Abstract
Background
Although there are data describing the onset of neurocognitive toxicity following radiation for patients with brain metastases, less is known about the potential for functional cognitive recovery (CR). This study sought to evaluate CR following neurocognitive function failure (NCF) in patients treated with stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and hippocampal avoidance (HA)-WBRT.
Methods
A pooled analysis of 3 (NCCTG N107C/CEC.3, NCCTG N0574, and NRG CC001) clinical trials was performed. Patients with trial-defined NCF and longitudinal cognitive testing were included. The primary endpoint was time to CR, defined as patients no longer exhibiting a 1 or more standard deviation decline from baseline on any cognitive test.
Results
A total of 288 patients were included, with a median follow-up of 12.2 months. The cumulative incidence of CR was 38% (95% confidence interval [CI] = 32.5% to 43.9%) at 6 months after NCF. Incidence of CR was significantly improved with post-op SRS vs WBRT (hazard ratio [HR] = 2.68, 95% CI = 1.43 to 5.03, P = .002) and with SRS vs SRS+WBRT (HR = 2.35, 95% CI = 1.16 to 4.79, P = .008). On multivariable analysis, SRS was highly prognostic of CR compared with WBRT (HR = 2.42, 95% CI = 1.70 to 3.45, P < .0001). Meta-analysis demonstrated that conformal RT techniques (SRS or HA-WBRT) conferred a significantly higher rate of CR compared with WBRT (pooled HR = 2.12, 95% CI = 1.49 to 3.02, P < .001); 68% of patients had long-term sustained CR.
Conclusions
A sizeable proportion of patients who experience NCF following brain radiation eventually attain full and sustained CR, thereby highlighting that neurocognitive decline may not be permanent. The use of conformal radiation techniques results in greater rates of neurocognitive recovery.
Introduction
Brain metastases continue to cause significant morbidity and mortality in adults with cancer, with an estimated 20% of patients developing brain metastases during the course of their disease.1 Recent advances in immunotherapy, targeted agents, chemotherapy, and radiotherapy have led to improved patient outcomes.2 For patients with limited brain metastases, stereotactic radiosurgery (SRS) is the preferred treatment option. However, patients with extensive burden of intracranial disease often require whole brain radiotherapy (WBRT), which is associated with higher rates of cognitive dysfunction.
Alliance/North Central Cancer Treatment Group (NCCTG) N107C/CEC.3 found that cognitive-deterioration free survival was significantly longer with postoperative SRS compared with postoperative WBRT.3 Similarly, Alliance/NCCTG N0574 concluded that cognitive failure at 3 months was significantly reduced with SRS alone as compared with SRS+WBRT for intact (up to 3) brain metastases.4 Finally, NRG Oncology CC001 established hippocampal avoidance (HA) using intensity-modulated radiotherapy (IMRT) during WBRT and memantine as the standard of care for patients needing WBRT given its significant benefit in delaying time to cognitive function failure.5 However, despite these recent trials showing reductions in cognitive toxicity with more conformal radiation techniques including SRS and HA-WBRT, a significant number of patients still experience cognitive decline.
Although there are data describing the onset and incidence of cognitive dysfunction following brain radiation, there is a paucity of data and research regarding the long-term cognitive changes and potential functional recovery that patients may experience after initial cognitive decline. Traditionally, clinical trials studying cognitive toxicity have viewed cognitive failure as a permanent endpoint, yet still frequently collect data beyond these points. In this context, we aimed to evaluate cognitive recovery following initial cognitive function failure in patients treated with SRS, HA-WBRT, or WBRT by analyzing pooled cognitive testing results from prospective cooperative group clinical trials.
Methods
We conducted a pooled analysis of Alliance/NCCTG N107C/CEC.3, Alliance/NCCTG N0574, and NRG CC001 clinical trials, using data obtained from the National Cancer Institute’s (NCI’s) National Clinical Trials Network (NCTN)/NCI Community Oncology Research Program data archive, utilizing the public-data access mechanism. The study details for all 3 trials were reported in prior primary outcome publications.3-5 Our institutional review board (IRB) approved the project and confirmed exemption (HP-00099872) as they deemed that this pooled analysis of publicly available data met the definition of Not Human Subjects Research and as such did not require further IRB oversight or informed consent.
