Department of Medical Oncology, Giovanni Paolo II Oncology Institute, Via Hanehman 10, 7016 Bari, Italy.
Lung Cancer. 2011 Apr;72(1):59-63. doi: 10.1016/j.lungcan.2010.07.013. Epub 2010 Aug 21.
More than 50% of brain metastases (BMs) occur in advanced non-small cell lung cancer (NSCLC) patients. Untreated patients with BMs have a poor prognosis with a median survival of 2 months. In most cases BMs are multiple and their optimal therapy is whole-brain radiation therapy (WBRT). The role of systemic therapies for these patients is still a matter for investigation due to concerns about the ability of these drugs to cross the blood-brain barrier (BBB). Cisplatin (CDDP) remains the backbone for medical treatment of NSCLC and fotemustine (FTM) is a nitrosurea able to cross the BBB.
Patients with advanced NSCLC, ECOG performance status (PS) 0-1 and multiple BMs not amenable to surgery or stereotactic radiotherapy were treated with 2 cycles of FTM 80 mg/m(2) days 1, 8 and CDDP 80 mg/m(2) day 1, every 3 weeks followed by WBRT 30 Gy (3 Gy daily in 10 fractions). Radiological restaging was performed before WBRT to assess the role of chemotherapy both for cranial and extracranial disease. Patients with disease control (DC: complete response plus partial response) received 4 more cycles. To assess the basic activities of daily living (ADL), the Barthel ADL Index was used to score patients' performance every 2 cycles. The trial design provides a two-step evaluation according to the optimal two-stage design of Simon. In the first phase 29 patients were enrolled in order to verify if this schedule showed more than 25% response rate both for cranial and extracranial disease. If so, enrollment added up to a total of 81 patients.
After the first evaluation 4 out of 29 patients were excluded from the study (3 untreated/1 not included for administrative reasons). At the time of the planned interim analysis patient's characteristics were the following: median age 61 years (range 44-70), M/F = 16/9, adenocarcinoma 11, squamous 5, large cell 2, undefined NSCLC 7; PS 0/1 in 11/14 cases, median Barthel Index score was 20 [13-20]. Three (12%) partial responses were observed, 9 subjects (36%) with stable disease and 13 (52%) showing disease progression. These data did not satisfy the pre-planned hypothesis and the study was stopped. At the time of the first evaluation before WBRT 12/25 (48%) patients had a systemic DC in contrast with 15/25 (60%) patients with BMs DC. Chemotherapy was relatively well tolerated with a prevalence of asthenia as the most relevant specific toxicity while the haematological toxicity was mild.
CDDP and FTM combined with WBRT do not represent a therapeutic option for patients with NSCLC. Therefore further studies to evaluate the combination of systemic treatments with WBRT are warranted.
超过 50%的脑转移瘤（BMs）发生在晚期非小细胞肺癌（NSCLC）患者中。未经治疗的 BMs 患者预后较差，中位生存期为 2 个月。在大多数情况下，BMs 是多发性的，其最佳治疗方法是全脑放疗（WBRT）。由于担心这些药物能够穿过血脑屏障（BBB）的能力，这些患者的全身治疗的作用仍在研究之中。顺铂（CDDP）仍然是治疗 NSCLC 的基础药物，福莫司汀（FTM）是一种能够穿过 BBB 的亚硝脲类药物。
患有晚期 NSCLC、ECOG 体能状态（PS）0-1 和无法手术或立体定向放疗的多发性 BMs 的患者接受 2 个周期的 FTM 80 mg/m²天 1、8 和 CDDP 80 mg/m²天 1，每 3 周一次，随后进行 30 Gy 的 WBRT（3 Gy 每日 10 次）。在进行 WBRT 之前进行影像学重新分期，以评估化疗对颅内外疾病的作用。疾病控制（DC：完全缓解加部分缓解）的患者接受了 4 个周期的治疗。为了评估基本日常生活活动（ADL），在每 2 个周期时使用巴氏 ADL 指数对患者的表现进行评分。试验设计根据西蒙的最优两阶段设计提供了两步评估。在第一阶段，招募了 29 名患者，以验证该方案是否对颅内外疾病的反应率超过 25%。如果是这样，总共招募了 81 名患者。
第一次评估后，有 4 名 29 名患者被排除在研究之外（3 名未治疗/1 名因行政原因未纳入）。在计划的中期分析时，患者的特征如下：中位年龄 61 岁（范围 44-70），M/F=16/9，腺癌 11 例，鳞状细胞癌 5 例，大细胞癌 2 例，未明确 NSCLC 7 例；PS 0/1 的分别为 11/14 例，中位巴氏 ADL 评分为 20 [13-20]。观察到 3 例（12%）部分缓解，9 例（36%）患者疾病稳定，13 例（52%）患者疾病进展。这些数据不符合预先计划的假设，因此研究停止。在第一次评估前进行 WBRT 时，与 25 例患者中的 15 例（60%）相比，有 12/25（48%）例患者的系统疾病得到了控制。化疗的耐受性相对较好，乏力是最相关的特异性毒性，而血液学毒性较轻。
CDDP 和 FTM 联合 WBRT 对 NSCLC 患者不是一种治疗选择。因此，需要进一步研究评估全身治疗联合 WBRT 的疗效。
