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Page 8 of 11 Kepka. J Cancer Metastasis Treat 2019;5:53 I http://dx.doi.org/10.20517/2394-4722.2018.114

phase III trial of standard-dose vs. high-dose PCI for LS SCLC (RTOG0212), patients underwent evaluation
for cognitive toxicity and quality of life effects. Patients receiving the higher-dose PCI were found to have a
25% increase in the rate of chronic cognitive toxicity compared with the standard-dose arm. However, 62%
of patients receiving the standard-dose PCI also developed cognitive toxicity, as assessed by the Hopkins
Verbal Learning Test (HVLT) Delayed Recall score . These data indicate that even the standard-dose of
[45]
PCI is associated with neurocognitive toxicity. It is also argued that with the improvement of survival,
neurotoxicity has greater chance to occur and negatively impact quality of life . Thus, the strategies to
[46]
reduce neurotoxicity in PCI and WBRT warrant further investigation. One of these strategies is hippocampal
avoidance (HA) during WBRT, based on the principle that proliferating neuronal progenitor cells in the
subgranular zone of the hippocampus play an essential role in memory function. Thanks to technological
advances and the availability of IMRT techniques, PCI and WBRT for BM with HA have been extensively
explored and even used in routine practice. The RTOG 0933 trial demonstrated that HA during WBRT for
BM was associated with a mean relative decline in the HVLT-Revised Delayed Recall score from baseline
to 4 months of 7.0% (95% confidence interval, 4.7%-18.7%), which was a significant improvement compared
with the historical control (P = 0.0003) . Recently, for the first time, the benefit of HA in WBRT for BM in
[47]
terms of preservation of neurocognitive function without compromising intracranial control was confirmed
in 518 patients included in a phase III trial (NRG Oncology CC001). The 6-month neurocognitive function
failure rate was 69% after WBRT without HA compared with 58% when using HA .
[48]

However, the safety of this approach for SCLC remains to be demonstrated, because the risk of impaired
intracranial control via underdosing some parts of the brain in the HA area persists in this very aggressive
malignancy. Some reports support the safety of such an approach, indicating the risk of failure in the HA
zone to be < 5% [25,49] . In contrast, other reports warn of the rapid implementation of HA in SCLC, with an
increased risk of failure of > 10% in the HA zone [50,51] . These contradictory data suggest that a potential
small benefit of hippocampal sparing in limiting the neuropsychological sequelae of brain radiation may be
obtained at the risk of failure in the spared region. In modeling studies, HA PCI in SCLC was more cost-
effective than conventional PCI provided that the risk of developing BM was not increased by more than
14%, or if neurocognitive dysfunction rates were reduced by at least 40% . These findings strongly support
[52]
the continued enrollment in ongoing cooperative group randomized trials on the value of HA PCI in SCLC:
NRG CC003 (USA), PREMER (Spain) , NCT01780675 (Holland).
[53]
Other strategy to reduce neurocognitive deterioration in patients after brain irradiation is the use of
neuroprotective medication. The only agent that seems be effective in this indication is memantine. It was
shown in the prospective study, that it delayed cognitive deterioration after WBRT, although at 24 weeks this
did not reach significance (P = 0.059) . Recently performed systematic review concluded that studies on
[54]
other medications, like methylphenidate and donepezil remain inconclusive in this regard .
[55]

CONCLUSION
To conclude, a standard radiation method for BM from SCLC remains WBRT. Stereotactic radiosurgery
is reserved for relapses after PCI or prior WBRT for overt BM. However, the advancement in technologies
allow for treatment of multiple metastases with omission of WBRT. Safety and benefit of such an approach
remain to be confirmed in a prospective trial. All such efforts are welcomed. The ENCEPHALON trial
launched at Heidelberg University Hospital randomizes patients with up to 10 metastases from SCLC to
radiosurgery of all lesions vs. WBRT. Primary endpoint of the study is neurocognitive function. Secondary
endpoints are intracranial control, overall survival and toxicity . Only such direct comparisons will give
[56]
evidence for safety of omission of WBRT in BM from SCLC. Mature data from the trials evaluating safety
of HA in SCLC are also eagerly awaited. Short survival of such patients with both WBRT and stereotactic
methods shows also that radiotherapy is not a sufficient treatment method in this indication. Combinations