In brief, Alliance/NCCTG N107C/CEC.33 was a phase 3 randomized controlled trial that compared postoperative SRS vs WBRT for the treatment of a resected brain metastasis. Up to 3 unresected metastases (<3 cm) were allowed; 194 patients were randomized to receive either postoperative SRS (12-20 Gy in a single fraction) or WBRT (30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Cognitive-deterioration free survival was the co-primary endpoint of this trial and cognitive failure was defined as a 1 SD drop from baseline in at least 1 of 6 cognitive tests (Hopkins Verbal Learning Test–Revised immediate recall, delayed recall, recognition, Trail Making Test [TMT]-A, TMT-B, and Controlled Oral Association Test [COWA]). Cognitive assessments were performed at months 6, 9, 12, 16, and 24.
Alliance/NCCTG N05744 was a phase 3 trial that compared SRS vs SRS + WBRT for 1-3 intact brain metastases; 213 patients were randomized to receive either SRS alone (20-24 Gy in a single fraction) or SRS (18-22 Gy in a single fraction) + WBRT (30 Gy in 12 fractions). The same definition of cognitive failure and tests were used in this trial, and the primary endpoint was 3-month cognitive failure rates; cognitive assessments were repeated at 6, 9, 12, 16, 24 months, and then yearly.
NRG Oncology CC0015 was a phase 3 trial that compared HA-WBRT + memantine with WBRT + memantine for unlimited number of brain metastases; 518 patients were randomized to receive WBRT ± HA (30 Gy in 10 fractions). The primary endpoint of this trial was time to cognitive function failure; the definition of cognitive failure was based on reliable change index (RCI) rather than standardized score differences. The same battery of cognitive tests was employed in this trial and performed at months 2, 4, 6, and 12. Twelve-month follow-up data were not made publicly available at the time of this analysis.
All patients who experienced cognitive failure as predefined in each trial and had at least 1 subsequent cognitive function testing datapoint were included in our analyses. Given a lack of consensus definition in the literature, cognitive recovery (CR) was defined as the absence of cognitive failure after initial toxicity. Because the available data were reported as standardized scores, we defined CR as patients no longer having a 1 SD decline from baseline on any test at a time point after their initial cognitive failure. In other words, patients had to score within 1 SD from baseline on all cognitive tests to meet the definition of CR. To assess if there was a particular pattern in which patients demonstrated cognitive recovery, we also explored recovery on individual cognitive tests; this endpoint was defined as at least a 1 SD improvement on any previously failed cognitive test.
Cumulative incidence function was used to estimate the incidence of CR. CR between arms and subgroups was tested using Gray’s test.6 Patients who passed away or did not have CR were censored. Prognostic variables associated with CR were analyzed using multivariable Cox proportional hazards modeling analysis. Given the differences in covariates collected in the 3 trials, shared variables of age, tumor histology, and performance status were used for multivariable analyses. To address possible confounding when considering the variance in definition of cognitive failure across trials, a meta-analysis with fixed effects model was performed. Heterogeneity among the studies was assessed using Cochran Q tests for heterogeneity and the Higgins I2 statistic. Comparison of categorical variables was assessed using a χ2 test; baseline test scores were compared with a t test. All statistical tests were 2-sided with 95% confidence intervals and related P values; P < .05 was considered to be statistically significant. All analyses were done with SAS 9.4 and STATA version 18 software.
Results
A total of 288 patients (N107C, n = 91; N0574, n = 33; CC001, n = 164) who experienced trial-defined cognitive function failure and had subsequent cognitive testing after their documented failure points were included in this pooled analysis. In addition, 283 and 287 patients were included in the CR and individual cognitive test analyses, respectively. The median follow-up for all patients was 12.2 months. Baseline characteristics for the patients included in this study are listed in Tables 1-3 and were well balanced. There were no differences in baseline cognitive scores apart from in N107C, where the patients in the WBRT arm had worse COWA scores (−1.22 vs −0.79, P = .037).
Table 1.
