in PFS or OS. While OS was similar in both arms of the TEMAVIR trial, both PFS and OS were longer in the TMZ ? BEV arm in the present study, although differences were not significant. In the TEMAVIR trial, radiotherapy was postponed for at least two months after diagnosis without an apparent worsening in OS. In the present study, radiotherapy was also postponed in order to allow evaluation of response. In fact, data from retrospective series indicate that moderate radiotherapy delays seem not to worsen survival [24, 25]. In the only phase III randomized trial
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comparing standard vs experimental neoadjuvant treatment, survival was not affected by delays of 12–16 weeks [20]. Although spontaneous hemorrhage has been reported in glioblastoma patients even if not receiving bevacizumab [26], in both our trial and the TEMAVIR, spontaneous hemorrhage occurred more frequently in the arm with bevacizumab. In particular, fatal intracranial bleeding occurred in 5.3 % of patients in the TEMAVIR trial and in 4.2 % in the present trial. This was a higher frequency than that observed in the recurrent setting, and in three large trials testing bevacizumab as first-line treatment mainly in resected patients (\3 %) [3, 4, 6–9]. We had expected that MGMT methylation analyses would confirm our previous findings that MGMT methylation in
J Neurooncol
serum can predict methylation in tumor [27] and would identify serum as a viable surrogate when sufficient tumor tissue is not available. However, this was not the case. MGMT methylation was successfully assessed in both tumor and serum in 50 patients and concordance of results was poor. Moreover, while tumor MGMT methylation correlated with PFS and OS, serum MGMT methylation did not. These findings may, however, be due to the relatively low sensitivity of the MSP method used. Perhaps the most controversial issue of the present study is the selection of response as the primary endpoint. In the present study, the use of RANO criteria, in conjunction with the centralized blinded review of response confirming investigator assessments and the neoadjuvant, pre-radiotherapy setting, enabled us to minimize the challenges involved in response evaluation [11, 28]. However, we cannot rule out the possibility that the effect of bevacizumab may have been limited to a pseudoresponse, as has been observed with other antiangiogenics [29]. Nevertheless, the more frequent stable neurologic symptoms observed during the neoadjuvant stage in patients treated with bevacizumab cannot be disregarded. In the recurrent setting, the BELOB randomized phase II trial compared bevacizumab alone versus bevacizumab plus lomustine versus lomustine alone. Only the combination regimen, which was associated with both, improved 9-month OS and a superior response rate, was selected for further comparison with lomustine in a phase III trial (EORTC 26101). Interestingly, objective response was associated with longer survival in both the single-agent bevacizumab group (HR 0.43) and in all patients receiving bevacizumab (HR 0.37), suggesting that reducing measurable disease can enable patients to attain longer OS [6]. A relationship between objective response and OS was also observed in the randomized BRAIN study [30]. While objective response has never been considered a good surrogate for longer survival in glioblastoma, there are increasing signs that it can have a positive impact on PFS or OS [31]. In our trial, patients treated with bevacizumab had a higher response rate, as well as longer PFS and OS, although differences in survival were not significant. This may be due to the relatively small number of patients included and the trial design, which was only powered to detect large differences in 1-year OS (from 37 to 66 %). In summary, the present study provides further evidence that neoadjuvant treatment with bevacizumab in combination with temozolomide may have superior efficacy in terms of response and tumor shrinkage than temozolomide alone in unresected glioblastoma patients, with no negative impact on survival. Acknowledgments The authors thank Anna del Prado (Marketing Farmace´utico & Investigacio´n Clı´nica, SL) for her invaluable assistance throughout the study.
Funding This study was funded by the Spanish Instituto Carlos III (FISS-ICIII: project EC08/00071). In addition, MSD provided neoadjuvant temozolomide and funds for MGMT assessment, and Roche-Spain provided funds for data management and the centralized review of response and progression. Compliance with ethical standards Conflict of interest of interest.
