Hippocampal-Sparing Brain Irradiation: The Future of Brain Metastases Treatment and Prevention?

Brain metastases (BMs) are frequently diagnosed in patients with SCLC and NSCLC, although the incidence is highest in SCLC.1
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 BMs are a negative prognostic factor and are associated with a decreased quality of life (QoL).2
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Therefore, it is important to prevent or to treat them early. Prophylactic cranial irradiation (PCI) significantly reduces BM incidence in both NSCLC and SCLC,1
^,5
with a hazard ratio (HR) of approximately 0.35. However, PCI comes with a 30% risk of irreversible neurocognitive decline (NCD; linked to hippocampal dose6
), resulting in a negative impact on QoL.1
^,7
^,8
After the diagnosis of BMs, treatment options depend on the number, location, and volume of the metastases; symptoms; and available systemic therapies.9
^,10
Local treatment options consist of surgery or radiotherapy (stereotactic [SRT] or whole-brain radiotherapy [WBRT]). WBRT, especially, can result in NCD.11
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To reduce the risk of neurotoxicity after PCI or WBRT, hippocampal avoidance (HA) has been evaluated, both alone and in combination with neuroprotective drugs. In the Table and below, the clinical trials evaluating HA with WBRT and PCI are summarized, and future directions are discussed.

Hippocampal-Avoidance Whole-Brain Radiotherapy (HA-WBRT)

HA-WBRT in the single-arm phase II RTOG 0933 trial showed less NCD compared with a historical WBRT cohort.13
Furthermore, data from the randomized phase III RTOG 0614 trial, although formally negative, demonstrated, as a secondary endpoint, that adding memantine to WBRT resulted in a longer time to NCD.14
Based on these promising results, the randomized phase III NRG CC001 trial was launched. In this trial, WBRT plus memantine, with or without HA, was evaluated in patients with BMs from a variety of solid malignancies. The primary endpoint was time to NCD, using the reliable change index on one of the tests. The addition of HA resulted in a significantly lower risk of NCD, with an HR of 0.74. This effect became robust at 4 months (executive functioning) and later, at 6 months (learning and memory), suggesting that patients with a life expectancy of more than 4 months would  benefit most.15

Hippocampal-Avoidance Prophylactic Cranial Irradiation (HA-PCI)

Because of a decrease in the incidence of BMs, combined with an aggregate OS benefit, PCI became standard-of-care for patients with SCLC whose disease responded to initial treatment.16
^,17
However, the role of PCI in extensive disease has been challenged on the basis of a Japanese phase III trial18
demonstrating that although the incidence of BMs decreased with PCI plus MRI follow-up compared with MRI follow-up alone, PCI alone did not result in an OS benefit. Furthermore, as stated above, PCI has been associated with a risk of NCD. To reduce this NCD, HA has also been evaluated in this setting. Recently, two randomized phase III trials (NCT01780675 and NCT02397733 [PREMER]) have been reported, with conflicting results.19
^,20
NCT01780675 did not show any difference in decline on the Hopkins Verbal Learning Test—Revised (HVLT–R) at 4 months compared with baseline; in both arms, approximately 30% of patients had HVLT–R decline. The study was powered to detect a difference of 5 points and aimed to show a 30% difference in the HVLT–R, which is specific to the function of the hippocampus, between groups at 4 months. Furthermore, for secondary neurocognitive endpoints such as motor function, processing speed, memory, executive function, and attention, no differences were found.19 In contrast, PREMER showed a significant difference in favor of the HA-PCI arm for NCD measured at 3 months by the Free and Cued Selective Reminding Test (21.7% vs. 5.1%, p = 0.01), which persisted at 6 months.20
Possible reasons for the divergent conclusions of these two trials include the method of measuring NCD, different time points for follow-up visits, or slightly different radiotherapy constraints. In addition, already impaired baseline NCD can influence these results (less benefit in more impaired patients), but these data are not yet available for NCT02397733. Compared with NRG CC001, the patients enrolled on NCT01780675 had less baseline neurocognitive impairment,21
but in the latter study, only patients with SCLC  were included. A larger phase III trial (NCT02635009, n = 392 planned) is ongoing and may close the discussion.

Future Directions

The role of WBRT is being challenged on the basis of the results of the QUARTZ trial (which showed no benefit compared with best supportive care in patients with NSCLC, and very poor prognosis),22
the increasing use of SRT for multiple BMs even in SCLC,23
as well as the introduction of systemic therapies (TKIs and immune checkpoint inhibition [ICI]) that have significantly improved OS in patients with advanced lung cancer who have also been diagnosed with BMs.24
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However, the QUARTZ trial was performed before the widespread introduction of these new systemic agents, not all patients qualify for SRT, and data on efficacy of TKIs in patients with neurological symptoms remain scarce. Because patients can obtain a prolonged survival with TKIs or ICI,24
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maintaining central nervous system function and avoiding the risk of NCD rises in importance. As delineated in the trials summarized above, it is suggested that HA-WBRT plus memantine is beneficial for patients with the expectation of prolonged survival; thus, we believe that this regimen should be evaluated prospectively, particularly in the subset of patients who will receive a TKI or ICI and whose BMs are not eligible for SRT. If SRT is feasible, the ongoing phase III NCT03550391 trial is of interest. In this trial, SRT for multiple BMs (5 to 15) is compared with HA-WBRT plus memantine in patients with a non-hematopoietic malignancy. 