Pretreatment characteristics for patients on NCCTG N107C/CEC.3.
| Characteristics | WBRT, no. (%) | SRS, no. (%) | P |
|---|---|---|---|
| No. of patients | 49 (53.8) | 42 (46.2) | |
| Age, years | .38 | ||
| Mean (SD) | 60.4 (9.2) | 58.7 (10.2) | |
| Sex | .27 | ||
| Male | 20 (40.8) | 22 (52.4) | |
| Female | 29 (59.2) | 20 (47.6) | |
| Race | .80 | ||
| White | 44 (89.8) | 37 (88.1) | |
| Non-White | 5 (10.2) | 5 (11.9) | |
| ECOG | .97 | ||
| 0 | 22 (44.9) | 18 (42.9) | |
| 1 | 25 (51.0) | 22 (52.4) | |
| 2 | 2 (4.1) | 2 (4.7) | |
| Histology | |||
| Non-lung | 17 (34.7) | 15 (35.7) | .92 |
| Lung | 32 (65.3) | 27 (64.3) | |
| Baseline cognitive test, mean z scores (SD) | |||
| HVLT-R total recall | −1.15 (1.22) | −1.00 (1.27) | .57 |
| HVLT-R delayed recall | −1.23 (1.33) | −1.02 (1.29) | .45 |
| HVLT-R delayed recognition | −0.48 (1.38) | −0.23 (0.98) | .33 |
| TMT-A, seconds | −1.45 (2.67) | −1.74 (2.91) | .62 |
| TMT-B, seconds | −2.01 (2.55) | −2.43 (3.37) | .51 |
| COWA | −1.22 (0.86) | −0.79 (1.04) | .037 |
Abbreviations: COWA = Controlled Oral Word Association; ECOG = Eastern Cooperative Oncology Group (Performance Status); HVLT-R = Hopkins Verbal Learning Test-Revised; SRS = stereotactic radiosurgery; TMT-A = Trail Making Test Part A; TMT-B = Trail Making Test Part B; WBRT = whole brain radiotherapy.
Table 2.
Pretreatment characteristics for patients on NCCTG N0574.
| Characteristics | SRS, no. (%) | SRS + WBRT, no. (%) | P |
|---|---|---|---|
| No. of patients | 14 (42.4) | 19 (57.6) | |
| Age, years | .79 | ||
| Mean (SD) | 58.6 (10.8) | 59.6 (10.3) | |
| Sex | .80 | ||
| Male | 5 (35.7) | 6 (31.6) | |
| Female | 9 (64.3) | 13 (68.4) | |
| Race | .034 | ||
| White | 11 (78.6) | 19 (100) | |
| Non-White | 3 (21.4) | 0 (0) | |
| ECOG | .52 | ||
| 0 | 11 (78.6) | 12 (63.2) | |
| 1 | 3 (21.4) | 6 (31.6) | |
| 2 | 0 (0) | 1 (5.2) | |
| Histology | |||
| Non-lung | 4 (28.6) | 5 (26.3) | .89 |
| Lung | 10 (71.4) | 14 (73.7) | |
| Baseline cognitive test, mean z scores (SD) | |||
| HVLT-R total recall | −1.12 (1.25) | −1.71 (1.06) | .15 |
| HVLT-R delayed recall | −0.93 (1.45) | −1.27 (1.18) | 0.47 |
| HVLT-R delayed recognition | −0.80 (2.63) | −0.47 (1.30) | 0.64 |
| TMT-A, seconds | −1.14 (1.29) | −2.02 (3.54) | 0.38 |
| TMT-B, seconds | −1.83 (2.32) | −3.38 (6.51) | 0.40 |
| COWA | −0.75 (1.00) | −0.51 (0.99) | 0.51 |
Abbreviations: COWA = Controlled Oral Word Association; ECOG = Eastern Cooperative Oncology Group (Performance Status); HVLT-R = Hopkins Verbal Learning Test-Revised; SRS = stereotactic radiosurgery; TMT-A = Trail Making Test Part A; TMT-B = Trail Making Test Part B; WBRT = whole brain radiotherapy.
Table 3.