The authors declare that they have no conflict
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CLINICAL STUDY
Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial Carmen Balana1 • Ramon De Las Penas2 • Juan Manuel Sepu´lveda3 • Miguel J. Gil-Gil4 • Raquel Luque5 • Oscar Gallego6 • Cristina Carrato7 • Carolina Sanz7 • Gaspar Reynes8 • Ana Herrero9 • Jose Luis Ramirez10 • Pedro Pe´rez-Segura11 • Alfonso Berrocal12 • Jose Maria Vieitez13 • Almudena Garcia14 Sergio Vazquez-Estevez15 • Sergi Peralta16 • Isaura Fernandez17 • Ivan Henriquez18 • Maria Martinez-Garcia19 • Juan Jose De la Cruz20 • Jaume Capellades21 • Pilar Giner22 • Salvador Villa`23
•
Received: 23 September 2015 / Accepted: 22 January 2016 Ó Springer Science+Business Media New York 2016
Abstract We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ ? BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m2,
This study has previously been presented in part as an oral presentation at the 2014 ASCO Annual Meeting, May–June 2014 (included in ASCO Highlights), as an oral presentation at the 39th ESMO Congress, September 2014, as a poster with discussion at the ASTRO 56th Congress, April 2014, and as a poster at the 11th EANO Meeting, October 2014.
Electronic supplementary material The online version of this article (doi:10.1007/s11060-016-2065-5) contains supplementary material, which is available to authorized users. & Carmen Balana [email protected] 1
2
Medical Oncology Service, Institut Catala` d’Oncologia, Hospital Universitari Germans Trias i Pujol, Carretera Canyet, s/n, 08916 Badalona, Spain Medical Oncology Service, Hospital Provincial de Castello´n, Castello´n, Spain
3
Medical Oncology Service, Hospital Universitario, 12 de Octubre, Madrid, Spain
4
Medical Oncology Service, Institut Catala` d’OncologiaIDIBELL, Hospitalet de Llobregat, Barcelona, Spain
5
Medical Oncology Service, Hospital Universitario Virgen de las Nieves, Granada, Spain
6
Medical Oncology Service, Hospital de Sant Pau, Barcelona, Spain
days 1–21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ ? BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ ? BEV arm were evaluable for response. Results favored the TMZ ? BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ ? BEV arm, though the difference did not reach statistical significance. MGMT methylation 7
Pathology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
8
Medical Oncology Service, Hospital Universitario La Fe, Valencia, Spain
9
Medical Oncology Service, Hospital Miguel Servet, Zaragoza, Spain
10
Cancer Molecular Biology Laboratory, Institut Catala` d’Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
11
Medical Oncology Service, Hospital Universitario Clı´nico San Carlos, Madrid, Spain
12
Medical Oncology Service, Hospital General Universitario de Valencia, Valencia, Spain
13
Medical Oncology Service, Hospital Universitario Central de Asturias, Oviedo, Spain
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in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ ? BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.
bevacizumab could be easily evaluated without the potential confounding effects of previous chemoradiotherapy. To test this hypothesis, we carried out a randomized phase II trial comparing temozolomide alone versus temozolomide plus bevacizumab as neoadjuvant and concurrent therapy in unresected glioblastoma patients (clinicaltrials.gov NCT01102595).
Keywords Bevacizumab Temozolomide Glioblastoma Neoadjuvant MGMT Serum MGMT
Patients and methods Introduction
Patients
The standard first-line treatment of glioblastoma is radiotherapy with concurrent and adjuvant temozolomide, based on the results of the EORTC-NCIC trial [1, 2]. However, patients with unresected tumors have a dismal prognosis, with no significant differences in overall survival (OS) between standard chemoradiotherapy and radiotherapy alone (9.4 vs. 7.8 months; hazard ratio [HR] 0.7) [1]. The absence of previous debulking surgery leads to greater neurological instability during treatment, indicating a clear need for alternative methods of reducing tumor size prior to chemoradiotherapy. Bevacizumab, a potent antiangiogenic agent, has demonstrated activity in recurrent glioblastoma [3–6]. In the first-line setting, however, three trials, including mainly resected patients, showed a benefit for bevacizumab in progression-free survival (PFS) but not in OS [7–9] . We hypothesized that in unresected patients, early administration of bevacizumab prior to standard radiotherapy plus temozolomide would shrink the tumor sufficiently to allow completion of the standard treatment. Moreover, in this neoadjuvant setting, the real activity of
Patients were eligible if they had unresected glioblastoma, diagnosed by biopsy, including stereotactic or open craniotomy, and had received no prior treatment. Candidates were required to have measurable disease (C2 cm) and stable or decreasing glucocorticoid doses within the 5 days before randomization. In patients undergoing craniotomy, post-operative magnetic resonance imaging (MRI) was mandatory within 72 h. Other inclusion criteria were as follows: age C 18 years, Eastern Cooperative Oncology Group (ECOG) PS 0–2, Barthel index C 50 %, adequate healing of craniotomy or cranial biopsy, normal baseline hematology and biochemistry and absence of proteinuria. Patients were excluded if they had a history of a prior malignant infiltrating disease during the last five years, uncontrolled arterial hypertension, inflammatory digestive disease, cardiac or vascular disease, or recent symptomatic intracranial hemorrhage on post-operative MRI or postbiopsy computerized tomography (CT). Written informed consent was obtained from all patients before registration, and the study was approved by the Ethics Committee of each participating hospital.
