Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) – a phase II prospective randomized multicenter trial (NOA-14, ARO 2015–3, DKTK-ROG)

Grosu, Anca‐Ligia; Frings, Lars; Bentsalo, Iryna; Oehlke, Oliver; Brenner, Franziska; Bilger, Angelika; Fennell, Jamina Tara; Rothe, Thomás; Schneider-Fuchs, Sabine; Graf, Erika; Schmoor, Claudia; Beck, Jürgen; Becker, Gerhild; Bock, Michael; Egger, Karl; Urbach, Horst; Lahmann, Claas; Popp, Ilinca

doi:10.1186/s12885-020-07011-z

Cited by 48 publications

(34 citation statements)

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“…When WBRT is inevitable, hippocampal avoidance in combination with memantine can also reduce cognitive impairment. 43 , 44 It is worth noting that the addition of EGFR TKI to WBRT does not further increase neurotoxicity according to a systematic review. 45 …”

Section: Discussionmentioning

confidence: 99%

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

et al. 2021

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Background The improved efficacy of tyrosine kinase inhibitors (TKI) mandates reappraisal of local therapy (LT) for brain metastases (BM) of oncogene-driven non-small-cell lung cancer (NSCLC). Patients and methods This study included all epidermal growth factor receptor-mutated (EGFR + , n = 108) and anaplastic lymphoma kinase-rearranged (ALK + , n = 33) TKI-naive NSCLC patients diagnosed with BM in the Thoraxklinik Heidelberg between 2009 and 2019. Eighty-seven patients (62%) received early LT, while 54 (38%) received delayed ( n = 34; 24%) or no LT ( n = 20; 14%). LT comprised stereotactic (SRT; n = 40; 34%) or whole-brain radiotherapy (WBRT; n = 77; 66%), while neurosurgical resection was carried out in 19 cases. Results Median overall survival (OS) was 49.1 months for ALK + and 19.5 months for EGFR + patients ( P = 0.001), with similar median intracranial progression-free survival (icPFS) (15.7 versus 14.0 months, respectively; P = 0.80). Despite the larger and more symptomatic BM ( P < 0.001) of patients undergoing early LT, these experienced longer icPFS [hazard ratio (HR) 0.52; P = 0.024], but not OS (HR 1.63; P = 0.12), regardless of the radiotherapy technique (SRT versus WBRT) and number of lesions. High-risk oncogene variants, i.e. non-del19 EGFR mutations and ‘short’ EML4-ALK fusions (mainly variant 3, E6:A20), were associated with earlier intracranial progression (HR 2.97; P = 0.001). The longer icPFS with early LT was also evident in separate analyses of the EGFR + and ALK + subsets. Conclusions Despite preferential use for cases with poor prognostic factors, early LT prolongs the icPFS, but not OS, in TKI-treated EGFR + /ALK + NSCLC. Considering the lack of survival benefit, and the neurocognitive effects of WBRT, patients presenting with polytopic BM may benefit from delaying radiotherapy, or from radiosurgery of multiple or selected lesions. For SRT candidates, the improved tumor control with earlier radiotherapy should be weighed against the potential toxicity and the enhanced intracranial activity of newer TKI. High-risk EGFR / ALK variants are associated with earlier intracranial failure and identify patients who could benefit from more aggressive management.

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Section: Discussionmentioning

confidence: 99%

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

et al. 2021

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“…Another clinical trial exploring hippocampal sparing prophylactic cranial irradiation in patients with small-cell lung cancer limited hippocampal D mean to 8 Gy in 10 fractions (5.6 Gy EQD2 α / β = 2) ( 21 ). In the ongoing prospective randomized HIPPORAD trial (NOA-14, ARO 2015-3, DRKS00004598), the hippocampal constraints include D 98% ≤ 9 Gy (6.2 Gy EQD2 α / β = 2), D 2% ≤ 17 Gy (14.5 Gy EQD2 α / β = 2), and an aimed D mean ≤ 10 Gy (7.1 Gy EQD2 α / β = 2) ( 20 ). The equivalent dose applied in our HA-WBRT-cohort was therefore in alignment with these data and could be considered sufficient for neurocognitive protection.…”

Section: Discussionmentioning

confidence: 99%

“…Hippocampal interventions were defined as hippocampal resections or RT to the head with a total mean hippocampal dose (D mean , summed across all RT series) ≥ 3 Gy (equivalent dose delivered in 2 Gy fractions [EQD2, α / β = 2]) and a total maximal hippocampal dose (D max , summed across all RT series) ≥ 14.4 Gy (EQD2, α / β = 2). The thresholds were set taking into consideration the strictest hippocampal constraints imposed in clinical trials ( 10 , 20 , 21 ).…”

