A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy

Figures & data

Table I. Patients’ baseline characteristics.

Total number of patients	n = 85
Median age, years (range)	51 (21–71)
Gender
Male	45 (53%)
ECOG Performance status
0	28 (33%)
1	39 (46%)
2	17 (20%)
Previous therapy
Extent of primary surgery
Needle biopsy only	17 (20%)
Partial resection	36 (42%)
Gross total resection	25 (29%)
Re-resection
At any time	49 (58%)
Preceding study entry	21 (25%)
Radiation therapy	85 (100%)
Chemotherapy
1 line	71 (84%)
2 lines or more	10 (12%)
Diagnosis		Summary of diagnoses
Glioblastoma multiforme WHO gr. IV	32 (38%)	All GBM gr. IV = 32
Anaplastic astrocytoma WHO gr. III	17 (20%)	All Glioma gr. III = 33
Anaplastic oligodendroglioma WHO gr. III	9 (11%)	All Glioma gr. II = 12
Anaplastic oligoastrocytoma WHO gr. III	7 (8%)	All others = 8
Ependymoma WHO gr. III	2 (2%)
Oligodendroglioma WHO gr. II	2 (2%)
Oligoastrocytoma WHO gr. II	2 (2%)
Astrocytoma WHO gr. II	8 (9%)
Gliosarcoma WHO gr. IV	2 (2%)
Medulloblastoma WHO gr. IV	1 (1%)
Meningioma WHO gr. lll	1 (1%)
Malignant Schwannoma WHO gr. lV	1 (1%)
Prolactinoma	1 (1%)
Steroid treatment
None	26 (31%)
< 50 mg prednisolone	22 (26%)
≥ 50 mg prednisolone	35 (41%)
Enzyme inducing anti-epileptic drug (EIAED) treatment
Yes	26 (31%)
Median time from initial diagnosis to entry in study (months, range)
Glioblastoma multiforme	12 (5–251)
All glioma gr. III	30 (8–173)
All glioma gr. II	20 (8–110)
Gliosarcoma WHO gr. IV	7 and 16
Ependymoma	17 and 6
Medulloblastoma WHO gr. IV	47
Meningioma WHO gr. III	229
Malignant Schwannoma WHO gr. IV	36
Prolactinoma	35

Figure 1. Summary of best radiographic responses for the 28 evaluable glioblastoma multiforme. Horizontal grey lines represent 1 25% and 2 50% change from baseline.

Table II. Clinical responses and outcomes for the glioma population. 95% confidence intervals are noted in parentheses.

Diagnosis	n	ORR (%)	SD (%)	PFS median (months)	PFS-6 (%)	OS median (months)	Landmark analysis at 4 months: responders vs. non-responders
							PFS median (months)	OS median (months)
Glioblastoma multiforme	32	25	59	5.2	28	7.9	7.3 (1.6–13.0)	13.4 (2.7–24.3)
		(11–43)	(41–76)	(3.1–7.2)	(14–47)	(6.3–9.6)	1.4 (0–2.8)	4.1 (2.9–5.5)
							(p = 0.01)	(p = 0.029)
Glioma grade III	33	21	45	3.7	30	6.9	7.5 (0–23.7)	20.9 (3.6–38.2)
		(9–39)	(28–64)	(3.0–4.3)	(16–49)	(3.4–10.3)	3.7 (1.1–6.3)	3.1 (0–7.8)
							(p = 0.48)	(p = 0.22)
Glioma grade II	12	0	75	5.2*	25	4.1*	N/A
		(0–26)	(43–95)	(2.0–8.4)	(5–57)	(0–8.9)

*= estimated PFS exceeds estimated OS as a result of large confidence intervals due to great variation and small numbers.

Table III. Responses and outcomes for individuals in the non-glioma population.

Diagnosis	n	Radiographic response for each case (%)	PFS (months)	OS (months)
Gliosarcoma grade IV	2	32	5.6	9.8
		40	3.8	6.0
Ependymoma grade III	2	17	1.6	8.5
		47	14.5	> 17.4
Medulloblastoma grade IV	1	n/a (extracranial disease)	6.1	22.3
Meningioma grade III	1	15	> 19.3	> 19.3
Schwannoma grade IV	1	38	6.8	8.2
Malignant Prolactinoma	1	54	> 31.2	> 31.2

OS, overall survival from enrollment; PFS, progression-free survival.

Table IV. Odds ratio of response for different clinical parameters. No statistically significant associations were found.

Clinical parameter	Defintion	Odds ratio estimate (with 95% confidence interval)
Tumor grade	Glioma grade IV vs. III	1.56 (0.42–5.81)
Tumor size	For a two-fold increase in cross-sectional area	0.95 (0.56–1.61)
Steroid use	No steroid vs. any steroid dose at inclusion	0.80 (0.20–3.11)
Age	For a 10-year increase in age	0.77 (0.44–1.379)
Performance status	PS = 0 vs. PS 1 or 2	0.89 (0.24–3.33)
Hypertension	Development or worsening of any grade of hypertension during treatment	0.86 (0.15–4.88)

Table V. Toxicity. All values indicate percentage of valid data. Only changes from baseline are reported.

	Grade 1–2 (%)	Grade 3–4 (%)	Grade 5 (%)
Thrombosis		6	1.2
Bleeding	23.8		2.4
Hypertension	18
Proteinuria		15.9
Neutropenia	13	5.2
Lymfocytopenia (only gr. 3–4 registered)		13.1
Thrombocytopenia (only gr. 3–4 registered)		4.8
Infections	14.3	8.3
Fever	9.6
Fatigue	48.8	7.2
Nausea	52.4	1.2
Vomiting	29.7
Mucositis	23.8
Liver enzymes	21.7	2.9
Diarrhea	40.5
Obstipation	28.6	1.2
Alopecia	36.1
Neurological symptoms	21	13.6
Allergic reactions	18.1
Osteonecrosis of the jaw	1.2