|Year : 2020 | Volume
| Issue : 6 | Page : 1215-1222
Hippocampal-sparing radiotherapy and neurocognitive impairment: A systematic literature review
Zanirato Rambaldi Giuseppe1, Cammelli Silvia2, Farina Eleonora2, Macchia Gabriella3, Ferro Marica3, Chiesa Silvia4, Balducci Mario4, Deodato Francesco3, Cilla Savino5, Buwenge Milly2, Giovanni P Frezza6, Zompatori Maurizio2, Alessio G Morganti2
1 Radiology Unit, Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Bologna, Italy
2 Department of Experimental, Radiation Oncology Center, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Bologna, Italy
3 Radiotherapy Unit, Fondazione di Ricerca e Cura “Giovanni Paolo II,” Catholic University of Sacred Heart, Campobasso, Italy
4 Department of Radiotherapy, Fondazione Policlinico Universitario “A. Gemelli,” Catholic University of Sacred Heart, Rome, Italy
5 Medical Physics Unit, Fondazione di Ricerca e Cura “Giovanni Paolo II,” Catholic University of Sacred Heart, Campobasso, Italy
6 Radiotherapy Department, Ospedale Bellaria, Bologna, Italy
|Date of Submission||09-Jul-2017|
|Date of Decision||02-Oct-2017|
|Date of Acceptance||26-Feb-2018|
|Date of Web Publication||26-Oct-2018|
Zanirato Rambaldi Giuseppe
Radiology Unit, Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, S.Orsola-Malpighi Hospital, Via Giuseppe Massarenti 9, 40126 Bologna
Source of Support: None, Conflict of Interest: None
Introduction: Whole-brain radiation therapy (WBRT) is an effective therapeutic modality in patients with brain metastases. However, nearly 90% of patients undergoing WBRT suffer from a neurocognitive function (NCF) impairment at diagnosis, and up to two-thirds will experience a further decline within 2–6 months after WBRT. Focal-dose reduction on bilateral hippocampus is thought to improve NCF preservation. The aim was to present a systematic review of clinical results on NCF after hippocampal-sparing (HS) WBRT.
Materials and Methods: A systematic review of published literature was performed on PubMed and the Cochrane Library. Only prospective clinical trials reporting NCF outcome in patients treated with HS-WBRT have been analyzed.
Results: A total of 165 patients from three studies were included. These studies are characterized by small sample size and different methods in terms of WBRT technique but with similar planning analysis and NCF assessment tests. No significant changes in NCF (i.e., verbal and nonverbal learning memory, executive functions, and psychomotor speed) between baseline and 4-month follow-up after RT and only a mean relative decline in delayed recall at 4 months (7% compared to 30% of historical control) were observed.
Conclusions: Considering preliminary results on NCF preservation, further studies seem justified in patients undergoing brain irradiation for brain metastases or referred for prophylactic cranial irradiation to evaluate long-term effects on NCF and quality of life.
Keywords: Brain metastases, hippocampal sparing, neurocognitive impairment, review, whole-brain radiotherapy
|How to cite this article:|
Giuseppe ZR, Silvia C, Eleonora F, Gabriella M, Marica F, Silvia C, Mario B, Francesco D, Savino C, Milly B, Frezza GP, Maurizio Z, Morganti AG. Hippocampal-sparing radiotherapy and neurocognitive impairment: A systematic literature review. J Can Res Ther 2020;16:1215-22
|How to cite this URL:|
Giuseppe ZR, Silvia C, Eleonora F, Gabriella M, Marica F, Silvia C, Mario B, Francesco D, Savino C, Milly B, Frezza GP, Maurizio Z, Morganti AG. Hippocampal-sparing radiotherapy and neurocognitive impairment: A systematic literature review. J Can Res Ther [serial online] 2020 [cited 2021 Dec 4];16:1215-22. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1215/244223
| > Introduction|| |
Cranial irradiation is an effective therapeutic modality in multiple different settings: whole-brain radiotherapy (WBRT) of brain metastases (BMs), prophylactic cranial irradiation (PCI) in small cell lung cancer (and controversially for nonsmall cell lung cancer), and cranial-spinal irradiation in pediatric central nervous system malignancies.