14
Medical Oncology Service, Hospital Marque´s de Valdecilla, Santander, Spain
15
Medical Oncology Service, Hospital Universitario Lucus Augusti, Lugo, Spain
16
Medical Oncology Service, Hospital Sant Joan de Reus, Reus, Spain
17
Medical Oncology Service, Hospital Xeral-Cies, Vigo, Spain
18
Radiation Oncology Service, Hospital Sant Joan de Reus, Reus, Spain
19
Medical Oncology Service, Hospital del Mar, Barcelona, Spain
20
Department of Preventive Medicine and Public Health, School of Medicine, Autonomous University of Madrid, Madrid, Spain
21
Radiology Service, Hospital del Mar, Barcelona, Spain
22
Pharmacy Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
23
Radiation Oncology Service, Institut Catala` d’Oncologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
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Study design Patients were randomized 1:1 to either the temozolomide (TMZ) or the bevacizumab (TMZ ? BEV) arm. Treatment in both arms was initiated within 21 days after a stereotactic biopsy and within 28 days after a craniotomy and was administered in three stages: neoadjuvant, concurrent, and adjuvant (Fig. 1a). In the TMZ arm, neoadjuvant treatment consisted of temozolomide (85 mg/m2, days 1–21, for two 28-day cycles) and concurrent treatment consisted of radiation (60 Gy in 2 Gy fractions, for 42 days) plus temozolomide (75 mg/m2/d) for a maximum of 49 days. In the TMZ ? BEV arm, patients received the same regimens but with the addition of bevacizumab (10 mg/kg) on days 1 and 15 of each cycle in the neoadjuvant stage and on days 1, 15 and 30 of the concurrent stage. In both arms, the concurrent stage was followed by a 28-day break in
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NEOADJUVANT STAGE
CONCURRENT STAGE
TMZ 85 mg/m2/days 1-21 Two 28-day cycles
ADJUVANT STAGE
4-week rest
RT 60 Gy/2 Gy/6w TMZ 75 mg/m2/d
4-week rest
RANDOMISATION
Unresectable Glioblastoma
(a)
TMZ 85 mg/m2/days 1-21
RT 60 Gy/2 Gy/6w TMZ 75 mg/m2/d BEV 10 mg/kg/days 1, 15, 30
BEV 10 mg/kg/days 1&15 Two 28-day cycles
Centralized Review of Response (RANO) Investigator-Assessed Response (RANO)
(b)
TMZ 150-200 mg/m2/days 1-5 Six 28-day cycles
Week 9
Week 21
Week 25
Randomly assigned (n=102)
Allocated to TMZ+BEV Arm (n=49)
Allocated to TMZ Arm (n=53)
Excluded (n=8 ) GBM not confirmed (n=2) Declined to parcipate (n=3) Clinical decline (n=2), Inclusion criteria not met (n=1)
Received allocated intervention (n=45) Discontinued neoadjuvant treatment (n=16) Progression (n=10) Toxicity (n=6) Concurrent treatment per protocol (n=23) Received adjuvant TMZ 1 cycle (n=19) ≥ 3 cycles (n=8) Completed 6 cycles (n=3)
Salvage therapy Palliative care (n=10) Radiotherapy alone (n=2) Radiotherapy/TMZ off protocol (n=9) Other (n=1)
Evaluable Response to neoadjuvant therapy (n= 43) PFS, OS, toxicity (n=45)
Excluded (n=1) Hemorrhage on MRI (n=1)
Received allocated intervention (n=48) Discontinued neoadjuvant treatment (n=11) Progression (n=2) Toxicity (n=9) Concurrent treatment per protocol (n=33) Received adjuvant TMZ 1 cycle (n=33) ≥ 3 cycles (n=13) Completed 6 cycles (n=5)
Salvage therapy Palliative care (n=5) Radiotherapy (n=1) Radiotherapy/TMZ off protocol (n=6) Other (n=4)
Evaluable Response to neoadjuvant therapy (n= 44) PFS, OS, toxicity (n=48)
Fig. 1 a Study design and b flow chart showing disposition of patients through the study. Treatment could be withheld due to either progression, toxicity or both. Patient numbers shown in the flow chart correspond to the final treatment administered
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treatment and then by adjuvant treatment with temozolomide for six cycles. A preplanned interim safety analysis was performed after the first ten patients were included in the TMZ arm [10]. The primary endpoint was investigator-assessed response after the neoadjuvant stage according to the Response Assessment in Neuro-Oncology (RANO) Criteria [11] although response was not confirmed one month later since concurrent treatment had already started by that time. Investigator-assessed response was subsequently reviewed by an independent radiologist who was blinded to study arm. Secondary endpoints were toxicity, neurological deterioration before radiation, treatment compliance, PFS, OS, 1-year survival, quality of life, and the impact on outcome of MGMT methylation in tissue and serum. Dose modification and treatment interruption Treatment was not started unless the granulocyte count was [ 1500/L and platelet count was [100,000/L. During the neoadjuvant stage, treatment was postponed for a maximum of two weeks if grade C 2 