Pretreatment characteristics for patients on NRG Oncology CC001.
| Characteristics | WBRT, no. (%) | HA-WBRT, no. (%) | P |
|---|---|---|---|
| No. of patients | 93 (56.7) | 71 (43.3) | |
| Age, years | .57 | ||
| Mean (SD) | 60.1 (10.4) | 59.2 (9.0) | |
| Sex | .68 | ||
| Male | 37 (39.8) | 26 (36.6) | |
| Female | 56 (60.2) | 45 (63.4) | |
| Race | .55 | ||
| White | 78 (83.9) | 57 (80.3) | |
| Non-White | 15 (16.1) | 14 (19.7) | |
| ECOG | .46 | ||
| 0 | 55 (59.1) | 46 (64.8) | |
| 1 | 38 (40.9) | 25 (35.2) | |
| Histology | |||
| Non-lung | 33 (35.5) | 27 (38.0) | .74 |
| Lung | 60 (64.5) | 44 (62.0) | |
| Baseline cognitive test, mean z scores (SD) | |||
| HVLT-R total recall | −1.13 (1.26) | −1.17 (1.24) | .86 |
| HVLT-R delayed recall | −0.94 (1.60) | −0.96 (1.38) | .90 |
| HVLT-R delayed recognition | −0.49 (1.42) | −0.40 (1.21) | .64 |
| TMT-A, seconds | −0.83 (2.45) | −1.05 (2.11) | .54 |
| TMT-B, seconds | −3.33 (12.1) | −2.83 (4.37) | .74 |
| COWA | −0.81 (1.10) | −0.59 (1.22) | .23 |
Abbreviations: COWA = Controlled Oral Word Association; ECOG = Eastern Cooperative Oncology Group (Performance Status); HA = hippocampal avoidance; HVLT-R = Hopkins Verbal Learning Test-Revised; TMT-A = Trail Making Test Part A; TMT-B = Trail Making Test Part B; WBRT = whole brain radiotherapy.
Overall, the pooled cumulative incidence of CR was 38% (95% CI = 32.5% to 43.9%) and 42% (95% CI = 36.1% to 48.0%) at 6 and 12 months after onset of cognitive failure, respectively (Figure 1). The cumulative incidence rates of improvement on any previously failed cognitive test were 73% (95% CI = 67.8% to 8.2%) and 76% (95% CI = 70.1% to 80.4%) for the same time points (Figure S1). For N107C, the incidence of CR was significantly greater with postoperative SRS as compared with WBRT (Gray’s test, HR = 2.68, 95% CI = 1.43 to 5.03, P = .002; Figure 2, A). Similarly for participants on N0574, receipt of SRS alone vs SRS+WBRT for intact brain metastases conferred a significantly greater likelihood of CR (HR = 2.35, 95% CI = 1.16 to 4.79, P = .008; Figure 2, B). Finally, there was also a trend toward higher cumulative incidence of CR with HA-WBRT vs WBRT for participants on CC001 (HR = 1.68, 95% CI = 0.98 to 2.87, P = .059; Figure S2). There were no significant differences in cumulative incidence of recovery on specific failed cognitive tests in the 3 trials that were based on treatment (N107C—HR = 1.46, 95% CI = 0.95 to 2.27, P = .09; N0574—HR = 1.18, 95% CI = 0.77 to 1.81, P = .42; CC001—HR = 1.09, 95% CI = 0.76 to 1.55, P = .64; Figures S3-S5).
Figure 1.
Cumulative incidence graph showing time to cognitive recovery in all patients.
Figure 2.
Cumulative incidence graph showing time to cognitive recovery in patients on N107C (A) and N0574 (B). Abbreviations: SRS = stereotactic radiosurgery; WBRT = whole brain radiotherapy.
Prognostic factors associated with CR were also analyzed. To estimate the potential cognitive recovery benefits of SRS vs WBRT, patients who received SRS alone were compared with patients who received some form of WBRT (SRS+WBRT, WBRT, or HA-WBRT). On multivariable pooled analysis, SRS was highly prognostic of CR compared with WBRT (HR = 2.42, 95% CI = 1.70 to 3.45, P < .0001; Table 4). HA-WBRT demonstrated near significant greater association with CR vs WBRT (HR = 1.56, 95% CI = 0.98 to 2.48, P = .061l; Table 5). Age (60 vs 60), tumor histology (lung vs non-lung),7 and performance status (0 vs 1 + 2) were not prognostic for CR on univariate or multivariable analysis.
Table 4.