Nearly 90% of patients affected by BM suffer from decline of neurocognitive function (NCF) at diagnosis, and up to two-thirds will experience further neurocognitive impairment (NCI) within 2–6 months after WBRT. Due to improvement in oncological treatments and consequent prolonged survival in patients receiving WBRT, NCI prevention is increasingly considered an emerging need in clinical practice.
Clinical studies suggest that radiation-induced damage of the hippocampus plays a considerable role in NCI, being demonstrated the association between delivered dose to the hippocampus and NCI. In fact, the pathogenesis of radiation-induced NCI may involve injury to proliferating neuronal progenitor cells in the hippocampus subgranular zone. Moreover, a recent study showed the development of a radiation dose-dependent hippocampal atrophy after brain tumor irradiation: quantitative magnetic resonance imaging (MRI) showed a median 6% hippocampal volume loss 1 year after radiotherapy (RT) with dose >40 Gy. Therefore, hippocampal-sparing WBRT (HS-WBRT) with focal-dose reduction on the hippocampus may be theoretically helpful.
Several planning studies evaluated the feasibility of HS-WBRT using different RT techniques: intensity-modulated radiation therapy (IMRT), intensity-modulated arc therapy, volumetric-modulated arc therapy (VMAT), tomotherapy, and stereotactic RT.,,,,,,,,,,,,, All these techniques were able to achieve adequate coverage of the planning target volume (PTV) while providing an efficient HS.
However, despite the clear technical feasibility of HS-WBRT, evidence about its impact on NCF is still limited and based on preliminary studies generally performed on small patient populations. Furthermore, no literature reviews addressed this clinical issue.
Therefore, the aim of this analysis is to present a literature review of the clinical effects of HS-WBRT on NCF in patients undergoing cranial irradiation.
| > Materials and Methods|| |
Type of studies
in this review, included were all prospective clinical trials reporting NCF outcome in patients treated with HS-WBRT. Case reports were excluded.
Type of participants
only studies enrolling patients suffering from BM with pathologically proven diagnosis of nonhematopoietic malignancy or undergoing PCI for lung cancer were included in this analysis.
Type of interventions
Eligible interventions were RT with any dose and fractionation schedule performed with a HS technique.
All systemic treatments regardless of antineoplastic agent type and use of single or combination protocols were allowed.
Studies were included in the analysis regardless of supportive therapy type or other treatments such as blood transfusions, analgesic treatments, or corticosteroids.
Neurocognitive function evaluation
All neurocognitive evaluation scales and tests were eligible to evaluate NCF impairment.
Type of outcome measures
primary endpoint of the analysis was to evaluate the NCF preservation after HS-WBRT and secondary endpoint was intracranial control of the disease using HS-WBRT.
Literature search strategy
A bibliographic search was performed based on the PRISMA methodology using PubMed and the Cochrane Library. The search algorithm was “hippocampal” [MeSH] AND “sparing” [MeSH] AND (“radiotherapy” OR “radiation therapy”). The research in PubMed and the Cochrane Library was complemented by an additional screening of the references of publication identified through the database. The search was not limited to a particular time interval. It was restricted to English-language peer-reviewed journal publications. Papers were independently selected and evaluated by two different authors (GZR and EF). Any discrepancies in the selection of papers and data collection were managed by the senior author (AGM). Potentially eligible studies were retrieved, and a full-text evaluation was performed as to whether it satisfied both inclusion and exclusion criteria.
Only clinical trials reporting NCF outcome of patients treated with HS-WBRT were included in the review process. Studies not reporting a complete NCF evaluation before and after treatment were excluded.
| > Results|| |
Through the literature search, performed as previously described, 82 papers were identified. [Figure 1] describes the process of paper selection. Nine papers underwent full-text examination. In this phase: one paper was excluded because it was a study protocol; two papers were excluded because they did not report a complete pre- and post-treatment NCF evaluation;, one paper was excluded because it referred to a pediatric population only estimating the risk of NCI; one paper was excluded because it was a planning study; and one paper was excluded because it reported the NCF outcome in patients undergoing cranial irradiation without HS technique. Therefore, three studies fulfilled the inclusion criteria and were included in this review, with a total of 165 patients enrolled.