toxicities were observed. In addition, if grade C 3 toxicities were observed, the temozolomide dose was reduced to 75 mg/m2/d. In the concurrent stage, biweekly blood analyses were performed and temozolomide (or temozolomide plus bevacizumab)— but not radiotherapy—was interrupted if hematological toxicity of any grade was observed, and weekly blood analyses were performed until recovery of normal levels. Bevacizumab treatment was stopped in case of a grade C 2 arterial or cardiac event or intestinal obstruction, grade C 3 venous thrombosis, hypertension adequately treated, hemorrhage, intestinal perforation, or proteinuria. If disease progression occurred during the neoadjuvant stage, patients were permitted to continue to the concurrent stage without having completed neoadjuvant therapy. In case of clinical decline at any time during the neoadjuvant stage, patients were treated off-protocol. Efficacy Disease assessment was planned at week 9 (after the neoadjuvant stage) or earlier if progression was suspected), at weeks 21 and 25 (after the concurrent stage), and every 12 weeks thereafter. Neurological progression was defined as irreversible neurological deterioration or a worsening of PS of 1 grade. Disease progression was defined as the need for dexamethasone use during [ 2 weeks without symptom remission. The centralized review of response and progression was performed by an independent radiologist. T2/FLAIR sequence changes were recorded as ‘‘?2’’ if the extension was obviously greater on visual examination, ‘‘?1’’ if the
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extension was greater than the previous assessment but required to be assessed in various sections, ‘‘0’’ without change, ‘‘-1’’ if the extension was reduced but required to be assessed in various sections, and ‘‘-2’’ if the extension was obviously improved on visual examination. Progression was also defined as the appearance of new hyperintense foci in T2/FLAIR or T1Gd sequences distinct from the initial lesion. Any progression observed at week 21 needed to be confirmed at week 25 to rule out pseudoprogression. If progression was confirmed at week 25, week 21 was considered the date of progression. Quality of life and adverse events Quality of life was measured with the validated core EORTC quality-of-life questionnaires QLQ-C30 and BN20 and will be reported in a separate paper. Adverse events were assessed throughout the study according to National Cancer Institute Common Terminology Criteria, version 3.0. MGMT methylation At the time of registration, paraffin-embedded tumor tissue blocks and serum samples were submitted for central pathological review and MGMT methylation analysis. MGMT methylation was analyzed in tumor and paired serum samples by investigators who were blinded both to treatment arm and to each other’s results, using methylation-specific PCR (MSP). Circulating DNA analysis and serum MGMT assessment were performed as previously described [12]. Statistical methods Patients were centrally randomized with a randomization list generated electronically in blocks of variable length without stratification. It was assumed that temozolomide induces 7 % of objective responses and 20 % of clinical benefit, defined as objective response or stable disease, in the neoadjuvant setting [13]. Assuming a statistical power of 80 % and accepting an alpha risk of 0.05 with a twosided test, we calculated that we would need 45 subjects in the TMZ Arm and 45 in the TMZ ? BEV arm to detect a 30 % difference in clinical benefit between the two arms. We estimated patient losses of 10 %. With 45 patients per arm, the study had only a statistical power of 80 % to detect an increase in 1-year survival of 37 % to 66 %, with an assumed 95 % confidence interval (CI). Categorical variables and response were compared with the v2 test or the Fisher’s exact test. Odds ratios (ORs) were calculated for response. All patients who began treatment were included in the analyses. PFS was defined
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as the time from inclusion to the first documented progression or death from any cause. OS was defined as the time from inclusion to death from any cause. Patients who were still progression-free or alive at the date of last contact were censored. Median PFS and OS were calculated with the Kaplan–Meier method and compared using the log-rank test. The Cox proportional hazards model was used to calculate HRs with their 95 % CIs. All statistical tests were two-sided and significance was set at 0.05. All analyses were performed with SPSS v21.0 (IBM).
