Adjuvant Whole Brain Radiotherapy vs. Observation after Radiosurgery or Surgical Resection of 1–3 Cerebral Metastases - Results of the EORTC 22952-26001 Study

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

The EORTC conducted a Phase III trial to define the role of adjuvant whole brain irradiation (WBRT) after local treatment (surgery [S] or radiosurgery [RS]) of a limited number of brain metastases in solid tumors with stable systemic disease. It was hypothesized that WBRT would increase the duration of functional independence by reducing the number of intracranial relapses.

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Materials/Methods 

Patients eligible for RS had 1–3 metastases of solid tumors (SCLC excluded) ≤3.5 cm in diameter (≤2.5 cm for 2–3 lesions) located outside the brainstem. For S, a complete resection of the metastatic lesions was mandatory. Only patients with no or stable systemic disease or with asymptomatic primary tumors and in good condition (WHO PS 0–2) were allowed. Patients were randomized to receive either WBRT or observation (OBS). Primary endpoint was survival with functional independence measured by the survival time with WHO PS ≤2. Secondary endpoints were time to intracranial progression, frequency of neurologic death, and overall survival. Analysis is by intent-to-treat (log–rank, two-sided a = 0.05).

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Results 

From 1996 to 2007, 359 patients were recruited, 353 were eligible. A total of 160 patients had resection of one (96%) or two (4%) metastases, and 185 (of 199 scheduled patients) had RS (marginal dose 20 Gy, target dose 25 Gy) of one (67%), two (23%), or three (10%) lesions. Adjuvant whole brain irradiation (30 Gy/10 fractions) was given to 166/180 patients, (92%) in the WBRT and to 4/179 patients (2%) in the OBS arm. Median survival time with WHO PS ≤2 was 10.0 months (95% CI, 8.1–11.7) in the OBS arm and 9.5 months (95% CI, 7.8–11.9) in the WBRT arm (p > 0.5). It was only significantly influenced by initial WHO PS and initial systemic disease status (p < 0.01). Overall survival was 10.9 months in the OBS and 10.7 months in the WBRT arm (p > 0.5). Cumulative incidence of intracranial progression at 6 and 24 months was 39.7% (95% CI, 32.5–46.8) and 54.2% (95% CI, 46.9–61.5) of the OBS patients, but only 15.2% (95% CI, 9.9–20.4) and 31.2% (95% CI, 24.4–38.0) of the WBRT patients. Both relapses at sites treated initially with S or RS (incidence at 24 months 31.3% vs. 16.4%) and at new intracranial sites (32.4 vs. 17.6%) were significantly reduced (p < 0.0001). In the RS group, 25/185 (14%) patients had radiologic signs of blood–brain barrier damage. Intracranial progression was a cause of the death in 77/179 patients (43%) of the OBS group and in 45/180 patients (25%) of the WBRT group.

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Conclusions 

After radiosurgery or surgery of a limited number of brain metastases, adjuvant whole brain radiotherapy reduces the frequency of intracranial relapses at both initially treated and new sites, and minimizes the risk of neurologic death. However, it fails to prolong the time period of functional independence and overall survival time.