Yuchao Ma¹, Ye Zhang², Nan Bi², Di Liu², Yingjie Xu², Hongmei Zhang², Junling Li², Yexiong Li²

¹Radiation Oncology, CancerHospital, Chinese Academy of Medical Sciences and Peking union          Medical College,

²Cancer Hospital, ChineseAcademy of Medical Sciences and Peking union   Medical College.

Objective: A prospective phase II trial was conductedto investigate the feasibility and safety of fractionated stereotacticradiotherapy (FSRT) combined with temozolomide (TMZ) for refractory brainmetastases. 

Method: Patients with ≥3 lesions (group A), the volume ofthe largest lesion ≥6cc (group B) or meningeal metastases (group C) wereenrolled. FSRT with or without whole brain radiotherapy (WBRT) was given to thepatients. The regular fractionation regimens of group A were 24Gy/24 Gy/1f, 36Gy/12Gy/3f or 40-48Gy/8-10 Gy/6-4f, depending on the volume and location of thelesions. In group B, the most common fractionation regimen was 52-52.5Gy/3-3.5 Gy/13-15f.While in group C, all patients were treated by WBRT 40-50 Gy/20-25f and boostedto 50-60Gy with FSRT for gross tumor. TMZ was administrated 75mg/m2concurrently, followed by 6 cycles of adjuvant TMZ (150mg/m2/d,d1-5, q28d) if necessary. The response was assessed by MRI after 2-3 monthsfrom treatment according to RTOG9508 criteria. Toxicity was recorded accordingto the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). The primary end point was local control (LC), and thesecondary end points were intracranial progression-free survival (PFS) andoverall survival (OS). Kaplan-Meier method was used.

Result: From 2010 to 2014, 56 patients (Male:female=27:29) were enrolled. The median age was 54 years old (range, 35-73).The major primary diagnosis was non-small cell lung cancer (66.1% patients).Twenty patients were group A (35.7%), 28 patients group B (50.0%), and 8patients group C (14.3%). The median number of lesions was 3(range, 1-22), andthe median gross tumor volume (GTV) was 10.63cc (0.62-142.81cc). FSRT wasadministrated as initial treatment (33 patients, 58.9%) and salvage treatment(23 patients, 41.1%). In group A, 9 patients (45.0%) had ≥5 lesions. In groupB, large-volume lesion with small-volume lesion took up 16/28 (57.1%), and themedian GTV was 18.4cc (6.00-142.81cc). The completion rates of concurrent andadjuvant TMZ were 100% and 35.7%. The median follow-up time was 15 months(range, 2-61 months). The CR+PR+SD rate was 98.2% (55/56). For all groups, themedian time of LC, intracranial PFS and OS were 13.5, 10.5 and 15 months,respectively. The 1-year LC, PFS and OS were 94.1%, 73.0%, and 63.2%,respectively. In group A, the median time of LC, intracranial PFS and OSwere 24, 18 and 24months, respectively. In group B and C, the results were 10,7.5, 10 months and 8.5, 8.5, 8.5months. In group B, 18 patients (64.3%)acquired replanning during the treatment, and the median volume shrinking ratewas 44.0% (7.0%-91.0%). The main toxicities were grade 1-2 nausea and vomiting,2 patients with grade 3 liver-function impairment, and 2 patients with grade 3myelosuppression.

Conclusion:FSRT combined with TMZ represents a safeand effective option for patients with refractory brain metastases. More than50 percent patients with large lesions may need replanning to reduce the riskof normal tissue damage.

Key Words: Refractory, BrainMetastases, FSRT Temozolomide