By Elizabeth Gore, MD
Posted: May 27, 2019
IN REFERENCE TO: De Ruysscher D, Dingemans AC, Praag J, et al. Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: A randomized phase III NVALT-11DLCRG-02 study. J Clin Oncol. 2018;36(23):2366-2377.
Dr. De Ruysscher et al. are commended for completing a well-designed phase III trial of prophylactic cranial irradiation (PCI) in patients with radically treated stage III NSCLC.1 The primary endpoint was incidence of symptomatic brain metastases at 2 years. The vast majority of patients were treated to 30 Gy in 10 or 12 fractions. The incidence of brain metastases at 2 years was 7% with PCI and 27.2% with observation (p = 0.001), consistent with the findings in RTOG 0214, another contemporary phase III study comparing PCI and observation in patients with stage III NSCLC.2 RTOG 0214 demonstrated a 1-year incidence of brain metastases of 7% with PCI versus 18% with observation (p = 0.004). Many other trials have consistently shown a decrease in brain metastases with PCI for NSCLC, although none have demonstrated improvement in overall survival. Completing a trial adequately powered to show a survival advantage has proven to be challenging for many reasons including imperfect selection criteria, physician bias, PCI toxicity, and patient reluctance to undergo randomization.
Prevention by some clinicians is viewed as less relevant now with the availability of MRI surveillance and early detection of brain metastases with effective and potentially curative treatment(s) now available. Aggressive treatment has changed the previously accepted perception of short survival once brain metastases are diagnosed. Also, trials with newer systemic therapies demonstrate blood–brain barrier penetration with decrease in the incidence of brain metastases; they can also effectively treat known metastases with the expectation of less central nervous system toxicity than PCI.
Mitigating Even the Acceptable Adverse Events from PCI
An interesting and important finding in this trial is the difference in physician- and patient-reported adverse events (AEs). Except for vomiting, all AEs were under reported by physicians relative to patients. Interestingly, fatigue and memory loss were more likely to be underreported by physicians for patients in the observation arm, emphasizing the need for patient-reported outcomes and pointing to a possible physician bias favoring observation. It has been suggested that even without improvement in survival, delay or prevention of brain metastases is clinically meaningful due to the deleterious effect of brain metastases on quality of life. In this trial, quality of life was worse at 3 months in the PCI arm and then returned to the same level as the observation arm thereafter. This occurred despite the significantly higher rate of symptomatic brain metastases in the observation arm, although it is unclear if AEs of brain metastases were captured in this analysis.
Although trials have consistently demonstrated that the toxicity of PCI is acceptable,3 toxicity remains a primary concern and limitation to the acceptance of PCI. Measures, such as use of pharmacologic agents and radiation therapy techniques that may mitigate or minimize the side effect of PCI, should be undertaken. Hippocampal avoidance (HA) whole-brain radiation therapy may play an important role based on the encouraging results of NRG CC001, which evaluated HA wholebrain radiation therapy for documented brain metastases,4 and the anticipated outcomes of a similar trial, NRG CC003 (NCT02635009), which is evaluating HA with PCI for small cell lung cancer. Additionally, careful selection of patients for PCI should incorporate known, preexisting toxicity risks including established microvascular disease, impaired baseline neurologic function, and residual side effects from primary therapy, particularly fatigue and memory impairment.
In this study, treating approximately five patients with PCI prevented one case of symptomatic brain metastases. Many more patients would need to be treated to result in cure or increased survival of even one patient. Better understanding of tumor and host factors that increase risk of brain failures will improve this ratio and perhaps identify a cohort of patients with locally advanced disease and perhaps a subset of patients with early-stage disease who are at high risk for brain metastases and for whom brain-directed therapy is clearly indicated.
PCI is effective, but there is no proven benefit in terms of overall survival, and therefore it is not currently considered standard of care. As stated by the authors, the pros and cons of PCI necessitate a shared-decision process between patients and physicians. ✦
About the Author: Dr. Gore is a professor and medical director of Radiation Oncology, Zablocki VA Medical Center, Medical College of Wisconsin
1. De Ruysscher D, Dingemans AC, Praag J, et al. Prophylactic cranial irradiation versus observation in radically treated stage III non-small-cell lung cancer: A randomized phase III NVALT-11DLCRG-02 study. J Clin Oncol. 2018;36(23):2366-2377.
2. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non–small-cell lung cancer: Primary analysis of Radiation Therapy Oncology Group Study RTOG 0214. J Clin Oncol. 2011;29(3):272-278.
3. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non–small-cell lung cancer: Neurocognitive and quality-of-life analysis. J Clin Onc. 2011;29(3):279-286.
4. Gondi V, Pugh S, Brown PD, et al. Preservation of Neurocognitive Function (NCF) with Conformal Avoidance of the Hippocampus during Whole-Brain Radiotherapy (HA-WBRT) for Brain Metastases: Preliminary Results of Phase III Trial NRG Oncology CC001. Int J Radiat Oncol Biol Phys. 2018;102(5):1607.