Cranial Irradiation Prevents CNS Metastases in SCLC

ASCO — Brain metastasis can be prevented in advanced small-cell lung cancer (SCLC) patients by prophylactic cranial irradiation (PCI) in those who respond to chemotherapy, according to a study by the European Organization for Research and Treatment of Cancer (EORTC) Radiation Oncology and Lung Cancer Groups. Ben Slotman, MD, PhD, professor and chairman of radiation oncology at VU Medical Center, Amsterdam, The Netherlands, reported the findings at the plenary session of the 43rd Annual Meeting of the American Society of Clinical Oncology (abstract 4).

"Improvements in treatment results for patients with advanced small-cell lung cancer have been minimal in the past 2 decades. Our findings represent a significant advance. Based on these study results, we believe that patients with extensive-disease small-cell lung cancer who respond to chemotherapy should routinely be offered PCI," Dr. Slotman said.

Approximately 20% of patients with advanced SCLC present with brain metastases at baseline and more than 50% develop them over 2 years. "Brain metastases have a major impact on the physical and psychological functioning of patients, Dr. Slotman said, "and response to systemic or local treatment is poor." He noted that a meta-analysis (Auperin et al, 1999) showed that PCI improved survival in limited-disease SCLC patients in complete remission.

The study included 286 extensive-disease SCLC patients who responded to four to six cycles of chemotherapy for primary disease. Patients were randomized to PCI, in doses ranging from 20 Gy/5 fractions to 30 Gy/12 fractions, or no PCI. CT or MRI of the brain was performed whenever any of the predefined key symptoms were present at baseline or during follow-up.

There were no significant differences in patient characteristics between the two arms, he said. Dr. Slotman pointed to the patients' median time since diagnosis (4.2 months in each arm) as "something to keep in mind when analyzing the survival curves," since survival was measured from the time of randomization (4 to 6 weeks after completion of four to six cycles of chemotherapy), not from the time of diagnosis or the start of chemotherapy. At the time of analysis, 89% of patients had been followed to progression or death.

Significantly fewer of the PCI-treated patients had brain metastases at 1 year from randomization: 14.6% vs 40.4%, for a 73% reduction in risk (P < .001).

The rate of symptomatic brain metastasis as the first event was 9.1% for PCI vs 35% for controls. "In nearly all cases, when symptomatic brain metastasis was the first event, it was followed by extracranial progression," Dr. Slotman said.

On the other hand, he said, extracranial disease progression was the first event in 76.2% of PCI patients vs 59.4% of controls, and was followed by brain metastases in about 10% of patients in each group.

There was no significant difference in the rate of extracranial disease progression between the two arms.

Of note, he said, PCI significantly prolonged failure-free survival and overall survival. Failure-free survival was increased from 15.5% to 23.9% at 6 months from randomization—a 24% reduction in risk with PCI (P = .02). Overall survival was increased from 13.3% to 27.1% at 1 year from randomization, for a 32% reduction in the risk of mortality (P = .003). "This was not a primary endpoint, but was one of the most important findings," Dr. Slotman said.

The treatment was well tolerated, with most adverse events being mild and manageable. The only grade 3 acute toxicity was headache in less than 5% of patients; the only grade 3 late reaction was severe headache and CNS dysfunction in three patients (2.2%).

Also of importance, Dr. Slotman said, global quality of life was not compromised by PCI treatment. Fatigue, for example, "showed some difference at 6 weeks and 3 months, but then went back to normal again," he said.