Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: Phase II study
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.
Section snippets
Patients eligibility
Eligibility criteria included cytological or histological confirmed NSCLC; BrM, in progression after WBRT and at least one previous line of chemotherapy for metastatic brain disease. Patients were also required to have evaluable or measurable brain disease assessed by CT or MRI scans, age between 18 and 80 years, an Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and a life expectance >3 months. Bone marrow function requirements included an absolute neutrophil count ≥1500 mm−3, a
Patient characteristics
The demographic and baseline disease characteristics of the evaluable patients are listed in Table 3.
A total of 30 consecutive patients entered the study and received the allocated treatment from October 2000 to July 2003. All patients were pre-treated with WBRT (30 Gy in 10 fractions of 300 cGy) and at least one line of chemotherapy for metastatic brain disease (18/30 and 5/30 of patients with second and third line of chemotherapy, respectively, for metastatic disease, regardless of brain
Discussion
Brain metastases from NSCLC are associated with poor prognosis despite aggressive treatment. Also, the majority of patients suffer debilitating neurological symptoms. The optimal treatment for patients with BrM continues to evolve. The recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group brain metastases trials identified three prognostic classes with median survival of 2.3 months (RPA Class III) to 7.1 months (RPA Class I). [15] Although WBRT
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2017, Annals of OncologyCitation Excerpt :Temozolomide, an alkylating agent, can penetrate the blood-brain barrier (BBB) in therapeutic concentrations (49). Intracranial RR ranging from 0% to 10% with temozolomide alone has been observed (50,51). The TACTIC study evaluated the role of erlotinib with concurrent radiotherapy in patients with brain metastases which were predominantly EGFR wild type (52).
The evolving clinical management of cerebral metastases
2017, European Journal of Surgical OncologyCitation Excerpt :Cisplatin regimes show a similar overall median survival in those with only extracranial metastatic disease compared to with brain metastases suggesting similarities in the chemosensitivity of the intracranial disease to that of primary tumour.86,87 Temozolamide, which has been widely shown to improve survival in primary brain tumours, gives an objective increase in response rate but no additional survival benefit in NSCLC.88–90 EGFR tyrosine kinase inhibitors (erlotinib and gefitinib) may offer a new possibility of frontline management for patients with brain metastases.
Systemic Treatment of Brain Metastases
2017, Hematology/Oncology Clinics of North AmericaCitation Excerpt :In the larger of the two studies, which enrolled 41 patients and including 22 with NSCLC, 2 patients (9%) had a partial response (PR).28 A second study investigated temozolomide in 30 patients with NSCLC with progression of brain metastases after at least 1 line of chemotherapy and WBRT.29 The dose of temozolomide was escalated to 200 mg/m2/d with subsequent cycles if no grade 3 or grade 4 hematologic toxicities were observed.
The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer
2016, Cancer Treatment ReviewsCitation Excerpt :This review discusses articles either exclusively conducted in NSCLC populations or, in the absence of sufficient studies, those with at least 50% of the study population consisting of NSCLC patients (Table 2) [11–48]. A total of 21 clinical trials with exclusively NSCLC populations with brain metastases were identified from the searches [12–14,16–27,30–35]. Overall, it appeared that OS was longer with WBRT-based regimens than with chemotherapy; molecularly targeted therapies also reported promising OS, often higher than reported in WBRT regimes (Table 3).