Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: Phase II study

Summary

Introduction:

The primary tumour type most likely to metastasize to the brain is lung cancer. In heavily pre-treated patients, limited therapeutic option is available and the results of availability therapies reported in literature are disappointing. The present phase II study was designed to assess the efficacy and safety of temozolomide (TMZ) as palliative treatment for brain metastases (BrM) in NSCLC patients pre-treated with WBRT and at least one line of chemotherapy for metastatic brain disease.

Material and methods:

Temozolomide was administered orally at 150 mg/mq/day for five consecutive days for the first cycle, doses were increased to 200 mg/mq/day for 5 days every 28 days for subsequent cycles if no grade 3/4 haematological toxicity was observed. Eligibility criteria included cytological or histological confirmed NSCLC; BrM, recurrent or progressing after WBRT and at least one line of chemotherapy. A total of 30 consecutive patients entered the study and received the allocated treatment.

Results:

Three patients (10%) achieved an objective response (OR) of BrM with two complete remission. Stable disease and progressive disease were achieved in 3 (10%) and 24 patients (80%), respectively. A correlation between response to TMZ and sensitivity to the previous first line chemotherapy was reported. Time to progression and overall survival were examined both for responder patients and for all included patients. For long-term survivors, we considered the patients who survived >12 months after the start of TMZ. According to this definition, three patients resulted long-term survivors: 2 with OR and 1 with stable brain disease. No grades 3 or 4 toxicity occurred. The total of treatment-related adverse events were mild or moderate (G1-2) in intensity. No patients discontinued TMZ as a result of treatment-related toxicity.

Discussion:

The results of the present trial clearly demonstrates that TMZ is active and safe in BrM NSCLC patients previously treated with WBRT and at least one line of chemotherapy.

Introduction

Among intra-cranial tumours, brain metastases (BrM) are more common than primary brain tumours. The primary tumour type most likely to metastasize to the brain is lung cancer. Among patients affected by advanced NSCLC up to 40% have BrM identifiable at autopsy [1]. Whole brain radiotherapy (WBRT) improves neurological symptoms in about 50% of patients and lengthens the median survival from 3 to 6 months [2]. Recent trials suggest that epipodophillotoxins alone or combined with cisplatin are very effective in treating NSCLC-related BrM and ifosfamide–mitomycin–cisplatin or gemcitabine–cisplatin combinations have been evaluated with similar good responses [3], [4], [5], [6], [7], [8], [9]. Temozolomide (TMZ) is a novel, oral, alkylating agent with virtually 100% bioavailability [10], [11], [12]. It is a new class of second generation imidazotetrazine pro-drugs that undergoes spontaneous conversion under physiological conditions to the active alkylating agent-MTIC, thus not requiring hepatic metabolism to become active. It crosses the blood–brain barrier and has showed activity in heavily pre-treated patients affected by BrM from NSCLC [10], [11], [12]. Concentrations of the drug in the central nervous system reach approximately 30–40% of plasma concentrations and clearance of TMZ is unaffected by co-administration with anticonvulsivants, antiemetics or dexamethasone. TMZ also has a good toxicity profile. The dose-limiting toxicity is not cumulative myelosuppression that rarely requires treatment delay or dose reduction.

The present phase II study was designed to assess the efficacy and safety of TMZ as palliative treatment for recurrent or progressing BrM in NSCLC patients pre-treated with WBRT and at least one line of chemotherapy for metastatic brain disease.