Results From December 2009 to April 2013, 102 patients from 18 Spanish hospitals were registered. Only 93 started treatment—45 in the TMZ arm and 48 in the TMZ ? BEV arm (Fig. 1b). Baseline characteristics were well-balanced between the two arms (Table 1). Sixteen patients in the TMZ arm and 11 in the TMZ ? BEV arm discontinued neoadjuvant treatment before completion, mainly due to disease progression in the TMZ arm (ten patients) and toxicity in the TMZ ? BEV arm (nine patients). Twenty-three patients (51.1 %) in the TMZ arm and 32 (66.7 %) in the TMZ ? BEV arm completed concurrent treatment as per protocol (P = 0.21). Nineteen patients (42.2 %) in the TMZ arm and 33 (70.2 %) in the TMZ ? BEV arm received at least one cycle of adjuvant temozolomide (P = 0.007). Three patients (6.7 %) in the TMZ arm and five (10.4 %) in the TMZ ? BEV arm completed all treatment as per protocol (P = 0.39) (Fig. 1b, Online Resource Table A1). Patients progressing during neoadjuvant treatment received standard chemoradiotherapy or other treatment offprotocol (Fig. 1b). Bevacizumab was administered as second- or further-line therapy in 24.4 % of patients in the TMZ arm and in 33.3 % of patients in the TMZ ? BEV arm. Response to neoadjuvant therapy Forty-three patients in the TMZ arm and 44 in the TMZ ? BEV arm were evaluable for investigator-assessed response (Fig. 1b). Before the first disease assessment at nine weeks, three patients in the TMZ ? BEV arm had died due to toxicity, one patient in each arm had withdrawn due to toxicity, and one patient in the TMZ arm had withdrawn consent. Three patients (6.7 %) in the TMZ arm and 11 (22.9 %) in the TMZ ? BEV arm attained a partial response (OR 4.2, 95 % CI 1.1-16.1, P = 0.04). Eleven patients (24.5 %) in the TMZ arm and 29 (60.4 %) in the TMZ ? BEV arm attained clinical benefit, defined as partial response or stable disease (OR 4.7, 95 % CI 1.911.5, P \ 0.001) (Table 2). The centralized review of
response provided similar results (Online Resource text and Table A2). Progression-free and overall survival With a minimum follow up of 18 months after the last patient was included, investigator-assessed PFS was 2.2 months (95 % CI 2.0–2.5) for patients in the TMZ arm and 4.8 months (95 % CI 4.0–5.6) for patients in the TMZ ? BEV arm (HR 0.70, 95 % CI 0.46–1.07, P = 0.10) (Fig. 2a). Findings of the centralized review of PFS were similar (Online Resource text and Table A2). Median OS was 7.7 months (95 % CI 5.4–10.0) in the TMZ arm, compared to 10.6 months (95 % CI 6.9–14.3) in the TMZ ? BEV arm (HR 0.68, 95 % CI 0.44–1.04, P = 0.07) (Fig. 2b). One-, 2- and 3-year survival rates were 29.6, 8.9 and 4.4 % in the TMZ arm, compared to 48.9, 20.5 and 10.9 % in the TMZ ? BEV arm. Multivariate analyses identified only TMZ ? BEV as an independent marker of longer PFS and OS (PFS: HR 1.58, 95 % CI 1.0–2.51, P = 0.05; OS: HR 1.68, 95 % CI 1.07–2.63, P = 0.02) (Online Resource Table A3). Toxicities During the neoadjuvant stage, more patients overall experienced toxicities in the TMZ ? BEV arm than in the TMZ arm (81.3 % vs. 64.4 %; P = 0.06). Patients in the TMZ ? BEV arm also experienced more grade 1–2 stomatitis. Clinically meaningful intracranial hemorrhage occurred in four patients in the TMZ ? BEV arm, including two deaths. A third patient in the TMZ ? BEV arm died from intestinal perforation. There was no other significant difference in frequency of toxicities between the two arms (Table 3). In spite of the higher toxicity profile in the TMZ ? BEV arm, fewer patients experienced neurological decline during the neoadjuvant stage than in the TMZ arm (12 [25 %] vs. 24 [53.3 %]; P = 0.005). Four patients in each arm died during the neoadjuvant stage. The most frequent cause of death was progression (8.9 %) in the TMZ arm and toxicity (8.3 %) in the TMZ ? BEV arm. In the concurrent stage, there was a higher frequency of grade 3–4 asthenia and grade 3–4 thrombosis in the TMZ arm. MGMT methylation Ninety tumor samples and 80 serum samples were available. MGMT methylation was successfully analyzed in tumor in 67 patients, in serum in 71, and in both tumor and serum in 50. There was only a fair concordance between tumor and serum (Kappa index = 0.259, P = 0.02) (Online Resource Table A4).