Section: Methodsmentioning

confidence: 99%

Hippocampus-Avoidance Whole-Brain Radiation Therapy Is Efficient in the Long-Term Preservation of Hippocampal Volume

et al. 2021

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Background and PurposeWith improved life expectancy, preventing neurocognitive decline after cerebral radiotherapy is gaining more importance. Hippocampal damage has been considered the main culprit for cognitive deficits following conventional whole-brain radiation therapy (WBRT). Here, we aimed to determine to which extent hippocampus-avoidance WBRT (HA-WBRT) can prevent hippocampal atrophy compared to conventional WBRT.Methods and MaterialsThirty-five HA-WBRT and 48 WBRT patients were retrospectively selected, comprising a total of 544 contrast-enhanced T1-weighted magnetic resonance imaging studies, longitudinally acquired within 24 months before and 48 months after radiotherapy. HA-WBRT patients were treated analogously to the ongoing HIPPORAD-trial (DRKS00004598) protocol with 30 Gy in 12 fractions and dose to 98% of the hippocampus ≤ 9 Gy and to 2% ≤ 17 Gy. WBRT was mainly performed with 35 Gy in 14 fractions or 30 Gy in 10 fractions. Anatomical images were segmented and the hippocampal volume was quantified using the Computational Anatomy Toolbox (CAT), including neuroradiological expert review of the segmentations.ResultsAfter statistically controlling for confounding variables such as age, gender, and total intracranial volume, hippocampal atrophy was found after both WBRT and HA-WBRT (p < 10−6). However, hippocampal decline across time following HA-WBRT was approximately three times lower than following conventional WBRT (p < 10−6), with an average atrophy of 3.1% versus 8.5% in the first 2 years after radiation therapy, respectively.ConclusionHA-WBRT is a therapeutic option for patients with multiple brain metastases, which can effectively and durably minimize hippocampal atrophy compared to conventional WBRT.

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“…In a propensity score-matched comparison against WBRT, Popp et al reported significantly improved local tumour control rates, intracranial PFS, reduction in neurological deaths and even better OS [ 12 ]. This has led the group to continue to a phase II HIPPORAD Trial comparing HA-WBRT+SIB against WBRT+SIB (German Clinical Trials Registry: DRKS00004598) [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol

et al. 2020

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Background Recent evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT) as the recommended treatment option in patients with good prognosis and multiple brain metastases as this results in better neurocognitive preservation compared to whole brain radiotherapy. However, there is often poor tumour control with this technique due to the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is given to patients who have a limited number of brain metastases, delivers a higher radiation dose to the metastases resulting in better target lesion control. With improvements in radiation technology, advanced dose-painting techniques now allow a simultaneous integrated boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve brain tumour control and preserve cognitive outcomes. This technique is abbreviated to HA-SIB-WBRT or HA-WBRT+SIB. Methods We hypothesise that the SIB in HA-SIB-WBRT (experimental arm) will result in better tumour control compared to HA-WBRT (control arm). This may also lead to better intracranial disease control as well as functional and survival outcomes. We aim to conduct a prospective randomised phase II trial in patients who have good performance status, multiple brain metastases (4–25 lesions) and a reasonable life expectancy (> 6 months). These patients will be stratified according to the number of brain metastases and randomised between the 2 arms. We aim for a recruitment of 100 patients from a single centre over a period of 2 years. Our primary endpoint is target lesion control. These patients will be followed up over the following year and data on imaging, toxicity, quality of life, activities of daily living and cognitive measurements will be collected at set time points. The results will then be compared across the 2 arms and analysed. Discussion Patients with brain metastases are living longer. Maintaining functional independence and intracranial disease control is thus increasingly important. Improving radiotherapy treatment techniques could provide better control and survival outcomes whilst maintaining quality of life, cognition and functional capacity. This trial will assess the benefits and possible toxicities of giving a SIB to HA-WBRT. Trial registration Clinicaltrials.gov identifier: NCT04452084. Date of registration 30th June 2020.

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Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) – a phase II prospective randomized multicenter trial (NOA-14, ARO 2015–3, DKTK-ROG)

Cited by 48 publications

References 57 publications

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

Effect of timing, technique and molecular features on brain control with local therapies in oncogene-driven lung cancer

Hippocampus-Avoidance Whole-Brain Radiation Therapy Is Efficient in the Long-Term Preservation of Hippocampal Volume

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol

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