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

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

Radiation Oncology
Jul 16, 2021
Lizza Hendriks
Dirk De Ruysscher
Dr. Lizza Hendriks and Dr. Dirk De Ruysscher
Lizza Hendriks, MD, PhD; Dirk De Ruysscher, MD, PhD

Brain metastases (BMs) are frequently diagnosed in patients with SCLC and NSCLC, although the incidence is highest in SCLC.1 ,2 ,3  BMs are a negative prognostic factor and are associated with a decreased quality of life (QoL).2 ,4 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 ,12 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 ,25 ,26 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 ,25 ,26 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 ,28 Because chemotherapy plus ICI is the new standard for patients with metastatic SCLC,16 ,17 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.


Table. Clinical Trials Evaluating HA With WBRT and PCI
Trial  Phase

n (% lung cancer)

Treatment Primary Endpoint Outcome Primary Endpoint


(RTOG 0933)13

II Single arm

100 (56% NSCLC)



(WBRT: 10x3Gy)

HVLT-R DR decline from baseline to 4 months

7% decline for HA-WBRT

Historical cohort (n = 208, 63% lung): 30% decline

42 analyzable patients at 4 months

NCT00566852 (RTOG 0614)14


Double blind, placebo controlled


(approx. 70% lung)

WBRT vs. memantine + WBRT


(WBRT: 15x2.5Gy)

HVLT-R DR decline from baseline to 24 weeks

Median decline 0 (WBRT + memantine) vs. -0.90 (WBRT), p = 0.059

149 analyzable patients at 24 weeks

(NRG CC001)15


(approx. 60% lung)

Memantine + HA-WBRT vs. me-mantine + WBRT


(WBRT: 10x3Gy)

Time to NCD (RCI) on at least one of the following (parts of) tests: HVLT–R, TMT, COWA

Lower risk of NCD in memantine + HA-WBRT (HR 0.74, 95% CI [0.58-0.95]), robust from 4 months

211 analyzable patients at 4 months





(all SCLC; 70% LD)


(PCI: 10x2.5Gy)

HVLT–R decline from baseline to 4 months

29% had 5 points or more decline at 4 months in HA-PCI group, 28% in PCI group (p = 1.00)

102 analyzable patients at 3 months

NCT02397733 (PREMER)20 III


(all SCLC; % LD NA)


(PCI: 10x2.5Gy

Free and Cued Selective Reminding Test decline from baseline to 3 months

21.7% for PCI vs. 5.1% for HA-PCI (p = 0.01)

Analyzable patients at 3 months unknown


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About the Authors

Lizza Hendriks

Lizza Hendriks

Dr. Hendriks is with the Department of Pulmonary Diseases, Maastricht University Medical Centre, GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands.
Dirk De Ruysscher MD, PhD

Dirk De Ruysscher

Dr. De Ruysscher is with the Department of Radiation Oncology (MAASTRO Clinic), Maastricht University Medical Centre, GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands.