Experts discuss the implications of research that found PCI reduces brain metastases in stage III NSCLC, but does not improve overall survival.
Oncologists have been debating the implications of research on prophylactic cranial irradiation (PCI) for non–small-cell lung cancer (NSCLC) that was presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting this past June. The NVALT-11 study, published in the Journal of Clinical Oncology, posits that PCI reduces the incidence of symptomatic brain metastases in patients with stage III NSCLC compared with observation. However, no difference in overall survival (OS) was observed between the two groups.
Kenneth Rosenzweig, MD, chair of Radiation Oncology, Mount Sinai Health System, reflected on the implications of the study in an interview with Cancer Network. “This trial, and previous trials like it, have demonstrated a reduction in the development of brain metastases but no improvement in overall survival. I believe this will negatively impact the adoption of PCI, since treatments typically only become the standard of care if there is a demonstrated survival advantage,” he said.
Other experts, however, believe other benefits of PCI might warrant its use, even given the absence of data showing improved OS. “If such therapies as PCI and whole-brain radiation therapy were associated with improved CNS control and sustained cognition, there might be sufficient justification for broad administration, even in the absence of an OS advantage,” wrote Chad G. Rusthoven, MD, of the University of Colorado School of Medicine, in a correspondence to the editor also published in The Journal of Clinical Oncology.
Side effects associated with PCI should also be taken into consideration, but only to a certain extent, according to Rosenzweig. “The side effects of PCI are well documented in this report. There is certainly a decrease in quality of life immediately after PCI, which subsided for the most part. This toxicity, which is expected after cranial irradiation, should be factored into any decision making regarding the use of PCI and would not, by itself, eliminate it as a potential therapy.”
Rosenzweig went on to reflect on the overall implications of the study. “Perhaps the most significant consideration in interpreting this report is the changes that have occurred in thoracic oncology since the NVALT-11 study closed in 2015. The use of immunotherapy in the treatment of lung cancer has become standard of care. I think it’s fair to say that no thoracic medical oncologist approaches their patients today the same way they did in 2015,” he told Cancer Network.
“Durvalamab, a programmed death ligand 1 inhibitor, was recently shown to improve overall survival in patients with locally advanced NSCLC after treatment with chemotherapy and radiation. It would therefore be difficult to offer PCI to patients who are eligible for durvalamab. I think PCI may have a role in certain patients after their initial treatment for NSCLC, but most likely not the majority of patients,” Rosenzweig added.
Previous research has shown that PCI administration in localized small-cell lung cancer can boost long-term survival; thus, this approach has also been tested in localized NSCLC, with phase III studies showing decreased brain metastases but no increase in OS.
Led by De Ruysscher et al, NVALT-11 randomized 175 patients with stage III NSCLC to receive either PCI (n = 87) or observation (n = 88) following concurrent or sequential chemotherapy plus or minus surgery. The primary outcome was the development of symptomatic brain metastases at 24 months. Secondary outcomes included adverse effects, survival, quality of life, quality-adjusted survival, and healthcare costs. Median follow-up was 48.5 months (95% CI, 39–54 months).
A total of 6 of 86 (7.0%) PCI patients developed brain metastases compared with 24 of 88 (27.2%) observation-only patients (OR, 4.96; 95% CI, 1.83–15.7; P = .001). In addition, PCI significantly lengthened the time to develop symptomatic brain metastases (HR, 0.23; 95% CI, 0.09–0.56; P = .0012).
Notably, OS did not differ in the PCI and control groups, which aligned with results of other phase III trials. Additionally, PCI increased cognitive disturbance and memory impairment. With respect to quality of life, this measure decreased only during the first 3 months post–PCI treatment and then mirrored the observation group.
Of interest, 4 patients (3 in the control group and 1 in the PCI group) harbored brain metastases on imaging without neurological symptoms.
“The absence of an effect-either beneficial or deleterious-on OS may be explained by the large extent of extracranial metastases that develop, a lack of statistical power in the current studies, the too-short follow-up time in some trials, or only a marginal effect,” wrote the authors. “Another explanation for the absence of improvement in OS may be the effect of subsequent treatment of (a)symptomatic brain metastases in the observation arm-for instance, by radiosurgery.”
Experimental strategies, such as sparing of the hippocampus, pharmacologic interventions, or MRI follow-up with radiosurgery for recurrences, could decrease the frequency of neurocognitive side effects, the researchers hypothesized.
On the basis of their results, the investigators “believe that the pros and cons of PCI necessitates a shared decision process between patients and physicians about its use.”