Temozolomide Plus Bevacizumab in Elderly Patients with Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial (ATAG).

LESSONS LEARNED: Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients with glioblastoma multiforme with poor performance status.Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study.
BACKGROUND: The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70.
MATERIALS AND METHODS: Patients aged ≥70 years with a KPS <70 and biopsy-proven GBM were eligible for this multicenter, prospective, nonrandomized, phase II trial of older patients with impaired performance status. Treatment consisted of TMZ administered at 130-150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeks.
RESULTS: The trial included 66 patients (median age of 76 years; median KPS of 60). The median overall survival (OS) was 23.9 weeks (95% confidence interval [CI], 19-27.6), and the median progression-free survival (PFS) was 15.3 weeks (95% CI, 12.9-19.3). Twenty-two (33%) patients became transiently capable of self-care (i.e., KPS >70). Cognition and quality of life significantly improved over time during treatment. Grade ≥3 hematological adverse events occurred in 13 (20%) patients, high blood pressure in 16 (24%), venous thromboembolism in 3 (4.5%), cerebral hemorrhage in 2 (3%), and intestinal perforation in 2 (3%).
CONCLUSION: This study suggests that TMZ + Bev treatment is active in elderly patients with GBM with low KPS and has an acceptable tolerance level. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Discussion

Our study indicates that tolerance to the Bev‐TMZ combination was acceptable in this population. Hematological toxicity greater than grade 3 was reported in 20% of patients. As expected, the most frequent adverse event observed with Bev was high blood pressure, which responded to antihypertensive treatment. Although the rate of thromboembolic events does not appear to be exceedingly high in this bedridden GBM population, the two cases of intestinal perforation can be ascribed to Bev; furthermore, Bev may have played a role in the two cases of cerebral hemorrhage.

An objective radiological response in one third of patients and the fact that one third of patients also became autonomous and capable of self‐care (i.e., KPS >70) is encouraging and in agreement with the observations of significant improvements in cognition and most quality‐of‐life scales during the treatment period. Additionally, the estimated OS median of 24 weeks (Figure 1) that we found appears higher that the 12 weeks OS that we found in a similar patient population treated with supportive care alone (personal data, unpublished).

Figure 1.

Kaplan‐Meier plot: experimental arm, primary assessment, total patient population. (A): Kaplan‐Meier estimates of overall survival. (B): Kaplan‐Meier estimates of progression‐free survival.

There was a trend for increased PFS and OS in patients with methylated promoter O‐6‐methylguanine‐DNA methyltransferase (MGMT) status; however, in contrast to our previous study that used TMZ alone, this difference did not reach statistical significance. This may reflect a lack of power. On the other hand, it is possible that some patients without methylated MGMT promoter also could benefit from Bev because its action is not believed to be influenced by MGMT methylation status.

Trial Information

Brain cancer – primary

Primary

None

Phase II

Single arm

Overall survival

Progression‐free survival

Tolerability

Health‐related quality of life

Cognitive functioning

Active and should be pursued further

Drug Information

Temozolomide

Small molecule

Alkylating agent

130–150 milligrams (mg) per square meter (m2)

Oral (p.o.)

Bevacizumab

Antibody

Angiogenesis – VEGF

10 mg milligrams (mg) per kilogram (kg)

IV

Every 2 weeks

Patient Characteristics

24

42

Median (range): 76 years (70–87 years)

Median: 0

The median postoperative Karnofsky performance status was 60 (range, 30–60)

Primary Assessment Method

Total Patient Population

71

66

66

66

n = 1

n = 20

n = 24

n = 15

15.3 weeks; CI, 12.9–19.3

23.9 weeks; CI, 19–27.6

Weeks

Kaplan‐Meier Plot Legend

Kaplan‐Meier estimates of overall survival (OS)

Phase II Experimental Adverse Events

Serious Adverse Events

Serious Adverse Events Legend

Serious adverse events included deep venous thrombosis (three cases), pulmonary embolism (two cases, including one fatal), intestinal perforation (two cases, including one fatal), and cerebral hemorrhage (two cases, including one fatal grade 5 toxicity).

