Combining molecular targeted agents with radiation therapy for malignant gliomas

Figures & data

Figure 1 Schematic representation of the effects of radiation and targeted agents on EGFR, VEGFR, and integrin-signaling pathways.

Notes: After stimulation by irradiation, activation of EGFR, VEGFR, and integrin receptors results in stimulation of downstream signaling pathways that can promote cell survival and proliferation, DNA repair, and angiogenesis in both glioma and endothelial cells. Targeted agents that block at various steps the interaction of EGF (cetuximab), VEGF (bevacizumab), and extracellular proteins containing the RDG-peptide (cilengitide) with their receptor and downstream effectors (EGFR inhibitor erlotinib and gefitinib, VEGFR inhibitor vandetanib, vatalanib and sorafenib, PKC-B inhibitor enzastaurin, and mTOR inhibitors everolimus and temsirolimus) may enhance the damaging effects of irradiation.
Abbreviations: EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; RDG-peptide, Arg-Gly-Asp peptide; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; integrin-R, integrin receptor; PTEN, phosphatase and tensin homologue; PI3K, phosphoinositide 3-kinase; Ras, Ras GTPase; mTOR, mammalian target of rapamycin; AKT, protein kinase B; Raf, rapidly accelerated fibrosarcoma; p53, tumor protein 53; MDM2, mouse double minute 2 homologue; BAD, Bcl-2-associated death promoter; MEK, mitogen-activated protein kinase kinase; MAPK, mitogen-activated protein kinase; PLC, phospholipase C; IP3, inositol trisphosphate; PKC, protein kinase C; DNA, deoxyribonucleic acid.

Table 1 Clinical trials of antiangiogenic agents and integrin inhibitors in combination with radiotherapy

Authors	Reference	Drug	Patients	Tumor	Drug dose	Outcomes
Narayana et al	40	Bevacizumab	15	Newly diagnosed HGGs	10 mg/kg every 14 days + RT + TMZ	PFS-12: 59.3% OS-12: 86.7%
Lai et al	11	Bevacizumab	70	Newly diagnosed GBM	10 mg/kg every 14 days + RT + TMZ	PFS: 13.6 months OS: 19.6 months
Vredenburgh et al	10	Bevacizumab	75	Newly diagnosed GBM	10 mg/kg every 14 days + RT + TMZ + irinotecan	PFS: 14.2 months OS: 21.2 months
Vredenburgh et al	43	Bevacizumab	125	Newly diagnosed GBM	10 mg/kg every 14 days + RT + TMZ + irinotecan	PFS-6: 87.2% PFS: 13.8 months
Narayana et al	41	Bevacizumab	51	Newly diagnosed GBM	10 mg/kg every 14 days + RT + TMZ	PFS-12: 51% OS-12: 85.1%
Hainsworth et al	44	Bevacizumab	68	Newly diagnosed GBM	10 mg/kg every 14 days + RT + TMZ + everolimus	PFS: 11.3 months OS: 13.9 months
Shapiro et al	47	Bevacizumab	24	Recurrent HGGs	10 mg/kg every 14 days + HFSRT (30 Gy)	PFS: 7.5 months OS: 12.2 months
Niyazi et al	48	Bevacizumab	20	Recurrent HGGs	10 mg/kg every 14 days + RT (36 Gy)	PFS: 244 days OS: 367.6 days
Hundsberger et al	49	Bevacizumab	14	Recurrent HGGs	10 mg/kg every 14 days + RT (39–55 Gy)	PFS: 5.1 months OS: 9 months
Drappatz et al	65	Vandetanib	13	Newly diagnosed GBM	100 mg/day to 200 mg/day + RT + TMZ	PFS: 8 months OS: 11 months
Fields et al	8	Vandetanib	14	Recurrent HGGs	100 mg/day to 200 mg/day + FSRS (36 Gy)	PFS: 3 months OS: 6 months
Broniscer et al	66	Vandetanib	21	Newly diagnosed pediatric brain tumor	50 mg/m^2 to 145 mg/m^2 + RT	OS-12: 37.5%
Brandes et al	73	Vatalanib	19	Newly diagnosed GBM	500 mg/day to 1,250 mg/day + RT + TMZ 750 mg twice/daily + TMZ	PFS: 6.8 months OS: 17.3 months
Gerstner et al	9	Vatalanib	19	Newly diagnosed GBM	250 mg twice/daily to 500 mg twice/daily + RT + TMZ 750 mg twice/daily + TMZ	PFS: 7.2 months OS: 16.2 months
Den et al	83	Sorafenib	11 7	Newly diagnosed HGGs	200 mg to 400 mg twice/daily + RT + TMZ	OS: 18 months
				Recurrent HGGs	200 mg to 400 mg twice/daily + HFSRT (35 Gy)	OS: 24 months
Butowski et al	96	Enzastaurin	66	Newly diagnosed GBM	250 mg/day + RT + TMZ	PFS: 36 weeks OS: 74 weeks
Stupp et al	13	Cilengitide	52	Newly diagnosed GBM	500 mg/day + RT + TMZ	PFS-6: 69% OS: 16.1 months
Nabors et al	14	Cilengitide	112	Newly diagnosed GBM	500 mg/day or 2,000 mg/day + RT + TMZ	PFS: 9.9 months OS: 19.7 months