Time to cognitive recovery: pooled multivariable Cox proportional hazards model comparing patients receiving SRS alone with WBRT.a
| Factor | Hazard ratio (95% CI) | P |
|---|---|---|
| Treatment arm (SRS vs WBRTb [R]) | 2.42 (1.70 to 3.45) | <.0001 |
| Age ( 60 vs 60 [R]) | 1.29 (0.91 to 1.84) | .15 |
| Histology (lung vs non-lung [R]) | 0.79 (0.55 to 1.13) | .20 |
| Performance status (0 vs 1-2 [R]) | 1.26 (0.88 to 1.84) | .19 |
Abbreviations: CI = confidence interval; HA-WBRT = hippocampal avoidant whole brain radiotherapy; R = referent; SRS = stereotactic radiosurgery.
WBRT includes patients who received WBRT alone, WBRT+SRS, or HA-WBRT.
Table 5.
Time to cognitive recovery: pooled multivariable Cox proportional hazards model comparing patients receiving HA-WBRT with WBRT.a
| Factor | Hazard ratio (95% CI) | P |
|---|---|---|
| Treatment arm (HA-WBRT vs WBRTb [R]) | 1.56 (0.98 to 2.48) | .061 |
| Age ( 60 vs 60 [R]) | 1.49 (0.943 to 2.35) | .087 |
| Histology (lung vs non-lung [R]) | 0.82 (0.52 to 1.29) | .38 |
| Performance status (0 vs 1-2 [R]) | 1.44 (0.89 to 2.33) | .14 |
Abbreviations: HA = hippocampal avoidance; R = referent; WBRT = whole brain radiotherapy.
WBRT includes patients who received WBRT alone, WBRT+SRS, or HA-WBRT.
A meta-analysis with fixed effects model was performed to quantify the collective benefit of more advanced brain radiation techniques in increasing the likelihood of CR after initial cognitive toxicity. There did not appear to be any evidence of observed heterogeneity among the studies (I2 was 0%). Overall, pooled HR analyses of the 3 studies continued to show that highly conformal radiation therapy technique (either SRS or HA using IMRT) compared with conventional WBRT conferred a significantly higher rate of CR (pooled HR = 2.12, 95% CI = 1.49 to 3.02, P < .001; Figure 3).
Figure 3.
Meta-analysis with fixed effects model of all 3 trials (N107C, N0574, and CC001). Abbreviations: CI = confidence interval; HA = hippocampal avoidance; H.R. = hazard ratio; SRS = stereotactic radiosurgery; WBRT = whole brain radiotherapy.
Postcognitive recovery time points were also assessed. There were 65 patients who had additional cognitive testing data after their documented CR time point (N107C, n = 27; N0574, n = 17; CC001, n = 21). The likelihood of maintaining CR was assessed in these patients. Overall, 44 of 65 patients (67.7%) had at least 1 subsequent follow-up clinical testing datapoint that demonstrated intact and maintained cognition after their initial cognitive toxicity and subsequent cognitive recovery time points (Table S1). The median time of maintained cognition after recovery was 6.5 months, 7.5 months, and 3 months for patients in N107C, N0574, and CC001, respectively.
Discussion
Multiple recent brain metastases radiation clinical trials have focused on preventing and delaying the onset to cognitive toxicity. Despite advances in more conformal types of radiation such as SRS in lieu of WBRT or HA-WBRT using IMRT and use of memantine during WBRT, a significant proportion of patients still suffer from cognitive function failure following radiation therapy. What remains uncertain are the long-term outcomes for these patients and whether these cognitive changes can be reversed or if they are in fact infinite and fixed in duration, as postulated by the design of the aforementioned clinical trials. In this pooled analysis of publicly available cognitive testing data from Alliance/NCCTG N107C/CEC.3, Alliance/NCCTG N0574, and NRG CC001, we sought to explore and quantify the prevalence of a novel concept of cognitive recovery.