Gondi et al. designed a Phase II multi-institutional trial in patients with BM 5-mm outside the hippocampal borders. They enrolled 100 patients who underwent HS-WBRT (30 Gy in 10 fractions) delivered with IMRT. NCF was evaluated with the Hopkins verbal learning test-revised (HVLT-R) at baseline and at 2-, 4- and 6-month follow-up. Primary endpoint was HVLT-R score decline from baseline to 4 months after the start of HS-WBRT and secondary endpoint was quality of life (QoL) evaluation after HS-WBRT. They observed a mean relative decline in HVLT-R score from baseline to 4 months of about 7%, significantly lower compared to the value (30%; P < 0.001) recorded in the PCI-P-120-9801 Phase III trial. Age ≥60 years, presence of at least minor neurologic symptoms at baseline, and higher hippocampal D100% predicted a stronger decline over time in HVLT-R. Even if only 42 patients were evaluable at 4-month follow-up, the authors concluded that HS-WBRT is associated with memory and QoL preservation compared to historical series.
Lin et al. reported the results of a Phase II study on HS-WBRT in patients with oligometastatic BM (≤3 metastatic foci at MRI with the largest diameter <4 cm) or in patients with lung cancer undergoing PCI. Twenty-five patients received HS-WBRT using VMAT with the following doses: 30 Gy in 12 fractions for palliative or adjuvant WBRT and 25 Gy in 10 fractions for PCI. NCF was evaluated with several neurocognitive tests: Wechsler memory scale-III (verbal and non-verbal episodic memory), modified card sorting test (conceptual formation and mental shifting), digit span subtest of the Wechsler adult intelligence scale – 3rd edition (verbal working memory), and psychomotor speed index. Patients were evaluated at baseline and at 4-month follow-up. Endpoints of the study were HS-WBRT feasibility and its impact on NCF. Only eight out of 25 patients were able to receive 4-month follow-up NCF assessment, and no significant differences between pre- and post-HS-WBRT neurocognitive assessment were observed, except for long-term memory on the world list. Based on these results, the authors concluded that HS-WBRT is a feasible technique able to preserve NCF.
The same group published a larger prospective trial on the effects of HS-WBRT on NCF. They enrolled 40 patients with the same indications and receiving the same treatment and NCF assessment as in the previous study. Based on the results of NCF score of 24 patients at 4-month follow-up, they found a significant association between better functional preservation in immediate recall and lower doses delivered to the hippocampus (maximal dose <12.6 Gy, D80% <6.8 Gy, and minimal dose <5.83 Gy delivered to bilateral hippocampus). However, no significant differences between pre- and post-HS-WBRT neurocognitive assessment were observed. Therefore, they concluded that hippocampal dosimetry correlates with neurocognitive outcomes and that modern VMAT can effectively reduce the hippocampal dose below dosimetric threshold while maintaining intracranial disease control.
Analysis of the selected studies
[Table 1] shows the study and treatment characteristics of the analyzed series. Based on selection criteria, all studies had a prospective design. The number of patients enrolled was 25–100 (median: 40). They enrolled patients with BM without lesions <5 mm from the hippocampus and two of them included even patients undergoing PCI. In one study, historical data on NCF from another trial were used as control group, due to ethical concerns about enrolling patients in a non-HS arm. Prescribed radiation dose was similar in the three studies: 25–30 Gy in 10–12 fractions. RTs were similar: IMRT in one case and VMAT in two other cases. For hippocampal contouring and HS-WBRT planning, all patients underwent an MRI scan of the brain with ≤1.5 mm thick axial slice. These images were fused with computed tomography (CT) simulation scans, and the bilateral hippocampal contours were manually generated on the fused MRI-CT images. These volumes were expanded by 5 mm to generate the hippocampal avoidance regions. The clinical target volume (CTV) was defined as the whole-brain parenchyma, and the PTV was defined as the CTV excluding the hippocampal avoidance regions. No setup margin was added to the CTV to define the PTV. NCF was assessed using several tests but similar regarding figural and verbal memory. Evaluations were performed at baseline before RT and with similar follow-up timing (4 months).
[Table 2] reports planning and clinical results as well as some notes emphasized by the authors. Hippocampal avoidance was achieved in all studies since radiation dose delivered to the 80%–100% of the hippocampal volume (D80%–100%) was <9 Gy and maximum dose was <16 Gy. In one study, significant memory preservation was observed in comparison with historical control arm. The other two studies did not report significant differences in NCF assessment performed pre- and post-RT.