Abbreviations: HGGs, high-grade gliomas; RT, radiotherapy; TMZ, temozolomide; PFS-12, 12-month progression-free survival; OS-12, 12-month overall survival; GBM, glioblastoma; PFS, progression-free survival; OS, overall survival; HFSRT, hypofractionated stereotactic radiation; FSRS, fractionated stereotactic radiosurgery; PFS-6, 6-month progression-free survival.

Table 2 Clinical trials of EGFR and mTOR inhibitors in combination with radiotherapy

Authors	Reference	Drug	Patients	Tumor	Drug dose	Outcomes
Krishnan et al	147	Erlotinib	19	Newly diagnosed GBM	100 mg/day to 150 mg/day for patients not on EIAEDs + RT 100 mg/day to 200 mg/day for patients on EIAEDs + RT	OS: 51 weeks OS: 66 weeks
Brown et al	149	Erlotinib	97	Newly diagnosed GBM	150 mg/day + RT + TMZ	PFS: 7.2 months OS: 15.3 months
Broniscer et al	148	Erlotinib	23 (3–25 years)	Newly diagnosed HGGs	70 mg/m^2 to 160 mg/m^2 + RT	PFS-12: 56% OS-12: 78%
Prados et al	4	Erlotinib	65	Newly diagnosed GBM or GS	100 mg/day to 200 mg/day for patients not on EIAEDs + RT + TMZ 200 mg/day to 500 mg/day for patients on EIAEDs + RT + TMZ	PFS: 8.2 months OS: 19.3 months
Peereboom et al	3	Erlotinib	27	Newly diagnosed GBM	50 mg/day to 150 mg/day + RT + TMZ	PFS: 2.8 months OS: 8.6 months
Schwer et al	150	Gefitinib	15	Recurrent HGGs	250 mg/day + FSRS	PFS: 7 months OS: 10 months
Geyer et al	151	Gefitinib	33 (3–21 years)	Newly diagnosed BSG or STMG	100 mg/m^2 to 375 mg/m^2 + RT	OS-12: 48% (BSG) OS-12: 28.8% (STMG)
Pollack et al	152	Gefitinib	43 (3–21 years)	Newly diagnosed gliomas	250 mg/m^2 + RT	PFS-12: 20.9% OS-12: 56.4%
Chakravarti et al	153	Gefitinib	147	Newly diagnosed GBM	500 mg/day + RT	PFS: 4.9 months OS: 11.1 months
Sarkaria et al	163	Temsirolimus	25	Newly diagnosed GBM	25 mg/week to 75 mg/week + RT + TMZ	OS: 13.3 months
Sarkaria et al	164	Everolimus	18	Newly diagnosed GBM	30 mg/week to 70 mg/week + RT + TMZ	SD: 15 patients

Abbreviations: EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin; GBM, glioblastoma; EIAED, enzyme-inducing antiepileptic drug; RT, radiotherapy; OS, overall survival; TMZ, temozolomide; PFS, progression-free survival; HGGs, high-grade gliomas; PFS-12, 12-month progression-free survival; OS-12, 12-month overall survival; GS, gliosarcoma; FSRS, fractionated stereotactic radiosurgery; BSG, brainstem glioma; STMG, supratentorial malignant glioma; SD, Stable Disease.