Cognitive recovery has been well documented in other disease states, such as in the post-surgery period,8 post-stroke9 or TBI,10 multiple sclerosis,11 Alzheimer’s disease and vascular dementia,12 epilepsy,13 and Parkinson’s disease.14 To the best of our knowledge, this study is the first to describe and use the concept of CR after brain irradiation. We chose a strict definition of CR, defined as the complete absence of cognitive failure after initial cognitive decline, rather than just a general improvement in test scores. This definition (no longer exhibiting a 1 or more SD decline from baseline on all cognitive tests at a time point after initially documented cognitive failure) was chosen to minimize the known variation in cognitive test scoring that can occur at the individual patient level and to better assess the patient’s global neurocognitive state after clinical trial defined cognitive decline.
Our analysis reveals that a sizeable proportion of patients who experience cognitive function decline following brain radiation eventually demonstrate CR. By 6 months, 38% of patients had CR. This number is likely even underestimating the true prevalence of CR, as the long-term cognitive testing data results from CC00115 were not yet available at the time of this analysis, and there did appear to be increasing separation and sustained improvement in cumulative incidence of CR in favor of hippocampal avoidance techniques. We also found that nearly 70% of patients with longer term cognitive testing data after documented recovery demonstrated sustained improvement in neurocognitive outcomes, supporting the idea that the positivity of the results for the endpoint of CR in this study was not just the result of random chance. Similarly, 73% of patients at 6 months had improved scores ( 1 SD improvement) on any previously failed cognitive test. This highlights the known variation in cognitive testing scores and affirms the need for more refined definitions of cognitive failure that include continued follow-up testing and permit patients to remain “at risk” for possible CR in the future.
This analysis also shows that, at both the individual trial level and on pooled analysis, conformal radiation techniques (ie, SRS and/or HA-WBRT using IMRT) compared to conventional WBRT not only delay and reduce the risk of cognitive deterioration but also potentially confer substantial benefits regarding improvement in cognitive recovery several months beyond initial cognitive decline for patients. These findings, therefore, further support the use of conformal radiation techniques for patients with brain metastases to maximize neurocognitive protection.
Other ongoing phase III trials that are collecting cognitive testing data include CCTG CE.7 (NCT03550391),16 which is comparing SRS and HA-WBRT + memantine for patients with 5-15 newly diagnosed brain metastases and NRG CC009 (NCT04804644), which is comparing SRS and HA-WBRT + memantine for patients with up to 10 brain metastases from small cell lung cancer. Recently, a phase 3 trial17 randomizing patients with 5-20 brain metastases to HA-WBRT and SRS showed similar overall survival but an improvement in the average of patient-reported severity and interference over the first 6 months using the MD Anderson Symptom Inventory-Brain Tumor module in the SRS arm. However, in contrast to the trials used in our analysis, this trial did not include cognitive testing data. It may be worthwhile to eventually use patient level cognitive testing data from more modern trials to assess prevalence of cognitive recovery.
Most important, these data may better help clinicians counsel patients about the likelihood of meaningful cognitive improvement after brain radiation and underscore that cognitive decline is not necessarily permanent. This has implications for the management of patients, highlighting the potential for recovery and adjustment in treatment strategies as the time postradiation lengthens. Cognitive rehabilitation programs may be increasingly more important for these patients to maximize potential for preservation of functioning.18-20 These findings, therefore, may also change the design of future clinical trials and cost-effectiveness models which have traditionally perceived cognitive decline as an irreversible condition or state.
One limitation of this study is that the definition of cognitive function failure was different in the 3 trials. N107C and N0574 used a 1 SD decline from baseline, whereas CC001 used the RCI. The variance in definitions across trials introduces some confounding when considering the “at risk” population in a combined analysis. To address this, we conducted a meta-analysis and forest plot to estimate the collective effect of conformal therapy and likelihood of cognitive recovery. There did not appear to be any significant heterogeneity in effect size among the studies (I2 = 0). Another potential limitation of this analysis is our defined outcome of recovery. To our knowledge, no other radiation oncology clinical trial studying cognitive toxicity outcomes has posited a definition of cognitive recovery and as such, we specifically chose to create a definition that would be as stringent as possible. Because the shared data reported were standardized, we defined CR as the absence of any cognitive failure (ie, patients having all subsequent test scores within 1 SD of their baseline scores). Whether total absence of cognitive failure necessarily equates to the presence of cognitive recovery remains uncertain, but we chose this definition in light of the trial-specific definitions of cognitive toxicity. We were also limited by the number of analyzable patients out of all the enrolled patients on the 3 trials (288/925, 31%). However, we were very selective in our patient selection, specifically focusing on patients that had both documented trial-defined cognitive failure and longitudinal cognitive testing beyond this time point. There, therefore, may be some inherent selection bias (patients living longer or those more likely to follow-up with subsequent cognitive testing) due to our strict criteria for eligibility in this analysis. We argue that this still represents the highest quality cognitive testing data of patients on prospective clinical trials rigorously followed with standardized battery of cognitive testing and thus is suitable for this analysis. Similarly, as with other clinical trials involving patients with brain metastases, attrition rates are important to acknowledge. Only 23% (65/288) of patients available for analysis had long-term cognitive testing data after their documented recovery time points which is likely a continued reflection of both poor survival and survey fatigue from repeated clinic visits for cognitive testing.