Maximal dose <12.60 Gy, D80% <6.80 Gy, and minimal dose <5.83 Gy delivered to bilateral hippocampus were significantly associated with functional preservation (immediate recall of verbal memory), with the minimal dose irradiating left hippocampus resulting an independent predictor of this specific NCI. No independent effects of right hippocampus-specific dosimetric parameters on verbal or nonverbal memory were observed. Moreover, in the same study, as the mean dose delivered to the left hippocampus (converted to EQD2, biologically equivalent dose in 2 Gy fractions) increases by one more Gy, there would be an approximately 4-fold increase in the risk of NCI in immediate recall of verbal memory.
A relevant dropout rate during follow-up was observed in all three studies: only 45% (mean) of enrolled patients received NCF assessment after treatment. The majority of not compliance at follow-up was attributed to deteriorated performance status and high patient death rate.
Overall HS-WBRT seems to preserve NCF since NCF scores were quite stable between baseline and 4-month assessment or only a significantly lower mean decline in HVLT-R DR at 4 months (7%) compared to historical control (30%).
None of the three studies included in this review evaluated the intracranial control of the disease after HS-WBRT, particularly the late onset of new metastases in the hippocampal avoidance regions.
| > Discussion|| |
Due to improved survival, NCF preservation is considered a relevant issue in patients undergoing WBRT. Although nearly 90% of patients affected by BM suffer from NCI at diagnosis, up to two-thirds will experience a further decline within 2–6 months after WBRT. The purpose of this systematic review of the literature was to evaluate the efficacy of the “HS” WBRT in preserving NCF. Very few data are available about this issue, and only three studies were included in this review.
All patients enrolled in these studies underwent HS-WBRT with different techniques but with similar hippocampal dosimetric results. Two of this studies, demonstrated no significant changes in NCF (verbal and nonverbal learning memory, executive functions, and psychomotor speed) between baseline and 4-month follow-up after RT. Although these studies are limited by the absence of a control group treated with conventional WBRT, each patient served as his/her own control by evaluating the score differences (baseline and 4-month posttreatment). The authors commented that patients fitting the same eligibility criteria and randomized to receive conventional WBRT without HS should be the ideal control group. However, ethical considerations can represent a limit, assuming that HS-WBRT could achieve similar oncological outcomes and more favorable NCF outcomes compared to conventional WBRT.
In contrast, the Gondi et al.'s study showed 7% (confidence interval95%: 4.7%–18.7%) decline in NCF score after HS-WBRT. However, this value was significantly lower compared to 30% mean decline in historical control group (P < 0.001). This difference compared to the other two studies might be due to the inclusion criteria since Gondi et al. enrolled patients with BM regardless of tumor burden, while Lin et al. and Tsai et al. included only patients with oligometastatic brain disease (resected or not) and patients referred for PCI. These better baseline conditions might explain the better NCF outcome.
In fact, worse baseline conditions have been correlated with unsatisfactory outcome. Bodensohn et al. published their experience in patients with primary brain tumors (anaplastic astrocytoma or glioblastoma multiforme) undergoing definitive or postoperative RT without HS. They reported that the differences in NCF decline due to radiation exposure of the hippocampus were less pronounced than expected, despite the fact that median average dose delivered to bilateral hippocampus was significantly high (37.6 Gy). However, their patient population included patients presenting with hippocampal unilateral and bilateral tumor involvement with a clear performance deficit at baseline and in worse clinical conditions compared to the other studies. Moreover, the NCF assessment was performed in a variable time follow-up (from 81 to 491 days) and therefore potentially too early to detect a significant impact almost in some patients.
HS-WBRT has the theoretical potential to foster the development of metastases near the hippocampus, but the analyzed studies did not report data on the onset of new metastases after WBRT. However, several studies,,,,,,,,, evaluating the pattern of BM distribution reported a very low incidence of metastases (3.3% of all metastases) within the hippocampal region in both unselected and specific tumors (i.e., SCLC, breast cancer, and melanoma) [Table 3]. In fact, only 8.8% of 1881 patients (presenting 9633 metastases) experienced hippocampal and perihippocampal localizations (respectively, 2.1% and 6.7%). We can assume that the risk of a posttreatment recurrence pursues the same patterns as at the time of the first diagnosis. On average, a very low percentage of BM develops in the hippocampus (1.1%), and also, the percentage of metastases developing within 5 mm margin from hippocampus is low (2.2%). Therefore, the pattern of BM confirms the safety of sparing this region while delivering WBRT.