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J Neurooncol Table 1 Patient characteristics
Characteristic
TMZ arm (N = 45) N (%)
TMZ ? BEV arm (N = 48) N (%)
P
Age (years) Median
62
62.9
0.73
Range
36–75
43–75
0.19
\50
4 (8.9)
1 (2.1)
C50
41 (91.1)
47 (97.9)
Male
25 (55.6)
31 (64.6)
Female
20 (44.4)
17 (35.4)
25 (55.6)
30 (62.5)
20 (44.4)
18 (37.2)
0
8 (17.8)
10 (20.8)
1
24 (53.3)
25 (52.1)
C2
13 (28.9)
13 (27.1)
Gender 0.37
Number of brain lesions 1 [1 ECOG PS
0.35
0.93
Barthel index 100 %
15 (34.1)
20 (43.5)
95–80 %
16 (36.4)
16 (34.8)
\80 %
13 (29.5)
10 (21.7)
0.62
MMS score \27
20 (47.6)
13 (28.9)
C27
22 (52.4)
32 (71.1)
Yes
28 (62.2)
28 (58.3)
No
17 (37.8)
20 (41.7)
14.1 5.1–52.8
14.7 3.6–50.0
0.59
0.21
0.07
Neurological deficit 0.70
Tumor surface (cm2)a Median Range Surgery Biopsy
35 (77.8)
42 (87.5)
Craniotomy
10 (22.2)
6 (12.5)
Yes
34 (75.6)
39 (81.3)
No
11 (24.4)
9 (18.8)
Successfully analyzedb
30 (66.7)
37 (77.1)
Methylated
12 (40.0)
20 (54.1)
Unmethylated
18 (60.0)
17 (45.9)
Successfully analyzedb
33 (73.3)
38 (79.1)
Methylated
3 (9.1)
8 (21.1)
Unmethylated
30 (90.9)
30 (78.9)
Baseline dexamethasone 0.37
MGMT in tumor tissue 0.18
MGMT in serum 0.25
ECOG Eastern Cooperative Oncology Group; PS performance status; MMS mini-mental status a b
Tumor surface is expressed as the product of the two diameters in T1Gd imaging axial plane
Although 96 % of tumor samples and 86 % of serum samples were processed for MGMT methylation analysis, not all results were informative. Percentages of methylated and unmethylated are given over number of samples successfully analyzed
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J Neurooncol Table 2 Investigator-assessed response TMZ arm (N = 45) N (%)
TMZ ? BEV arm (N = 48) N (%)
Odds ratio (95 % CI)
P
Complete response
–
–
–
–
Partial response
3 (6.7)
11 (22.9)
4.2 (1.1–16.1)
0.04
Stable disease
8 (17.8)
18 (37.5)
2.8 (1.1–7.1)
0.03
Clinical benefit (PR ? SD)
11 (24.5)
29 (60.4)
4.7 (1.9–11.5)
\0.001
Progressive disease
32 (71.1)
15 (31.3)
5.4 (2.2–13.2)
\0.001
Not evaluablea
2 (4.4)
4 (8.3)
–
–
PR partial response; SD stable disease a
Three patients in the TMZ ? BEV arm had died due to toxicity; one patient in each arm had been withdrawn due to toxicity; one patient in the TMZ arm had withdrawn consent before the first disease assessment at nine weeks
Fig. 2 a Progression-free survival and b overall survival by treatment arm
Both PFS and OS were longer in patients with MGMT methylation in tumor (PFS: 5.8 vs. 2.2 months; HR 0.31, 95 % CI 0.18–0.55, P \ 0.001; OS: 13.3 vs. 5.3 months; HR 0.40, 95 % CI 0.24–0.68, P = 0.001) (Online Resource Fig. 1a, b). This difference in outcome between patients with and without MGMT methylation in tumor held true when each of the two arms was analyzed separately (Online Resource Fig. 2a, b, Online Resource Table A4). MGMT methylation in serum was not associated with PFS or OS.
