In my last few weeks as a GRACE guest faculty, I have been struck by the number of forum discussions that deal with brain metastases. Brain metastases are a growing problem in non-small cell lung cancer (NSCLC), as well as in multiple other cancers. Why is this? Twenty years ago, patients who developed brain metastases were usually at the end-stage of their cancer, with widely metastatic disease and few systemic treatment options. The prognosis for these patients was very poor, but not really because of the brain metastases. Brain metastases were simply a marker that the cancer was taking over and patients often were on hospice care at that point. Some of the fatalism of those days still holds over to today, but the clinical picture of a patient with brain metastases has changed dramatically.
Now, we have many more effective systemic therapies. Unfortunately, most of those therapies do not penetrate the blood-brain barrier (BBB) very well. The brain thus becomes a "sanctuary site" for cancer cells, where they can hide out and start to grow while the cancer cells in the rest of the body are susceptible to chemotherapy or targeted therapies. I am increasingly seeing brain metastases in stage IV patients with good control of cancer in the rest of their body. I am also seeing more patients with earlier stage lung cancer where the brain is the only place that the cancer has relapsed. This is particularly true of patients with locally advanced (stage III) NSCLC. And this was the motivation behind a rather disappointing trial that was presented at ASCO recently.
Patients with stage III lung cancer have very high rates of brain metastases. Published studies show rates of brain metastases of 30-55%. More importantly, up to 30% of patients have brain metastases as the first site of recurrence. Even though many patients do well with treatment for brain metastases, it would certainly be desirable to prevent this from happening. In small cell lung cancer (SCLC), for instance, prophylactic cranial irradiation (PCI) is now standard practice for both limited-stage and extensive stage patients. Not only does PCI decrease the incidence of brain metastases but it improves survival in SCLC, another disease where the brain is a common site of relapse.
The investigators of tthe trial by the Radiation Therapy Oncology Group (RTOG 0214) hoped that similar results would emerge for patients with locally advanced NSCLC. The trial included patients with stage IIIA and IIIB NSCLC who had undergone treatment and had not progressed with their initial treatment (chemoradiation for most, with 1/3 of patients having undergone surgery). The primary endpoint of the trial was overall survival. Secondary endpoints included disease-free survival, incidence of CNS metastases, neurocognitive function, and quality of life. The trial was designed with a target accrual of 1058. This target accrual for a clinical trial is calculated by statisticians as the number needed to accurately access your hypothesis. Unfortunately, accrual of patients was VERY slow, and though the trial was open for six years, only 356 patients were enrolled. For this reason, the trial closed early.
Result showed no difference in overall survival or disease-free survival, but there was a statistically significant decrease in the risk of developing brain metastases among recipients of PCI. Specifically, the incidence of brain metastases was 7.7% for those who received PCI versus 18% for those who did not over the twelve months of follow-up. As had been previously observed, patients with non-squamous histologies were at higher risk of brain metastases.
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The results on quality of life and neurocognitive function have not yet been reported but should be available soon.
I think this trial demonstrates clearly that the prevention of brain metastases is an area we need to focus on in the coming years. Is PCI the answer in NSCLC? We will probably never know for sure. It is difficult to convince patients to undergo brain radiation with the idea that it might prevent brain metastases, particularly if they are just starting to feel better as the recover from very challenging combined modality therapy of chemo and chest radiation. It appears that PCI prevents relapse in the brain in a minority of patientswhile the majority would receive the therapy without it helping. Is it worth it without a survival benefit and when radiation is available if and when a patient develops brain metastases? While acute toxicity of PCI was low in this study (hair loss, skin reactions and fatigue are most common), we don’t yet have data on quality of life and neurocognitive function, which is something that many patients are concerned about as a potential complication.
I think we need to focus on finding molecular markers that predict for brain metastases. Then we can focus on treating patients who are at higher risk, potentially with PCI. Better yet, I hope that our knowledge of molecular markers that predict brain metastases will lead to effective systemic therapies that can enter the brain without much toxicity.
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