Postoperative neoadjuvant temozolomide before radiotherapy versus standard radiotherapy in patients 60 years or younger with anaplastic astrocytoma or glioblastoma: a randomized trial

Introduction: A pilot study of temozolomide (TMZ) given before radiotherapy (RT) for anaplastic astrocytoma (AA) and glioblastoma (GBM) resulted in prolonged survival compared to historical controls receiving RT alone. We therefore investigated neoadjuvant TMZ (NeoTMZ) in a randomized trial. During enrollment, concomitant and adjuvant radio-chemotherapy with TMZ became standard treatment. The trial was amended to include concurrent TMZ. Patients and methods: Patients, after surgery for GBM or AA, age ≤60 years and performance status (PS) 0–2, were randomized to either 2–3 cycles of TMZ, 200 mg/m2 days 1–5 every 28 days, followed by RT 60 Gy in 30 fractions or RT only. Patients without progressive disease after two TMZ cycles, received the third cycle. From March 2005, TMZ 75 mg/m2 was administered daily concomitant with RT. TMZ was recommended first-line treatment at progression. Primary endpoint was overall survival and secondary safety. Results: The study closed prematurely after enrolling 144 patients, 103 with GBM and 41 with AA. Median age was 53 years (range 24–60) and 89 (62%) were male. PS was 0–1 for 133 (92%) patients, 53 (37%) had complete surgical resection and 18 (12%) biopsy. Ninety-two (64%) received TMZ concomitant with RT. Seventy-two (50%) were randomized to neoadjuvant treatment. For the overall study population survival was 20.3 months for RT and 17.7 months for NeoTMZ (p = .76), this not reaching the primary objective. For the preplanned subgroup analysis, we found that NeoTMZ AA patients had a median survival of 95.1 months compared to 35.2 months for RT (p = .022). For patients with GBM, no difference in survival was observed (p = .10). MGMT and IDH status affected outcome. Conclusions: No advantage of NeoTMZ was noted for the overall study population or subgroup of GBM, while NeoTMZ resulted in 5 years longer median survival for patients diagnosed as AA.引言：一项针对间变性星形细胞瘤（anaplastic astrocytoma, AA）和胶质母细胞瘤（glioblastoma, GBM）患者在放疗（radiotherapy, RT）前给予替莫唑胺（temozolomide, TMZ）的先导性研究显示，相较于仅接受放疗的历史对照队列，患者的生存期得到延长。基于此，我们开展了一项针对新辅助替莫唑胺（neoadjuvant TMZ, NeoTMZ）的随机对照试验。在试验入组阶段，同步联合替莫唑胺的放化疗方案成为标准治疗手段，因此本试验被修订为纳入同步替莫唑胺治疗方案。 患者与方法：针对经手术治疗的GBM或AA患者，年龄≤60岁且体能状态（performance status, PS）评分0~2分者，按随机原则分为两组：一组接受2~3个周期的替莫唑胺治疗（200mg/m²，第1~5天，每28天为1周期），随后接受30分割、总剂量60Gy的放疗；另一组仅接受放疗。完成2个周期替莫唑胺治疗后未出现疾病进展的患者，可接受第3个周期治疗。自2005年3月起，同步放疗期间给予每日75mg/m²的替莫唑胺治疗。疾病进展后推荐替莫唑胺作为一线治疗方案。本试验的主要终点为总生存期，次要终点为安全性。 结果：本试验共入组144例患者后提前终止，其中103例为GBM患者，41例为AA患者。受试者中位年龄为53岁（范围24~60岁），男性89例（占比62%）。133例（92%）患者的PS评分为0~1分，53例（37%）接受了根治性手术切除，18例（12%）仅行活检。92例（64%）患者接受了同步替莫唑胺联合放疗。72例（50%）患者被随机分配至新辅助治疗组。在全部研究人群中，单纯放疗组患者的中位生存期为20.3个月，新辅助替莫唑胺组为17.7个月（p=0.76），未达到主要研究终点。针对预先设定的亚组分析显示，新辅助替莫唑胺治疗的AA患者中位生存期为95.1个月，而单纯放疗组为35.2个月（p=0.022）；在GBM患者中未观察到生存期差异（p=0.10）。O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）及异柠檬酸脱氢酶（IDH）状态对预后存在影响。 结论：对于全部研究人群或GBM亚组患者，新辅助替莫唑胺治疗未展现出生存获益；但对于确诊为AA的患者，新辅助替莫唑胺治疗可使中位生存期延长5年。