Conclusions
More than one-third of patients who experience cognitive function failure following brain radiation develop a full cognitive recovery, with two-thirds being sustained. The use of more conformal radiation techniques such as SRS and HA-WBRT as opposed to conventional WBRT confer higher rates of functional recovery. These findings may help better counsel patients and clinicians about the likelihood of meaningful cognitive improvement, importantly underscoring that neurocognitive decline is not necessarily permanent. This, therefore, has important implications for clinical trial design and for the management of patients with brain metastases.
Supplementary Material
Acknowledgments
This manuscript was prepared using data from datasets (NCT01372774: D1, D2, D3; NCT00377156: D1, D2, D4; NCT02360215: D1) from the NCTN Data Archive of the National Cancer Institute’s (NCI’s) NCTN. Data were originally collected from clinical trial NCT numbers (NCT01372774 [Stereotactic Radiosurgery or Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases That Have Been Removed By Surgery], NCT00377156 [Stereotactic Radiation Therapy With or Without Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases], and NCT02360215 [Memantine Hydrochloride and Whole-Brain Radiotherapy With or Without Hippocampal Avoidance in Reducing Neurocognitive Decline in Patients With Brain Metastases]). All analyses and conclusions in this manuscript are the sole responsibility of the authors and do not necessarily reflect the opinions or views of the clinical trial investigators, the NCTN, or the NCI. Previously presented in part at the 2024 Annual Meeting of the American Society for Radiation Oncology in oral presentation format.
Contributor Information
Hua-Ren R Cherng, Department of Radiation Oncology, University of Maryland Medical Center, Baltimore, MD, United States.
Kai Sun, Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, Baltimore, MD, United States; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States.
Soren M Bentzen, Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, Baltimore, MD, United States; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, United States.
Paul D Brown, Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States.
Terri S Armstrong, National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States.
Joshua D Palmer, Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Vinai Gondi, Department of Radiation Oncology, Northwestern Medicine Cancer Center and Proton Center, Warrenville, IL, United States.
Minesh P Mehta, Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, United States.
Mark V Mishra, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, United States.
Author contributions
Hua-Ren Ryan Cherng (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing), Kai Sun (Data curation, Formal analysis, Resources, Software, Writing—review & editing), Søren Bentzen (Data curation, Formal analysis, Methodology, Resources, Software, Validation, Writing—review & editing), Paul D. Brown (Conceptualization, Methodology, Writing—review & editing), Terri S. Armstrong (Methodology, Writing—review & editing), Joshua D. Palmer (Conceptualization, Methodology, Writing—review & editing), Vinai Gondi (Conceptualization, Methodology, Writing—review & editing), Minesh P. Mehta (Conceptualization, Methodology, Writing—review & editing), and Mark V. Mishra (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing)
Supplementary material
Supplementary material is available at JNCI: Journal of the National Cancer Institute online.
Funding
This work was supported by grant P30CA134274 from the National Cancer Institute at the National Institutes of Health. This manuscript’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. The funders had no role in the design of the study, collection, analysis, interpretation of the data, or the writing of the manuscript and the decision to submit it for publication.
Conflicts of interest
P.D.B. discloses an UptoDate contribution outside of this submitted work. M.P.M. reported receiving personal fees from Xoft, Novocure, Kazia, Telix, and Zap and stock ownership in Chimerix, outside of this submitted work. V.G. discloses honoraria from UpToDate outside of this submitted work. M.V.M. has received payment or honoraria from Humanetics; and holds stock in GE Healthcare, outside of this submitted work. The other authors declare no competing interests pertaining to this article.
