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PREMER Trial – Hippocampal Avoidance in Prophylactic Cranial Irradiation in Small Cell Lung Cancer – Guidance and Discussion Topics

October 13, 2021

Prophylactic cranial irradiation (PCI) is considered a standard of care in limited stage-small cell lung cancer (LS-SCLC) and controversial in extensive stage-small cell lung cancer (ES-SCLC). PCI has often been omitted in the past due to concern for late-term neurotoxicity.

PCI has been thought to be helpful as originally established in the 1999 Auperin meta-analysis suggesting an overall survival benefit with PCI. However, in light of well-known and well-demonstrated neurotoxicity of whole brain radiotherapy (WBRT), hippocampal avoidance has emerged in recent years as an attractive strategy to maintain the therapeutic ratio in various scenarios of WBRT. Recent research efforts in SCLC have gone so far as to suggest that stereotactic radiosurgery (SRS) may be appropriate in select candidates.

This month’s #RadOnc #JC seeks to take a deep dive into the PREMER trial conducted in Spain investigating the role of hippocampal avoidance-PCI (HA-PCI) in SCLC, particularly in the modern era of advanced imaging, therapeutics, and radiotherapy. The article we will be discussing can be found here:

Rodríguez de Dios N, Couñago F, Murcia-Mejía M, 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;39(28):3118-3127. doi:10.1200/JCO.21.00639

We are grateful to have Drs. Javier Luna and Felipe Counago join us to discuss their involvement in this project, as well as Dr Vinai Gondi and Prof. Søren Bentzen to share their expert opinions and perspectives. Our conversation will begin Saturday October 16th at 8 AM CST with plans to discuss globally through the weekend. We will have our live hour on Sunday October 17th at 8 AM CST (3PM Spain). We will end at approximately 9 AM CST on Sunday October 17th.

Guiding Topics:

T1. Background: PREMER is a critical phase III trial to help us understand the use of PCI in a modern context of the changing landscape of SCLC. When and how did this trial conception originate?

T2. Background: What are the biological and pathophysiological bases for the use of PCI in SCLC? How are these different for LS-SCLC vs ES-SCLC?

T3. Methods: The primary endpoint for comparing PCI +/- hippocampus avoidance was the delayed free recall (DFR) score of the Free and Cued Selective Reminding Test (FCSRT), assessed at 3 months after end of treatment. How well has the FCSRT been validated prior to its inclusion in this trial? How does it compare to the Hopkins Verbal Learning Test (HVLT)?

T4. Methods: How was radiotherapy performed in terms of target volumes? What dose constraints were used to optimize HA-PCI? In terms of research methodology, was this a superiority trial or a non-inferiority trial?

T5. Results: What were the primary and secondary findings of the PREMER trial? How does this impact modern clinical practice of LS-SCLC?

T6. Discussion: In 1999, the Auperin meta-analysis established the superiority of PCI in LS-SCLC in those with a complete response to chemotherapy. How has the finding of this landmark study been shaped over the past 20 years?

T7. Discussion: About 70% of the patients enrolled had LS-SCLC, while 30% had ES-SCLC. Does this heterogeneous cohort of patients potentially impact the findings of the PREMER trial?

T8. Discussion: In light of NRG-CC001 being published, HA-WBRT with memantine has now been proven to preserve neurocognitive function without compromising PFS or OS in a different cohort of patients than the PREMER trial. How does this help guide decisionmaking for PCI in SCLC along with the findings of the PREMER trial?

T9. Discussion: FIRE-SCLC was a large cohort study that suggested that stereotactic radiosurgery (SRS) for SCLC was associated with a shorter time to CNS progression without a detriment in overall survival when compared to whole brain radiotherapy (WBRT). This suggests that in a carefully selected SCLC patient, SRS may be appropriate. How can SRS and/or PCI be used in CNS management of SCLC? Should it be different in LS-SCLC and ES-SCLC?

T10. Discussion: Immunotherapy has emerged as an essential tool in ES-SCLC, as in the IMPOWER-133 trial. Some immunotherapy/targeted therapy agents have CNS penetrance, as has been more commonly demonstrated in NSCLC. Will systemic therapy agents play a larger role in CNS treatment of SCLC? How may this affect the use of CNS-directed radiotherapy in SCLC?

T11. Discussion: An insightful editorial compared this trial to several others, which had conflicting results showing the neurocognitive protection provided by HA-PCI. Until results of the NRG CC-003 are published, how should HA-PCI be implemented in clinical practice for SCLC?


  1. Rodríguez de Dios N, Couñago F, Murcia-Mejía M, 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;39(28):3118-3127. doi:10.1200/JCO.21.00639
  2. Aupérin A, Arriagada R, Pignon JP, 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;341(7):476-484. doi:10.1056/NEJM199908123410703
  3. Brown PD, Gondi V, Pugh S, et al. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol. 2020;38(10):1019-1029. doi:10.1200/JCO.19.02767
  4. Rusthoven CG, Yamamoto M, Bernhardt D, et al. Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study [published correction appears in JAMA Oncol. 2020 Sep 1;6(9):1473]. JAMA Oncol. 2020;6(7):1028-1037. doi:10.1001/jamaoncol.2020.1271
  5. Liu SV, Reck M, Mansfield AS, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055
  6. Brown PD, Parsons MW, Rusthoven CG, Gondi V. Hippocampal Avoidance Prophylactic Cranial Irradiation: A New Standard of Care?. J Clin Oncol. 2021;39(28):3093-3096. doi:10.1200/JCO.21.01632
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