First, only three studies were included in this review reporting results based on limited sample size at follow-up evaluation (<50 patients in all studies), and none of them was a randomized clinical trial. Moreover, in two studies,, from the same group, it was not possible to establish if there was an overlap of patients' populations: They reported different data and different endpoints, with similar results. We decided to include both studies in this review because of the qualitative nature of our analysis.
Furthermore, no evaluation of QoL based on patient-reported outcomes was performed, which should be one of the most important endpoints in palliative treatments. In all three studies, a relevant dropout rate (mean: 55%) was observed. The majority of not compliance at follow-up might be attributed to deteriorated performance status or early patient's death. Being deteriorated performance status, one reason for lack of compliance, it could represent a bias, especially in two studies., In fact, reported results were probably based on better-performing patients.
In addition, these studies did not evaluate some other potential patient/disease-related factors affecting patients' NCF changes, such as the extent of brain edema caused by mass effect or surgical intervention, nutritional condition, electrolyte imbalance, and confounding effect of increased intracranial pressure. Moreover, none of the analyzed studies evaluated the onset of new metastases in the hippocampal-avoiding regions.
Finally, given the limited follow-up time of these studies, the efficacy of HS technique in preventing long-term (i.e., beyond 6 months) NCI produced by WBRT could not be assessed.
The overall conclusion is that future studies of HS-WBRT appear justified in patients undergoing brain irradiation for BM or referred for PCI, considering the feasibility and safety profile of HS-RT and preliminary results on NCF preservation. To confirm the safety of this technique, it would be helpful if these studies could analyze the site of new BM following HS-WBRT. In addition, it would be interesting to evaluate the potential combined neuroprotective effects of hippocampal avoidance in addition to prophylactic neuroprotective drugs, such as memantine, during brain irradiation. Moreover, it would be useful to improve the selection of patients who would experience the best benefits in clinical practice: As shown using a mathematical model, HS-WBRT is a cost-effective therapy for long-term survivors (12–24 months). Furthermore, new studies could evaluate whether baseline biomarkers of white matter injury and hippocampal volumetry at MRI are potential predictors of cognitive decline and differential benefit from HS-WBRT.
One of the most interesting perspectives in the treatment of BM is the possibility to irradiate the whole brain with simultaneous integrated boost on metastases in oligometastatic patients. Therefore, it would be interesting to evaluate the possibility to combine this technique with HS RT, to maximize intracranial tumor control, and to reduce NCI after RT.
Moreover, novel indications could be considered for HS technique, such as the treatment of primary brain tumors, in which a reasonable protection seems to be possible in about half of all cases, or other neoplasms: head and neck cancers, and particularly nasopharynx and maxillary tumors, and pituitary and base of skull neoplasms.
Finally, it is known that WBRT for metastatic tumors has, in many cases, a palliative aim and many patients suffer from neurologic symptoms, memory decline, and pain. For these reasons, future studies should answer the question whether NCF preservation based on HS techniques has a positive impact on patients QoL evaluated by patient reported outcome measures.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Gondi V, Tomé WA, Mehta MP. Why avoid the hippocampus? A comprehensive review. Radiother Oncol 2010;97:370-6.
Pinkham MB, Sanghera P, Wall GK, Dawson BD, Whitfield GA. Neurocognitive effects following cranial irradiation for brain metastases. Clin Oncol (R Coll Radiol) 2015;27:630-9.
Attia A, Page BR, Lesser GJ, Chan M. Treatment of radiation-induced cognitive decline. Curr Treat Options Oncol 2014;15:539-50.
Redmond KJ, Mahone EM, Terezakis S, Ishaq O, Ford E, McNutt T, et al.
Association between radiation dose to neuronal progenitor cell niches and temporal lobes and performance on neuropsychological testing in children: A prospective study. Neuro Oncol 2013;15:360-9.
Marsh JC, Gielda BT, Herskovic AM, Abrams RA. Cognitive sparing during the administration of whole brain radiotherapy and prophylactic cranial irradiation: Current concepts and approaches. J Oncol 2010;2010:198208.
Seibert TM, Karunamuni R, Bartsch H, Kaifi S, Krishnan AP, Dalia Y, et al.
Radiation dose-dependent hippocampal atrophy detected with longitudinal volumetric magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2017;97:263-9.
