Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma

Abstract

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m/2day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5-15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2-35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of cytotoxic chemotherapy and other cytotoxic therapies in the management of progressive glioblastoma in adults

“…Table 1A summarizes the 6 studies [6][7][8][9][10][11] that examined the use of TMZ at doses different than what published by Stupp et al [4]. Table 1B summarizes 6 studies [12][13][14][15][16][17] reporting on the use of TMZ in combination with other cytotoxic agents. All of these studies provided Class III evidence.…”

Combining therapy with recombinant human endostatin and cytotoxic agents for recurrent disseminated glioblastoma: a retrospective study

“…Although the effect of CPT-11 combined with TMZ or bevacizumab in recurrent glioblastoma was investigated in sevaral studies, the status of dissemination of enrolled patients was not mentioned [21,22].…”

Metronomic therapy in pediatric oncology: A snapshot

“…In brain tumors, temozolomide, either alone or with radiotherapy, other regimens with irinotecan, and combined oral metronomic biodifferentiating antiangiogenic therapy (COMBAT) have been extensively evaluated with encouraging results in palliative settings .…”

“…66 In brain tumors, temozolomide, either alone or with radiotherapy, other regimens with irinotecan, and combined oral metronomic biodifferentiating antiangiogenic therapy (COMBAT) have been extensively evaluated with encouraging results in palliative settings. 72,73,75,84 Studies on mixed population of R/R tumors suggests that therapy is most effective in LGGs. 30 Although similar regimens have shown efficacy in medulloblastoma as well, 73,75 there are others that suggest that metronomic treatment is not an effective modality in HGGs.…”