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

Elderly patients aged 65 years and older account for approximately 45% of patients with glioblastoma multiforme (GBM) [1], and this figure is expected to rise concurrently with the aging population of most countries [2]. Unfortunately, few trials have been performed in this setting [3], [4], [5], [6], [7]. In elderly patients with good functional status (Karnofsky performance status [KPS] >70 or Eastern Cooperative Oncology Group score 0–2), the standard treatment is now the combination of radiotherapy (RT) and temozolomide (TMZ; concomitant and adjuvant). In elderly patients with poor functional status at the time of diagnosis (KPS <70), there is no standard treatment. One trial suggested that accelerated 1‐week RT could be of help, but this trial mixed various populations, including younger patients and elderly patients in good clinical condition [8]. In elderly, bedridden patients with unresectable GBM, the benefit of radiotherapy is unproven and questionable; indeed, it requires daily trips to the hospital, resulting in increased fatigue and an increased risk of acute complications, including intracranial hypertension and herniation, particularly when high doses per fraction are used. In this very difficult patient population, we previously showed that TMZ alone was associated with improvement in functional status in one third of cases and appeared to increase survival compared with supportive care alone [9].

Bevacizumab (Bev) is an antiangiogenic monoclonal antibody targeting vascular endothelial growth factor that is commonly used in GBM. Although recent phase III studies did not show a significant effect of adding Bev to alkylating agents (TMZ or nitrosoureas) on overall survival (OS), a favorable impact of this combination on progression‐free survival was demonstrated both as a first‐line treatment and in the recurrent setting [10], [11], [12], [13], [14], [15], [16].

Treatment of GBM in elderly patients with impaired functional status is challenging. In a recursive partitioning analysis, the estimated median OS in elderly patients with GBM with a KPS <70 without surgical resection was only 10 weeks (95% CI, 9–13.5) [17]. In a recent phase II trial focusing on this frail elderly population, we found that TMZ alone was helpful with a median OS of 25 weeks (95% CI, 19–28); 25% of patients became able to provide self‐care and had significant improvements in quality of life and cognition before disease progression [9].

In this study, we evaluated the efficacy and safety of the upfront combination of TMZ + Bev as an initial treatment for elderly patients with GBM and impaired functional status (KPS <70). Bev has a well‐known steroid‐sparing effect, presumably because of the blood‐brain and blood‐tumor barrier restoration [10]. Indeed, corticosteroids could be reduced (in 56% of cases) or even discontinued (10%) in our patients with inoperable tumors. This steroid‐sparing effect is clearly favorable given the poor tolerance of elderly patients for steroids [18].

Although the analysis included only 66 patients (5 patients were excluded because they did not take any dose of treatment), the precision obtained at the end of the trial of the estimation of the median survival was higher than expected (standard error of 5 weeks instead of 14 weeks). Additionally, the estimated OS median of 24 weeks that we found appears higher that the 12 weeks of OS that we found in a similar patient population treated with supportive care alone (personal data, unpublished). However, it is comparable to the 25 weeks that we reported in similar patients receiving TMZ alone [9]. Whether this combination is superior to TMZ alone remains to be demonstrated by a randomized study.

See http://www.TheOncologist.com for supplemental material available online.

Table 1.

Baseline patient characteristics

Abbreviations: Bev, bevacizumab; MMSE, mini‐mental state examination; TMZ, temozolomide.

Table 2.

Number of patients with grade ≥ 3 adverse events

Table 3.

Variations in MMSE and HRQoL scores over time before progression

Abbreviations: HRQoL, health‐related quality of life; MMSE, mini‐mental state examination; QLQ‐BN20, quality of life questionnaire, brain cancer module; QLQ‐C30, quality of life core questionnaire.