ICI also appears to reduce BM incidence.27
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Because chemotherapy plus ICI is the new standard for patients with metastatic SCLC,16
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the role of PCI in this setting is even more controversial. MRI versus PCI plus MRI follow-up trials allowing ICI are ongoing (e.g., NCT04155034) and may provide answers. Another possibility that could reduce the risk of NCD is the use of low-dose PCI, as ICI and radiotherapy appear to act synergistically.29
This is currently being evaluated in stage III NSCLC in the NVALT28/PRL01 trial (NCT04597671), in which HA-PCI is allowed (but not mandated). Although BM incidence is the primary outcome, NCD is the key secondary outcome. In this trial, risk factors and predictive biomarkers for NCD are also being evaluated, as this has not been done extensively in the previous PCI trials.30

In conclusion, HA, especially when combined with memantine, may prove promising for patients with lung cancer and BMs who have a good prognosis. Future trials should specifically focus on this patient subgroup and include the evaluation of risk factors and biomarkers for NCD.

• 1. a. b. c. Pechoux CL, Sun A, Slotman BJ, et al. Prophylactic cranial irradiation for patients with lung cancer. Lancet Oncol. 2016;17:e277-e293.
• 2. a. b. Riihimaki M, Hemminki A, Fallah M, et al. Metastatic sites and survival in lung cancer. Lung Cancer. 2014;86:78-84.
• 3. Gavrilovic IT, Posner JB. Brain metastases: epidemiology and pathophysiology. J Neurooncol. 2005;75:5-14.
• 4. Roughley A, Damonte E, Taylor-Stokes G, et al. Impact of Brain Metastases on Quality of Life and Estimated Life Expectancy in Patients with Advanced Non-Small Cell Lung Cancer. Value Health. 2014;17:A650.
• 5. Witlox WJA, Ramaekers BLT, Zindler JD, et al. The Prevention of Brain Metastases in Non-Small Cell Lung Cancer by Prophylactic Cranial Irradiation. Front Oncol. 2018;8:241.
• 6. Ma TM, Grimm J, McIntyre R, et al. A prospective evaluation of hippocampal radiation dose volume effects and memory deficits following cranial irradiation. Radiother Oncol. 2017;125:234-240.
• 7. Li J, Bentzen SM, Li J, et al. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys. 2008;71:64-70.
• 8. Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys. 2013;86:656-664.
• 9. Planchard D, Popat S, Kerr K, et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:iv192-iv237.
• 10. NCCN guidelines Non-Small Cell Lung Cancer. version 4.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
• 11. Greene-Schloesser D, Robbins ME. Radiation-induced cognitive impairment—from bench to bedside. Neuro Oncol. 2012;14(suppl 4):iv37-44.
• 12. Saad S, Wang TJ. Neurocognitive Deficits After Radiation Therapy for Brain Malignancies. Am J Clin Oncol. 2015;38:634-640.
• 13. a. b. Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014;32:3810-3816.
• 14. a. b. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol. 2013;15:1429-1437.
• 15. a. b. c. 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;38:1019-1029.
• 16. a. b. Dingemans A-MC, Früh M, Ardizzoni A, et al. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32:P839-853.
• 17. a. b. NCCN guidelines Version 3.2021 Small Cell Lung Cancer. Available at https://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf.
• 18. Takahashi T, Yamanaka T, Seto T, 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;18:663-671.
• 19. a. b. Belderbos J, De Ruysscher D, De Jaeger K, et al. Phase III randomized trial of Prophylactic Cranial Irradiation with or without Hippocampus Avoidance in SCLC (NCT01780675). J Thor Oncol. 2021;16:840-849.
• 20. a. b. c. De Dios N, Murcia M, Counago F, et al. Phase III trial of prophylactic cranial irradiation with or without hippocampal avoidance for small-cell lung cancer. Int J Radiat Oncol. 2019;105:S35-S36.
• 21. Belderbos J, De Ruysscher D, De Jaeger K, et al. Why Did the Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampus Avoidance in SCLC Not Reveal a Difference? J Thor Oncol. 2021;16:E42-E45.
• 22. Mulvenna P, Nankivell M, Barton R, et al. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016;388:2004-2014.
• 23. 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. JAMA Oncol. 2020;6:1028-1037.
• 24. a. b. Schoenmaekers J, Paats MS, Dingemans A-MC, et al. Central nervous system metastases and oligoprogression during treatment with tyrosine kinase inhibitors in oncogene-addicted non-small cell lung cancer: how to treat and when? Transl Lung Cancer Res. 2020;9:2599-2617.
• 25. a. b. Henon C, Remon J, Hendriks LE. Combination treatments with immunotherapy in brain metastases patients. Future Oncol. 2020;16:1691-1705.
• 26. a. b. Chen Y, Paz-Ares L, Dvorkin M, et al. First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC (CASPIAN): Impact of brain metastases on treatment patterns and outcomes. J Clin Oncol. 2020;38:S9068.
• 27. Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018;379:2342-2350.
• 28. Higgins K, Curran W, Liu S, et al. Patterns of disease progression after carboplatin/etoposide + atezolizumab in extensive-stage small-cell lung cancer (ES-SCLC). Int J Radiat Oncol. 2020;108:1398.
• 29. Vanneste BGL, Van Limbergen EJ, Dubois L, et al. Immunotherapy as sensitizer for local radiotherapy. Oncoimmunology. 2020;9:1832760.
• 30. Zeng H, Hendriks LEL, van Geffen WH, et al. Risk factors for neurocognitive decline in lung cancer patients treated with prophylactic cranial irradiation: A systematic review. Cancer Treat Rev. 2020;88:102025.