Discussion We have performed a randomized phase II trial to compare response to temozolomide alone versus temozolomide plus bevacizumab as neoadjuvant therapy in unresected glioblastoma patients. The addition of bevacizumab conferred a higher response rate (22.9 vs. 6.7 %; P \ 0.001) and greater clinical benefit (60.4 vs. 24.5 %; P \ 0.001). These results were confirmed upon centralized blinded review. PFS (4.8 vs. 2.2 months) and OS (10.6 vs. 7.7 months) were also longer in patients treated with the
combination of bevacizumab plus temozolomide, though the difference did not reach statistical significance. Neurological deterioration was significantly lower among patients treated with bevacizumab plus temozolomide (25 vs. 53.3 %; P = 0.005), and treatment completion rates were slightly higher (77.1 vs. 64.4 %; P = 0.18). Glioblastoma is frequently left unresected [14–16] and unresected patients have a dismal prognosis [1]. Attempts to reduce the tumor by means other than surgery have been explored in multiple non-randomized [13, 17–19] but few randomized [20–22] trials, with varying results. The neoadjuvant setting, with response evaluation performed prior to starting concurrent therapy, seemed optimal for the comparison of response to temozolomide alone versus temozolomide plus bevacizumab, since any potential confounding factors arising from prior administration of temozolomide or radiotherapy [11, 23] would easily be ruled out. The TEMAVIR trial [21] also evaluated bevacizumab as first-line treatment in unresected patients, comparing standard temozolomide plus radiotherapy with four cycles of bevacizumab and irinotecan administered prior to and after standard concurrent therapy. Although PFS was longer in
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J Neurooncol Table 3 Adverse events during the neoadjuvant and the concurrent stages of the trial Neoadjuvant stage TMZ arm N = 45 (%)
Concurrent stage TMZ ? BEV arm N = 48 (%)
P
TMZ arm N = 45 (%)
TMZ ? BEV arm N = 48 (%)
P
15 (33.3)
23 (47.9)
0.15
Any toxicity
29 (64.4)
39 (81.3)
0.06
Death during treatmenta
4 (8.9)
4 (8.3)
1
Grade 3–4
Grade 5
Grade 3–4
Grade 5
Grade 3–4
Grade 5
Grade 3–4
Grade 5
Non-bevacizumab related toxicities (%) Hematologic Anemia
1 (2.2)
–
1 (2.1)
–
–
–
–
–
Leucopenia
2 (4.4)
–
1 (2.1)
–
–
–
1 (2.1)
–
Neutropenia
3 (6.7)
–
1 (2.1)
–
–
–
2 (4.2)
–
Febrile neutropenia
2 (4.4)
–
1 (2.1)
–
–
–
–
–
Lymphopenia
1 (2.2)
–
1 (2.1)
–
3 (6.7)
–
8 (16.7)
–
Thrombocytopenia
5 (11.1)
–
1 (2.1)
-
–
–
3 (6.1)
–
Medullar aplasiab
–
–
–
1 (2.1)
–
–
–
–
Nausea & vomiting
–
–
1 (2.1)
–
–
–
–
–
Stomatitis Constipation
– –
– –
– –
– –
– –
– –
– –
– –
Asthenia
1 (2.2)
–
2 (4.2)
–
3 (6.7)
–
–
–
Infection
3 (6.6)
–
5 (10.4)
–
–
–
–
–
Liver
3 (6.6)
–
1 (2.1)
–
–
–
1 (2.1)
–
Non-hematologic
Bevacizumab-related toxicities (%) Hypertension
–
–
2 (4.2)
–
–
1 (2.1)
–
Proteinuria
–
–
–
–
–
–
–
Hemorrhage
–
–
1 (2.1)
Intracranial hemorrhagec
–
–
2 (4.2)
Thrombotic event
3 (6.6)
–
2 (4.2)
–
–
1 (2.1)
Intestinal perforation
d
a
Four patients in the TMZ arm died due to disease progression
b
One patient died due to medullar aplasia
2 (4.2) 1 (2.1)
–
–
–
–
–
–
–
–
3 (6.7)
–
–
–
–
–
–
–
c
In the TMZ ? BEV arm, four patients had intracranial hemorrhages, one grade 3, one grade 4, and two grade 5. Differences in frequency of grade C 3 hemorrhages between arms were not significant (0.24) d
One patient had grade 3 intestinal perforation and one had grade 5
the experimental arm, the trial did not reach its primary endpoint of an increase from 50 to 66 % in 6-month PFS. In contrast, the present study reached its main endpoint of higher response, although it was not powered to detect differences in PFS or OS. While OS was similar in both arms of the TEMAVIR trial, both PFS and OS were longer in the TMZ ? BEV arm in the present study, although differences were not significant. In the TEMAVIR trial, radiotherapy was postponed for at least two months after diagnosis without an apparent worsening in OS. In the present study, radiotherapy was also postponed in order to allow evaluation of response. In fact, data from retrospective series indicate that moderate radiotherapy delays seem not to worsen survival [24, 25]. In the only phase III randomized trial