Nevelsky A, Ieumwananonthachai N, Kaidar-Person O, Bar-Deroma R, Nasrallah H, Ben-Yosef R, et al.
Hippocampal-sparing whole-brain radiotherapy using Elekta equipment. J Appl Clin Med Phys 2013;14:4205.
Han G, Liu D, Gan H, Denniston KA, Li S, Tan W, et al.
Evaluation of the dosimetric feasibility of hippocampal sparing intensity-modulated radiotherapy in patients with locally advanced nasopharyngeal carcinoma. PLoS One 2014;9:e90007.
Kazda T, Jancalek R, Pospisil P, Sevela O, Prochazka T, Vrzal M, et al.
Why and how to spare the hippocampus during brain radiotherapy: The developing role of hippocampal avoidance in cranial radiotherapy. Radiat Oncol 2014;9:139.
Dunlop A, Welsh L, McQuaid D, Dean J, Gulliford S, Hansen V, et al.
Brain-sparing methods for IMRT of head and neck cancer. PLoS One 2015;10:e0120141.
Rong Y, Evans J, Xu-Welliver M, Pickett C, Jia G, Chen Q, et al.
Dosimetric evaluation of intensity-modulated radiotherapy, volumetric modulated arc therapy, and helical tomotherapy for hippocampal-avoidance whole brain radiotherapy. PLoS One 2015;10:e0126222.
Kothavade V, Jamema SV, Gupta T, Pungavkar S, Upasani M, Juvekar S, et al.
Which is the most optimal technique to spare hippocampus?-Dosimetric comparisons of SCRT, IMRT, and tomotherapy. J Cancer Res Ther 2015;11:358-63.
Oehlke O, Wucherpfennig D, Fels F, Frings L, Egger K, Weyerbrock A, et al.
Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: Local tumour control and survival. Strahlenther Onkol 2015;191:461-9.
Pokhrel D, Sood S, Lominska C, Kumar P, Badkul R, Jiang H, et al.
Potential for reduced radiation-induced toxicity using intensity-modulated arc therapy for whole-brain radiotherapy with hippocampal sparing. J Appl Clin Med Phys 2015;16:131-41.
Giaj Levra N, Sicignano G, Fiorentino A, Fersino S, Ricchetti F, Mazzola R, et al.
Whole brain radiotherapy with hippocampal avoidance and simultaneous integrated boost for brain metastases: A dosimetric volumetric-modulated arc therapy study. Radiol Med 2016;121:60-9.
Kim KH, Cho BC, Lee CG, Kim HR, Suh YG, Kim JW, et al.
Hippocampus-sparing whole-brain radiotherapy and simultaneous integrated boost for multiple brain metastases from lung adenocarcinoma: Early response and dosimetric evaluation. Technol Cancer Res Treat 2016;15:122-9.
Lee K, Lenards N, Holson J. Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs. intensity-modulated radiation therapy case study. Med Dosim 2016;41:15-21.
Hofmaier J, Kantz S, Söhn M, Dohm OS, Bächle S, Alber M, et al.
Hippocampal sparing radiotherapy for glioblastoma patients: A planning study using volumetric modulated arc therapy. Radiat Oncol 2016;11:118.
Pokhrel D, Sood S, McClinton C, Shen X, Lominska C, Saleh H, et al.
Treatment planning strategy for whole-brain radiotherapy with hippocampal sparing and simultaneous integrated boost for multiple brain metastases using intensity-modulated arc therapy. Med Dosim 2016;41:315-22.
Smyth G, Evans PM, Bamber JC, Mandeville HC, Welsh LC, Saran FH, et al.
Non-coplanar trajectories to improve organ at risk sparing in volumetric modulated arc therapy for primary brain tumors. Radiother Oncol 2016;121:124-31.
Brodin NP, Munck af Rosenschöld P, Blomstrand M, Kiil-Berthlesen A, Hollensen C, Vogelius IR, et al.
Hippocampal sparing radiotherapy for pediatric medulloblastoma: Impact of treatment margins and treatment technique. Neuro Oncol 2014;16:594-602.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009;151:264-9, W64.
Hauswald H, Habl G, Krug D, Kehle D, Combs SE, Bermejo JL, et al.
Whole brain helical tomotherapy with integrated boost for brain metastases in patients with malignant melanoma-a randomized trial. Radiat Oncol 2013;8:234.
Pinkham MB, Bertrand KC, Olson S, Zarate D, Oram J, Pullar A, et al.
