Brown Details the Evolving Role of PCI and HA-PCI in Small Cell Lung Cancer

As cognitive dysfunction remains a concern for patients with extensive-stage (ES) and limited-stage (LS) small cell lung cancer (SCLC) who are treated with prophylactic cranial irradiation (PCI), hippocampal avoidance-PCI (HA-PCI) is a way to improve the therapeutic ratio, according to a presentation by Paul D. Brown, MD, at The Radiation Oncology Summit: ACRO 2024.

“PCI decreases the rate of brain metastases but there are cognitive risks,” Brown, a radiation oncologist at Mayo Clinic in Rochester, Minnesota, said. “HA-PCI improves the therapeutic ratio [and regarding] MRI surveillance and salvage [therapy] vs HA-PCI, ongoing trials are looking at that.”

PCI was first proposed in the 1970s as the increased risk of brain metastases in patients with SCLC was recognized. PCI became the standard-of-care (SOC) for LS-SCLC in 1999 after findings from a meta-analysis revealed a 35% increase in overall survival (OS) at 3 years with PCI, and it later became a SOC for those with ES-SCLC following data from the phase 3 EORTC RCT trial (NCT00016211), which showcased an OS benefit with PCI (P = .003). However, the NCCN made PCI optional for those with ES-SCLC in 2017 and recommended MRI surveillance.

Moreover, Brown highlighted that there are “no randomized data evaluating MRI surveillance with or without PCI in LS-SCLC [and] additional data [are] needed to resolve equipoise regarding PCI in ES-SCLC. Modern studies [are] needed,” he noted, adding that immunotherapy may reduce the brain metastases rate.

Brown cited a meta-analysis of 109 studies including 56,770 patients who received MRI screening with or without PCI and noted that randomized trials, such as the phase 3 MAVERICK (NCT04155034) and the PRIMA-LUNG (NCT04790253) studies, are currently recruiting patients and further evaluating MRI surveillance with or without PCI in LS-SCLC and ES-SCLC. In MAVERICK patients with no prior brain metastases and no brain metastases on MRI after first-line therapy will be stratified by limited vs extensive disease, if they received immunotherapy, and performance status. MRI surveillance is scheduled at 3, 6, 9, 12, 18, and 24 months, and radiation therapy is recommended at the time of brain metastases.

Brown explained that regarding improving the therapeutic ratio with an improvement in efficacy and decrease in toxicity, “with PCI, we've [attempted] to improve efficacy. PCI99 looked at doing a higher dose of PCI 36 Gy vs standard dose 25 Gy in 10 [fractions] and had no improvement in survival with the higher dose, if anything had worse cognitive outcomes. That's not going to work for us. We can’t improve the therapeutic ratio by getting better brain control, so how about decreasing toxicity? Well, one way to do that might be to do HA-PCI.”

Notably, no difference in OS was observed in a phase 3 study (NCT01780675) that evaluated RCT PCI vs HA-PCI or in the phase 3 PREMER study (NCT02397733) which evaluated the same regimen, both in patients with SCLC. In PREMER, cognitive preservation was improved with HA-PCI at 3 and 6 months in 118 patients whereas it was not in the other phase 3 study at 4 or 8 months in 168 patients.

The phase 2/3 NRG CC003 trial (NCT02635009) comparing PCI with HA-PCI in patients with SCLC is currently underway to further evaluate the role of HA-PCI given at 25 Gy in 10 fractions.

Background on Cognitive Dysfunction With PCI

Brown cited the MD Anderson Cancer Center Prospective NP study, which was published in 1995 and found that, prior to PCI, 97% of patients had cognitive dysfunction. The dysfunction most frequently manifested in terms of verbal memory, followed by frontal lobe dysfunction and fine motor incoordination.

“This is something I've seen in my practice with SCLC before patients even get to PCI,” Brown said. “I've always wondered, what's the cause [and] it’s likely multifactorial—it can be smoking history [and] the disease process itself definitely plays a role. A small subset of the patients underwent further cognitive testing after the PCI, and they saw that their cognitive function was stable over time. To my knowledge, there's been 2 randomized studies of PCI vs no PCI.”

In the first study, PCI 85, at 2 years 40% of patients who received PCI of 24 Gy in 8 fractions (n = 149) had brain metastases compared with 67% for those who did not receive PCI (n = 151).

“[There was] no difference in survival, [but there was] a trend in the survival benefit with the addition of PCI. What we’re interested in is cognitive outcomes [and there wasn’t] a difference between the 2 groups—some areas would favor the PCI groups and some cognitive domains would favor the observation group,” Brown said. “They didn't see any difference between emerging cognitive outcomes or quality of life [in this study].”

In the PCI 85 study mood and walking both favored the PCI-treated group whereas higher functions, cerebellar function, and cranial nerves favored the no PCI group.

Reference

Brown, P. CNS disease in SCLC: Conflicting trial results, how do we go forward? Presented at: The Radiation Oncology Summit: ACRO 2024; March 13-16, 2024; Orlando, Florida.