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comparing standard vs experimental neoadjuvant treatment, survival was not affected by delays of 12–16 weeks [20]. Although spontaneous hemorrhage has been reported in glioblastoma patients even if not receiving bevacizumab [26], in both our trial and the TEMAVIR, spontaneous hemorrhage occurred more frequently in the arm with bevacizumab. In particular, fatal intracranial bleeding occurred in 5.3 % of patients in the TEMAVIR trial and in 4.2 % in the present trial. This was a higher frequency than that observed in the recurrent setting, and in three large trials testing bevacizumab as first-line treatment mainly in resected patients (\3 %) [3, 4, 6–9]. We had expected that MGMT methylation analyses would confirm our previous findings that MGMT methylation in
J Neurooncol
serum can predict methylation in tumor [27] and would identify serum as a viable surrogate when sufficient tumor tissue is not available. However, this was not the case. MGMT methylation was successfully assessed in both tumor and serum in 50 patients and concordance of results was poor. Moreover, while tumor MGMT methylation correlated with PFS and OS, serum MGMT methylation did not. These findings may, however, be due to the relatively low sensitivity of the MSP method used. Perhaps the most controversial issue of the present study is the selection of response as the primary endpoint. In the present study, the use of RANO criteria, in conjunction with the centralized blinded review of response confirming investigator assessments and the neoadjuvant, pre-radiotherapy setting, enabled us to minimize the challenges involved in response evaluation [11, 28]. However, we cannot rule out the possibility that the effect of bevacizumab may have been limited to a pseudoresponse, as has been observed with other antiangiogenics [29]. Nevertheless, the more frequent stable neurologic symptoms observed during the neoadjuvant stage in patients treated with bevacizumab cannot be disregarded. In the recurrent setting, the BELOB randomized phase II trial compared bevacizumab alone versus bevacizumab plus lomustine versus lomustine alone. Only the combination regimen, which was associated with both, improved 9-month OS and a superior response rate, was selected for further comparison with lomustine in a phase III trial (EORTC 26101). Interestingly, objective response was associated with longer survival in both the single-agent bevacizumab group (HR 0.43) and in all patients receiving bevacizumab (HR 0.37), suggesting that reducing measurable disease can enable patients to attain longer OS [6]. A relationship between objective response and OS was also observed in the randomized BRAIN study [30]. While objective response has never been considered a good surrogate for longer survival in glioblastoma, there are increasing signs that it can have a positive impact on PFS or OS [31]. In our trial, patients treated with bevacizumab had a higher response rate, as well as longer PFS and OS, although differences in survival were not significant. This may be due to the relatively small number of patients included and the trial design, which was only powered to detect large differences in 1-year OS (from 37 to 66 %). In summary, the present study provides further evidence that neoadjuvant treatment with bevacizumab in combination with temozolomide may have superior efficacy in terms of response and tumor shrinkage than temozolomide alone in unresected glioblastoma patients, with no negative impact on survival. Acknowledgments The authors thank Anna del Prado (Marketing Farmace´utico & Investigacio´n Clı´nica, SL) for her invaluable assistance throughout the study.
Funding This study was funded by the Spanish Instituto Carlos III (FISS-ICIII: project EC08/00071). In addition, MSD provided neoadjuvant temozolomide and funds for MGMT assessment, and Roche-Spain provided funds for data management and the centralized review of response and progression. Compliance with ethical standards Conflict of interest of interest.
The authors declare that they have no conflict
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