Should Prophylactic Cranial Irradiation Be Used in Patients with Stage III Non-Small Cell Lung Cancer?

This is an evaluation of PCI in stage III Non-Small-Cell Lung Cancer.  While the incidence of symptomatic brain metastases is reduced, neurological toxicity is increased and no effect on survival is demonstrated. This trial reconfirms that routine administration of PCI is not a current standard of care. Read the associated article by De Ruysscher et al on JCO.org. This JCO Podcast provides observations and commentary on the JCO article 'Prophylactic Cranial Irradiation (PCI) Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer (NSCLC): A Randomized Phase III NVALT-11/ DLCRG-02 Study' by De Ruysscher et al. My name is Everett Vokes, and I am the Chairman and Professor of Medicine at the University of Chicago in Chicago, United States of America. My oncologic specialty is head and neck and lung cancer. De Ruysscher et al present a randomized trial evaluating the role of prophylactic cranial irradiation, referred to as PCI in this podcast, in patients with stage III non-small-cell lung cancer treated with curative intent. In doing so they have addressed an important issue. Brain metastases are a frequent site of treatment failure and can occur in isolation from additional system disease. It has been postulated that PCI could prolong survival and disease-free survival. In localized small-cell lung cancer, PCI has already been shown to decrease the incidence of brain metastases by about 50% with an impact on long-term survival. However, it is well established that PCI can lead to neurocognitive decline associated with reduced quality of life. Specifically, the authors initially staged patients with a contrast enhanced brain CT or MRI and randomized patients to observation or PCI after concurrent or sequential chemoradiotherapy with or without surgery. Patients were randomized 1:1; PCI was designated to start at a maximum of 6 weeks after the last chemoradiotherapy and could be given as 36 Gy in 18 fractions, 30 Gy in 12 fractions or 30 Gy in 10 fractions. Patients were then monitored for disease progression including symptomatic brain metastases within 24 months from the time of randomization as primary endpoint. Quality of life measurements were performed as well. Key symptoms were defined as signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures and focal neurological symptoms. MRI or CT was triggered by such symptoms. The initial goal was to randomize 300 patients. However, accrual was slow and was decreased to 175 randomized patients overall. Between 2009 and 2012, 195 patients were registered, 175 were randomized, 87 to PCI and 88 to observation. The proportion of patients developing symptomatic brain metastases two years after therapy was 7% in the PCI group and 27% in the control group. This compares to a historical average of approximately 30%. PCI thus did decrease the cumulative incidences of symptomatic brain metastases. However; neurological adverse events were also increased. In particular, grade I-II memory impairment and cognitive disturbance were significantly increased in the PCI arm. Non-neurologically events such as alopecia, fatigue and headache were also significantly more frequent in the PCI group. When evaluating patient reported adverse events, headache was reported to occur significantly more frequently in the PCI arm. Of interest, neurological side effects tended to increase over time after PCI whereas non-neurological adverse events were highest during PCI and decreased over time. Overall survival at median follow-up of 51 months was not improved, with a hazard ratio of 0.9. PCI did significantly increase time to develop brain metastases, and the median progression-free survival was slightly longer at 12.3 versus 11.5 months in the PCI group, but again this was not statistically significant.. Overall, this study does demonstrate that PCI can significantly reduce the incidence of symptomatic brain metastases in patients with stage III non-small cell lung cancer. However, this comes at the cost of increased neurological adverse events even though most of these were mild in nature. Furthermore, an impact on overall survival was not demonstrated. It could be argued that this study was somewhat small and that a larger study could have shown a more pronounced effect, especially on progression-free survival, which did show a trend favoring PCI. On the other hand, symptomatic brain metastases nowadays can be treated at the time of recurrence with SBRT and other modern radiotherapy techniques. In addition, the recent durvalumab trial (PACIFIC) demonstrating that consolidation durvalumab can increase progression-free survival also demonstrated a reduction in brain metastases in durvalumab treated patients, suggesting that improved systemic therapy may emerge as a better approach to tackling the clinical problem of brain metastases in stage III NSCLC. So is PCI a recommended standard of care for patients with stage III NSCLC? While I congratulate the authors on conducting this ambitious and randomized trial addressing an important key question, my answer is no. Treatment with durvalumab is an evolving new standard and neurological side effects of PCI are not to be ignored. Treating patients with cranial radiation at the time of actual progression seems like the better approach in the meantime. This concludes this JCO Podcast. Thank you for listening.