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. 2025 Aug 11:JCO2500221.
doi: 10.1200/JCO-25-00221. Online ahead of print.

Hippocampal Avoidance During Prophylactic Cranial Irradiation for Patients With Small Cell Lung Cancer: Randomized Phase II/III Trial NRG-CC003

Vinai Gondi  1 , Stephanie L Pugh  2   3 , Minesh P Mehta  4 , Jeffrey S Wefel  5 , Wolfgang A Tomé  6 , Alexander Y Sun  7 , John Grecula  8 , Kristin J Redmond  9 , Shannon Fogh  10 , Laurie Gaspar  11 , Andre Konski  12 , Joseph Bovi  13 , Clifford G Robinson  14 , Benjamin Corn  15 , Gregory M Videtic  16 , Benjamin H Lok  7 , Harold A Yoon  17 , John H Heinzerling  18 , Albert S DeNittis  19 , Ronald C McGarry  20 , Kiran Devisetty  21 , Vijayananda Kundapur  22 , Abraham J Wu  23 , Edward C McCarron  24 , Isabelle Thibault  25 , Edmund L Simon  26 , Andrew M Baschnagel  27 , Samir Narayan  28 , Jondavid Pollock  29 , Rebecca Paulus  2   3 , Lisa A Kachnic  30 ; NRG Oncology
Affiliations

Hippocampal Avoidance During Prophylactic Cranial Irradiation for Patients With Small Cell Lung Cancer: Randomized Phase II/III Trial NRG-CC003

Vinai Gondi et al. J Clin Oncol. .

Abstract

Purpose: Hippocampal avoidance (HA) during therapeutic whole-brain radiotherapy reduces the risk of neurocognitive function (NCF) toxicity in patients with brain metastasis. This trial hypothesized that HA during prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) leads to noninferior intracranial relapse (ICR) and reduction in NCF toxicity.

Methods: This randomized phase II/III trial enrolled patients with SCLC, no brain metastases, and response to chemotherapy. The primary end points were 12-month ICR (noninferiority design, randomized phase II) and 6-month Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) failure (phase III). Secondary end points were failure in any NCF test, health-related quality of life (HRQOL), overall survival (OS), and toxicity.

Results: From December 2015 to June 2022, 393 patients were randomly assigned. The median age was 64 years. Stage and memantine usage were balanced. The median follow-up was 17.0 months (all patients) and 30.8 months (alive patients). HA-PCI had noninferior 12-month ICR rate (PCI 14.8% v HA-PCI 14.7%, P < .0001). Six-month HVLT-R DR deterioration was not significantly different (PCI 30.0% v HA-PCI 25.5%, P = .28). Addition of HA to PCI reduced the risk of failure in any NCF test (adjusted hazard ratio [HR], 0.78; 95% CI [0.61 to 0.99]; P = .039). Addition of HA to PCI was not associated with longitudinal change in any HRQOL domain. There were no differences in OS (adjusted HR, 0.88 [95% CI, 0.67 to 1.14]; P = .33) or grade ≥3 toxicity (PCI 31.4% v HA-PCI 30.7%, P = .88).

Conclusion: Although the study did not meet its primary end point of DR preservation, HA during PCI reduces the risk of overall neurocognitive toxicity with noninferior ICR risk and similar survival.

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Figures

Figure 1
Figure 1
CONSORT Diagram.
Figure 2
Figure 2
(A) Time to intracranial relapse and (B) Overall survival. PCI, prophylactic cranial irradiation; HA-PCI, hippocampal avoidant prophylactic cranial irradiation.
See this image and copyright information in PMC

References

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