Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma

Abstract

The aim of this paper is to explore the efficacy of whole brain radiotherapy (WBRT) versus WBRT concurrent with erlotinib in patients with multiple brain metastases of lung adenocarcinoma. WBRT was administered at 30Gy/10f in both arms. In the combination arm, 150 mg erlotinib was given each day, starting the first day of radiotherapy and continuing for 1 month following the end of radiotherapy. Thereafter, pemetrexed or docetaxel monotherapy or the best supportive therapy was given to both arms. The intracranial objective response rate and the local progression-free survival (LPFS) were primary endpoints. Toxicity, progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Thirty-one patients in the WBRT group and 23 patients in the combination group were enrolled from November 2009 to December 2011. In the WBRT and the combination arms, respectively, the objective response rate was 54.84% and 95.65% (P = 0.001), the median local progression-free survival was 6.8 months and 10.6 months (P = 0.003), the median PFS was 5.2 months and 6.8 months (P = 0.009), and median OS was 8.9 months and 10.7 months (P = 0.020). In the combination group, there were no differences of LPFS, PFS, and OS between the epidermal growth factor receptor (EGFR) mutation patients and EGFR wild-type patients. No Grade 4 or higher side effects were observed in either group. A multivariate analysis indicated that erlotinib was the most important prognostic factor for a prolonged survival. Data showed that erlotinib in combination with WBRT had a tolerable toxicity profile and prolonged the LPFS, PFS, and OS of lung adenocarcinoma patients with multiple brain metastases compared with WBRT monotherapy.

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO)

“…73,74 A phase II study from China has reported that the combination of WBRT and erlotinib has tolerable toxicities, and suggested a prolonged PFS and OS (class IIb). 75 Conversely, phase II (class IIa and b) 76,77 and phase III (class I) 78 trials in patients with NSCLC brain metastases not enriched for EGFR mutations failed to demonstrate a superiority of the combination of erlotinib with either SRS or WBRT over radiotherapy alone, with a suggestion of worse outcome in patients receiving the combined therapy. A Chinese phase II trial of WBRT with concurrent icotinib, another EGFR inhibitor, has suggested that the combination could improve survival compared with historical controls.…”

Optimizing outcomes in EGFR Mutation-Positive Nsclc: Which Tyrosine Kinase Inhibitor and When?

“…In an effort to increase drug concentrations in the brain, several studies have assessed high-dose regimens of gefitinib or erlotinib in patients with EGFR mutation-positive NSCLC and brain metastases [67,69]. A number of retrospective studies have assessed the combination of first-generation EGFR TKIs with whole-brain radiation therapy (WBRT), which is thought to increase permeability of the bloodbrain barrier [72][73][74]. These studies indicate that concomitant WBRT may enhance the intracranial activity of first-generation TKIs.…”

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future

“…Nevertheless radiotherapy did not improve disease response and no significant differences in ORR were documented. In general, cranial irradiation caused a rate of neurological adverse events higher than that reported in studies with TKIs alone (84)(85)(86), but lower than that of the concurrent upfront WBRT/TKIs studies (92,93). By limiting the analysis to prospective studies, there was no significant difference in intracranial disease control and survival outcomes between concurrent upfront WBRT plus TKIs and TKIs alone.…”

“…Concomitant therapy was also compared both to EGFR-TKI alone and WBRT alone (90,92,97,98,123). Ceresoli et al (90), in a previously mentioned study, evaluated 41 NSCLC pts with BM.…”