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This phase II clinical trial involves the use of hippocampal-sparing together with stereotactic radiosurgery (SRS) for the treatment of brain metastases. The standard of care in the treatment of brain metastases is cranial radiation, but this can be associated with significant neurocognitive sequelae, including reduced verbal memory, spatial memory, attention and problem solving. This can be minimized with the use of SRS, rather than whole brain radiotherapy (WBRT).
Additionally, some of the neurotoxicity has been linked to damage in neural progenitor cells contained within the hippocampus. A recent phase III clinical trial has demonstrated reduced neurocognitive decline with use of hippocampal-sparing techniques in WBRT. This trial aims to see if this can be further improved by combining SRS and hippocampal-sparing.
Primary objective: To determine the rate of neurocognitive failure with hippocampal-sparing stereotactic radiosurgery compared to neurocognitive failures rates with hippocampal-sparing whole brain radiotherapy (using NRG-CC001 with the same population as our comparison), assessed at baseline and at months 3, 6 and 12 (+/- 2 weeks), and with failure defined as any decline in at least one of the following tests (of note, we will be using alternate forms to avoid practice effects): Hopkins Verbal Learning Test for total recall, delayed recall and delayed recognition, Controlled oral word association, Trail making tests parts A and B, Brief visuospatial memory test-revised.
Secondary objectives:
(I) To determine if hippocampal-sparing preserves neurocognitive function, assessed at baseline and months 3, 6 and 12 (+/- 2 weeks), and defined as decline in at least one of the following tests (of note, we will be using alternate forms to avoid practice effects): Hopkins Verbal Learning Test for total recall, delayed recall and delayed recognition, Controlled oral word association, Trail making tests parts A and B, Brief visuospatial memory test-revised.
(II) To determine the incidence of adverse events up to 12 months post-treatment, as measured by common terminology criteria for adverse events (CTCAE v3.0) (III) Quality of life As measured using MD Anderson Symptom Inventory for Brain tumor (MDASI-BT)'s four subscales: symptom severity, symptom interference, neurologic failure and cognitive factor score; and individual items (fatigue, neurologic factor items and cognitive factor items).
(III) Oncologic outcomes will also be assessed at surveillance every 3 months, as is standard of care; time to intracranial progression, overall survival. These will be estimated using Kaplan-Meier method.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| SRS with hippocampal-sparing | Experimental | Stereotactic radiosurgery with hippocampal-sparing |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hippocampal-sparing | Radiation | Dose constraint placed on hippocampi to minimize dose to hippocampi, while maintaining target coverage (at least 98% of brain metastasis volume must receive 100% of prescription dose). |
| Measure | Description | Time Frame |
|---|---|---|
| Time to Neurocognitive Failure | Neurocognitive failure is defined as the first failure, defined as a neurocognitive decline in at least one of the following tests; Hopkins Verbal Learning Test for total recall, delayed recall and delayed recognition; Controlled oral word association; Trail making tests part A and B; Brief visuospatial memory test revised. | Baseline, 3 months, 6 months, 12 months (+/- 2 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Neurocognitive Preservation | Neurocognitive failure is defined as the first failure, defined as a neurocognitive decline in at least one of the following tests; Hopkins Verbal Learning Test for total recall, delayed recall and delayed recognition; Controlled oral word association; Trail making tests part A and B; Brief visuospatial memory test revised. | Baseline, 3 months, 6 months, 12 months (+/- 2 weeks) |
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Inclusion Criteria:
Exclusion Criteria:
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32058845 | Background | Brown PD, Gondi V, Pugh S, Tome WA, Wefel JS, Armstrong TS, Bovi JA, Robinson C, Konski A, Khuntia D, Grosshans D, Benzinger TLS, Bruner D, Gilbert MR, Roberge D, Kundapur V, Devisetty K, Shah S, Usuki K, Anderson BM, Stea B, Yoon H, Li J, Laack NN, Kruser TJ, Chmura SJ, Shi W, Deshmukh S, Mehta MP, Kachnic LA; for NRG Oncology. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol. 2020 Apr 1;38(10):1019-1029. doi: 10.1200/JCO.19.02767. Epub 2020 Feb 14. |
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We do not plan to make individual patient data available to other researchers
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| ID | Term |
|---|---|
| D001932 | Brain Neoplasms |
| ID | Term |
|---|---|
| D016543 | Central Nervous System Neoplasms |
| D009423 | Nervous System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D016634 | Radiosurgery |
| ID | Term |
|---|---|
| D011878 | Radiotherapy |
| D013812 | Therapeutics |
| D013238 | Stereotaxic Techniques |
| D019635 | Neurosurgical Procedures |
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All patients will undergo hippocampal-sparing stereotactic radiosurgery
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| Stereotactic radiosurgery | Radiation | Stereotactic radiosurgery (SRS) with prescription dose determined based on size of brain metastasis; 21 or 24 Gy in a single fraction if less than or equal to 20 mm, 18Gy in a single fraction in 21 - 30 mm, 15 Gy in a single fraction or 30 Gy in 5 fractions if 31 - 40 mm (physician discretion). |
|
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| Change from M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score | M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) Symptom Severity Score is a 28-item multi-symptom patient-reported outcome that measures severity of symptoms experience by patients, 9 specific items for patients with brain tumors. Each item ranges from 0 (best condition) to 10 (worst condition). A subscale score (Symptom Severity) is the average of the subscale items, given that a specified minimum numbers of items were completed. | Baseline, 3 months, 6 months, 12 months (+/- 2 weeks) |
| Intracranial Progression-Free Survival | Intracranial progression-free survival time defined as time from registration to the date of progression in the brain or death from any cause. Overall survival rates are estimated by Kaplan-Meier method. Patients last known to be alive with be censored at date of last contact. Analysis will be planned after neurocognitive failure is reported. | Baseline, 3 months, 6 months, 12 months (+/- 2 weeks) |
| Overall Survival | Overall survival time defined as time from registration to the date of death from any cause. Overall survival rates are estimated by Kaplan-Meier method. Patients last known to be alive with be censored at date of last contact. Analysis will be planned after neurocognitive failure is reported. | Baseline, 3 months, 6 months, 12 months (+/- 2 weeks) |
| Number of Patients with Grade3+ Adverse Event | Adverse events will be graded using Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to severity of adverse event; graded from 1 to 5. Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening/disabling, Grade 5 death related to adverse event | Baseline, 3 months, 6 months, 12 months (+/- 2 weeks) |
| D001927 |
| Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D013514 |
| Surgical Procedures, Operative |
| D008919 | Investigative Techniques |