Hippocampal-sparing radiotherapy: The new standard of care for world health organization grade II and III gliomas? J Clin Neurosci 2014;21:86-90.
Bodensohn R, Corradini S, Ganswindt U, Hofmaier J, Schnell O, Belka C, et al.
A prospective study on neurocognitive effects after primary radiotherapy in high-grade glioma patients. Int J Clin Oncol 2016;21:642-50.
Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner 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;32:3810-6.
Mehta MP, Rodrigus P, Terhaard CH, Rao A, Suh J, Roa W, et al.
Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 2003;21:2529-36.
Lin SY, Yang CC, Wu YM, Tseng CK, Wei KC, Chu YC, et al.
Evaluating the impact of hippocampal sparing during whole brain radiotherapy on neurocognitive functions: A preliminary report of a prospective phase II study. Biomed J 2015;38:439-49.
] [Full text]
Tsai PF, Yang CC, Chuang CC, Huang TY, Wu YM, Pai PC, et al.
Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: A prospective study. Radiat Oncol 2015;10:253.
Ghia A, Tomé WA, Thomas S, Cannon G, Khuntia D, Kuo JS, et al.
Distribution of brain metastases in relation to the hippocampus: Implications for neurocognitive functional preservation. Int J Radiat Oncol Biol Phys 2007;68:971-7.
Gondi V, Tome WA, Marsh J, Struck A, Ghia A, Turian JV, et al.
Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: Safety profile for RTOG 0933. Radiother Oncol 2010;95:327-31.
Marsh JC, Herskovic AM, Gielda BT, Hughes FF, Hoeppner T, Turian J, et al.
Intracranial metastatic disease spares the limbic circuit: A review of 697 metastatic lesions in 107 patients. Int J Radiat Oncol Biol Phys 2010;76:504-12.
Harth S, Abo-Madyan Y, Zheng L, Siebenlist K, Herskind C, Wenz F, et al.
Estimation of intracranial failure risk following hippocampal-sparing whole brain radiotherapy. Radiother Oncol 2013;109:152-8.
Wan JF, Zhang SJ, Wang L, Zhao KL. Implications for preserving neural stem cells in whole brain radiotherapy and prophylactic cranial irradiation: A review of 2270 metastases in 488 patients. J Radiat Res 2013;54:285-91.
Hong AM, Suo C, Valenzuela M, Haydu LE, Jacobsen KD, Reisse CH, et al.
Low incidence of melanoma brain metastasis in the hippocampus. Radiother Oncol 2014;111:59-62.
Kundapur V, Ellchuk T, Ahmed S, Gondi V. Risk of hippocampal metastases in small cell lung cancer patients at presentation and after cranial irradiation: A safety profile study for hippocampal sparing during prophylactic or therapeutic cranial irradiation. Int J Radiat Oncol Biol Phys 2015;91:781-6.
Sun B, Huang Z, Wu S, Shen G, Cha L, Meng X, et al.
Incidence and relapse risk of intracranial metastases within the perihippocampal region in 314 patients with breast cancer. Radiother Oncol 2016;118:181-6.
Wu SG, Sun JY, Tong Q, Li FY, He ZY. Clinical features of brain metastases in breast cancer: An implication for hippocampal-sparing whole-brain radiation therapy. Ther Clin Risk Manag 2016;12:1849-53.
Guo WL, He ZY, Chen Y, Zhou D, Tang K, Wang P, et al.
Clinical features of brain metastases in small cell lung cancer: An implication for hippocampal sparing whole brain radiation therapy. Transl Oncol 2017;10:54-8.
Savitz ST, Chen RC, Sher DJ. Cost-effectiveness analysis of neurocognitive-sparing treatments for brain metastases. Cancer 2015;121:4231-9.
Ferro M, Chiesa S, Macchia G, Cilla S, Bertini F, Frezza G, et al.
Intensity modulated radiation therapy with simultaneous integrated boost in patients with brain oligometastases: A Phase 1 study (ISIDE-BM-1). Int J Radiat Oncol Biol Phys 2017;97:82-90.
Bodensohn R, Söhn M, Ganswindt U, Schupp G, Nachbichler SB, Schnell O, et al.
Hippocampal EUD in primarily irradiated glioblastoma patients. Radiat Oncol 2014;9:276.
[Table 1], [Table 2], [Table 3]
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