Editor’s Note: This is Part 1 of a series on the NRG-CC003 trial, specifically regarding prophylactic brain irradiation and stereotactic brain radiotherapy for metastases. Part 1 discusses incorporating HA-PCI as an emerging strategy to mitigate PCI-related neurotoxicity. Stay tuned for Part 2 in the coming weeks.
For decades, small-cell lung cancer (SCLC) has been considered the model for the central nervous system (CNS) as a sanctuary site of the disease. The historical reliance on whole-brain radiotherapy (WBRT), either prophylactically (PCI) after response to systemic therapy or therapeutically for established brain metastases, was justified by SCLC’s high predilection for multifocal CNS dissemination.1,2,3 Yet this approach carries a well-documented risk of neurocognitive toxicity.4 Contemporary strategies increasingly seek to protect the normal brain while maintaining disease control, driven by the availability of high-resolution MRI surveillance, neuroprotective pharmacology (e.g., memantine), and conformal techniques that spare eloquent structures.5,6
Recent prospective data provide timely guidance: the randomized NRG-CC003 trial evaluated hippocampal avoidance during PCI (HA-PCI), and a prospective phase II study tested stereotactic radiosurgery (SRS/SRT) as initial therapy for 1-10 SCLC brain metastases under intensive MRI surveillance.7,8 Together, these trials add new data to clinical decision-making and clarify trade-offs between intracranial control and preservation of cognitive function.
The Case for Hippocampal Avoidance During PCI
NRG-CC003 was a randomized phase II/III study enrolling adults with SCLC who had no brain metastases on protocolized volumetric MRI and who had responded to chemotherapy (with or without thoracic radiotherapy). Patients were randomly assigned to standard PCI versus HA-PCI with a prescription of 25 Gy in 10 fractions.
The phase II primary endpoint tested 12-month intracranial relapse (ICR) for noninferiority, and the phase III primary endpoint assessed Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall at 6 months. Secondary endpoints included failure in any neurocognitive function (NCF) test, health-related quality of life (HRQOL), overall survival (OS), and toxicity. Rigorous credentialing and real-time central plan review ensured quality control of hippocampal sparing across participating centers.
From 2015 to 2022, 393 patients with limited or extensive SCLC were randomized. Median age was 64. HA-PCI achieved noninferior 12-month ICR (PCI 14.8% vs. HA-PCI 14.7%; one-sided noninferiority p < 0.0001). The phase III primary endpoint, 6-month HVLT-R Delayed Recall deterioration, did not differ significantly (PCI 30% vs. HA-PCI 25.5%; p = 0.28). Notably, HA-PCI reduced the risk of failure in any NCF test (adjusted hazard ratio [HR] 0.78, 95% CI 0.61–0.99; p = 0.039), with no differences in OS (adjusted HR 0.88, 95% CI 0.67–1.14; p = 0.33), HRQOL, or grade ≥ 3 toxicity (31.4% vs. 30.7%; p = 0.88).
Although the primary endpoint of the study was not met, these data suggest HA-PCI may be considered a brain-sparing alternative for patients who elect prophylactic irradiation, achieving comparable ICR while lowering overall neurocognitive toxicity risk in some dimensions.
The NRG-CC003 results align with the broader experience that hippocampal-sparing techniques can mitigate the neurocognitive footprint of WBRT without compromising disease outcomes when implemented carefully. Prior work established the biological plausibility of hippocampal sensitivity (impact on neural progenitor cells) and the feasibility of hippocampal-sparing planning.
In a multicenter phase III trial (PREMER), Rodríguez de Dios et al. (2021) showed that HA-PCI led to significantly less decline in delayed recall at 3 months (5.8% vs. 23.5% with standard PCI). HA-PCI patients had better preservation of multiple memory scores up to 6–24 months, with no increase in brain metastases or difference in OS.9 The NRG-CC003 trial confirmed that although the primary endpoint (6-month Hopkins Verbal Learning Test recall) was not met, HA-PCI significantly reduced overall neurocognitive failure without compromising 12-month intracranial control, and no differences in OS or high-grade toxicity were observed.
By contrast, an earlier Dutch phase III trial (Belderbos et al., 2021) did not find a statistically significant cognitive benefit for HA-PCI at 4 months (28% vs. 29% memory decline), despite similar 2-year brain metastasis rates (16-20%).10 Differences in cognitive assessments, lack of memantine use, and sample size may have explained the discrepant findings. Importantly, each of these studies showed that sparing the hippocampus did not increase brain failure risk.
Given these data, incorporating HA-PCI (with modern planning techniques like IMRT/VMAT) is an emerging strategy to mitigate PCI-related neurotoxicity, although the magnitude of benefit seems modest at best.
References:
- 1. Kepka L, Socha J, Sas-Korczynska B. Radiotherapy for brain metastases from small-cell lung cancer in distinct clinical indications and scenarios. J Thorac Dis. 2021 May;13(5):3269–78.
- 2. Aupérin A, Arriagada R, Pignon JP, Le Péchoux C, Gregor A, Stephens RJ, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476–84.
- 3. Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664–72.
- 4. Wilke C, Grosshans D, Duman J, Brown P, Li J. Radiation-induced cognitive toxicity: pathophysiology and interventions to reduce toxicity in adults. Neuro Oncol. 2018 Apr 9;20(5):597–607.
- 5. Gleim N, Turcas A, Minniti G, Grosu AL, Kazda T, Harat M, et al. Neuroprotection in radiotherapy of brain metastases – a European pattern-of-care analysis by the ESTRO CNS Focus group. Radiother Oncol. 2025 Aug;209:111000.
- 6. Takahashi T, Yamanaka T, Seto T, Harada H, Nokihara H, Saka H, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 May;18(5):663–71.
- 7. Gondi V, Pugh SL, Mehta MP, Wefel JS, Tomé WA, Sun AY, et al. Hippocampal Avoidance During Prophylactic Cranial Irradiation for Patients With Small Cell Lung Cancer: Randomized Phase II/III Trial NRG-CC003. J Clin Oncol. 2025 Aug 11;JCO2500221.
- 8. Aizer AA, Tanguturi SK, Shi DD, Catalano PJ, Shin KY, Ricca I, et al. Stereotactic Radiosurgery in Patients With Small Cell Lung Cancer and 1-10 Brain Metastases: A Multi-Institutional, Phase II, Prospective Clinical Trial. J Clin Oncol. 2025 Sep 20;43(27):2986–97.
- 9. Rodríguez de Dios N, Couñago F, Murcia-Mejía M, Rico-Oses M, Calvo-Crespo P, Samper P, et al. Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study. J Clin Oncol. 2021 Oct 1;39(28):3118–27.
- 10. Belderbos JSA, De Ruysscher DKM, De Jaeger K, Koppe F, Lambrecht MLF, Lievens YN, et al. Phase 3 Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampus Avoidance in SCLC (NCT01780675). J Thorac Oncol. 2021 May;16(5):840–9.
