A Phase 3 Trial of Whole Brain Radiation Therapy and Stereotactic Radiosurgery Alone Versus WBRT and SRS With Temozolomide or Erlotinib for Non-Small Cell Lung Cancer and 1 to 3 Brain Metastases: Radiation Therapy Oncology Group 0320

Abstract

Background A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the bloodbrain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. Methods and Materials NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy×15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m2/day× 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150–200 mg/m2/day ×5 days/month) could be continued for as long as 6 months after WBRT þ SRS. The primary endpoint was OS. Results After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT þ SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). Conclusion The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.

Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO)

“…73,74 A phase II study from China has reported that the combination of WBRT and erlotinib has tolerable toxicities, and suggested a prolonged PFS and OS (class IIb). 75 Conversely, phase II (class IIa and b) 76,77 and phase III (class I) 78 trials in patients with NSCLC brain metastases not enriched for EGFR mutations failed to demonstrate a superiority of the combination of erlotinib with either SRS or WBRT over radiotherapy alone, with a suggestion of worse outcome in patients receiving the combined therapy. A Chinese phase II trial of WBRT with concurrent icotinib, another EGFR inhibitor, has suggested that the combination could improve survival compared with historical controls.…”

Concurrent Whole Brain Irradiation With or Without Temozolomide in Treatment of Brain Metastases From Breast Cancer.

“…However, individually, only one out of 7 randomized controlled trials RCTs included in this meta-analysis showed a some survival improvement following the addition of temozolomide to radiotherapy, with median survival times of 7and 8.6 months in the RT arm and TMZ plus RT arm, respectively (15). In four randomized controlled trials that compare radiotherapy to concomitant TMZ and RT, the OS was lower in patients who were treated with combination TMZ and RT (11,(19)(20)(21) It is hard to compare the results of our study, that was performed on a homogenous group of patients ;with the previously mentioned studies which included more heterogeneous groups of patients and with different treatment regimens.…”

A hybrid volumetric dose verification method for single‐isocenter multiple‐target cranial SRS

“…All plans used A 6 MV flattening filter free beam with the maximum repetition rate of 1400 MU/min and were calculated with 2° CP increment and a 2 mm isotropic dose grid resolution. The prescriptions followed RTOG 0320 protocol,24 depending on the target size: 24 Gy to the planning target volume (PTV) <2 cm, 18 Gy to the PTV between 2.1–3 cm, and 15 Gy to the 3.1–4 cm PTV. Plans 4‐6 also employed common OAR objectives from the same protocol.…”