The interesting letter from Di Perri permit us to discuss more extensively the findings of our study and future clinical application of brain RT [1Nicosia L. Allegra A.G. Giaj-Levra N. Bayani R. Darzikolaee N.M. Mazzola R. et al.Repeated HyperArc radiosurgery for recurrent intracranial metastases and dosimetric analysis of recurrence pattern to account for diffuse dose effect on microscopical disease. Clinical and Translational.Radiat Oncol. 2024; 48Google Scholar]. The management of brain metastases (BM) significantly evolved in the last years with the introduction of systemic agents and precise RT technology that are allowing to administer effective treatments with limited side effects. In this regards, mono-isocentric techniques are very appealing for treating simultaneously multiple BMs. On one hand, they permit very steep dose gradient with limited toxicity, an important reduction in the time required for patients, treatment slots and costs [2Alongi F. Nicosia L. Figlia V. et al.Long-term disease outcome and volume-based decision strategy in a large cohort of multiple brain metastases treated with a mono-isocentric linac-based Stereotactic Radiosurgery technique.Clin Transl Oncol. 2021; 23: 1561-1570https://doi.org/10.1007/s12094-020-02550-0Crossref PubMed Scopus (13) Google Scholar, 3Alongi F. Fiorentino A. Ruggieri R. Ricchetti F. Kupelian P. Cost-effectiveness of Linac-based single-isocenter non-coplanar technique (HyperArcTM) for brain metastases radiosurgery.Clin Exp Metastasis. 2018; 35: 601-603https://doi.org/10.1007/s10585-018-9933-7Crossref PubMed Scopus (10) Google Scholar], on the other hand they carry with them inevitably a certain diffuse low dose to the healthy brain. Several evidence already documented the role of low radiation dose in controlling the microscopic disease, so we hypothesize how to exploit this inevitable and peculiar characteristic of monoisocentric technique to obtain a clinically relevant effect. In particular:1)Being aware that low dose isodoses have had a larger volume than high dose isodoses, we corrected the number of BMs per isodose volume, as already explained in methods section (n° of new BMs/isodose level volume) [1Nicosia L. Allegra A.G. Giaj-Levra N. Bayani R. Darzikolaee N.M. Mazzola R. et al.Repeated HyperArc radiosurgery for recurrent intracranial metastases and dosimetric analysis of recurrence pattern to account for diffuse dose effect on microscopical disease. Clinical and Translational.Radiat Oncol. 2024; 48Google Scholar]. So the dose of 7 Gy resulted corrected per isodose volume and truly representative of low radiation dose effect.2)The effect of intracranial failure after WBRT should be weighted with the extracranial disease control. In fact, systemic progression might also determine a new intracranial metastatic wave [2Alongi F. Nicosia L. Figlia V. et al.Long-term disease outcome and volume-based decision strategy in a large cohort of multiple brain metastases treated with a mono-isocentric linac-based Stereotactic Radiosurgery technique.Clin Transl Oncol. 2021; 23: 1561-1570https://doi.org/10.1007/s12094-020-02550-0Crossref PubMed Scopus (13) Google Scholar]. Therefore, we included only patients without systemic progression after HyperArc to exclude systemic progression as a potential source of new BMs. Moreover, In the meta-analysis from Sahgal et al. [4Sahgal A. Aoyama H. Kocher M. et al.Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis.Int J Radiat Oncol Biol Phys. 2015; 91: 710-717https://doi.org/10.1016/j.ijrobp.2014.10.024Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar] the risk of intracranial relapse between SRS and SRS + WBRT was not significantly different for patients ≤ 50 years and the difference was observed only in those > 50 years. Also, a study from Nakano et al. showed that a dose reduction to the brain was not associated with increased brain failure [5Nakano T, Aoyama H, Onodera S, et al. Reduced-dose WBRT combined with SRS for 1-4 brain metastases aiming at minimizing neurocognitive function deterioration without compromising brain tumor control. Clin Transl Radiat Oncol. 2022;37:116-129. Published 2022 Sep 27. doi:10.1016/j.ctro.2022.09.005.Google Scholar]3)Apart from preclinical studies, there are several trial clinically addressing the effect of low RT dose to the hippocampi. Even if results regarding hippocampal-avoidance (HA) technique are not definitive yet [6Liu R. Gong G. Meng K. Du S. Yin Y. Hippocampal sparing in whole-brain radiotherapy for brain metastases: controversy, technology and the future. Front.Oncol. 2024; 14 (Published 2024 Jan 24)1342669https://doi.org/10.3389/fonc.2024.1342669Crossref Scopus (1) Google Scholar], it was demonstrated the possibility to positively impact on neucognitive function. For example, the phase II trial RTOG 0933 demonstrated that a dose to the 100 % of the hippocampi not exceeding 9 Gy during WBRT might preserve neurocognitive function [7Gondi V. Pugh S.L. Tome W.A. 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: 3810-3816https://doi.org/10.1200/JCO.2014.57.2909Crossref PubMed Scopus (868) Google Scholar]. The phase II trial of Westover et al. used a treatment concept more similar to that proposed in our paper: a lower WBRT dose (20 Gy/10 fx) with a boost of 40 Gy to the BM and a hippocampi dose not exceeding 16 Gy. The results showed only a 10.6 % mean decline in verbal memory performance without sacrifing intracranial control [8Westover K.D. Mendel J.T. Dan T. et al.Phase II trial of hippocampal-sparing whole brain irradiation with simultaneous integrated boost for metastatic cancer.Neuro Oncol. 2020; 22: 1831-1839https://doi.org/10.1093/neuonc/noaa092Crossref PubMed Scopus (36) Google Scholar]. Despite the limitations of a retrospective study, we believe that the strategy of low-dose WBRT plus SRS/SRT could be proposed to long-surviving patients especially in those where systemic drugs permit a long-lasting disease control and where the early resort to WBRT might be detrimental for their quality of life. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