Data availability
All datasets are available through the National Clinical Trials Network (NCTN) Data Archive of the National Cancer Institute’s (NCI’s) NCTN. The link for the archive is https://nctn-data-archive.nci.nih.gov/.
References
- 1. Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep. 2012;14:48-54. 10.1007/S11912-011-0203-Y/METRICS [DOI] [PubMed] [Google Scholar]
- 2. Vogelbaum MA, Brown PD, Messersmith H, et al. Treatment for brain metastases: ASCO-SNO-ASTRO Guideline. Neuro Oncol. 2022;24:331-357. 10.1093/NEUONC/NOAB262 [DOI] [PubMed] [Google Scholar]
- 3. Brown PD, Ballman KV, Cerhan JH, et al. Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017;18:1049-1060. 10.1016/S1470-2045(17)30441-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316:401-409. 10.1001/JAMA.2016.9839 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Brown PD, Gondi V, Pugh S, et al. ; 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;38:1019-1029. 10.1200/JCO.19.02767 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Gray BJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141-1154. [Google Scholar]
- 7. Cherng HRR, Sun K, Bentzen S, et al. Evaluating the heterogeneity of hippocampal avoidant whole brain radiotherapy treatment effect: a secondary analysis of NRG CC001. Neuro Oncol. 2024;26:911-921. 10.1093/NEUONC/NOAD226, [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Newman S, Wilkinson DJ, Royse CF. Assessment of early cognitive recovery after surgery using the Post-operative Quality of Recovery Scale. Acta Anaesthesiol Scand. 2014;58:185-191. 10.1111/AAS.12234, [DOI] [PubMed] [Google Scholar]
- 9. Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet. 2011;377:1693-1702. 10.1016/S0140-6736(11)60325-5 [DOI] [PubMed] [Google Scholar]
- 10. Cicerone KD, Goldin Y, Ganci K, et al. Evidence-based cognitive rehabilitation: systematic review of the literature from 2009 through 2014. Arch Phys Med Rehabil. 2019;100:1515-1533. 10.1016/j.apmr.2019.02.011 [DOI] [PubMed] [Google Scholar]
- 11. Feinstein A, Amato MP, Brichetto G, et al. ; CogEx Research Team. Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis (CogEx): a randomised, blinded, sham-controlled trial. Lancet Neurol. 2023;22:912-924. 10.1016/S1474-4422(23)00280-6 [DOI] [PubMed] [Google Scholar]
- 12. Bahar-Fuchs A, Clare L, Woods B. Cognitive training and cognitive rehabilitation for mild to moderate Alzheimer’s disease and vascular dementia. Cochrane Database Syst Rev. 2013;2013:CD003260. 10.1002/14651858.CD003260.PUB2, [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Baxendale S. Cognitive rehabilitation and prehabilitation in people with epilepsy. Epilepsy Behav. 2020;106:107027. 10.1016/j.yebeh.2020.107027 [DOI] [PubMed] [Google Scholar]
- 14. Giustiniani A, Maistrello L, Danesin L, Rigon E, Burgio F. Effects of cognitive rehabilitation in Parkinson disease: a meta-analysis. Neurol Sci. 2022;43:2323-2337. 10.1007/S10072-021-05772-4 [DOI] [PubMed] [Google Scholar]
- 15. Gondi V, Deshmukh S, Brown PD, et al. Sustained preservation of cognition and prevention of patient-reported symptoms with hippocampal avoidance during whole-brain radiation therapy for brain metastases: final results of NRG Oncology CC001. Int J Radiat Oncol Biol Phys. 2023;121:571-580. 10.1016/J.IJROBP.2023.04.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Roberge D, Brown PD, Whitton A, et al. The future is now—prospective study of radiosurgery for more than 4 brain metastases to start in 2018! Front Oncol. 2018;8:380. 10.3389/FONC.2018.00380 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Aizer A, Tanguturi SK, Benham G, et al. Stereotactic radiation versus hippocampal avoidance whole brain radiation in patients with 5-20 brain metastases: a multicenter, phase 3 randomized trial. J Clin Oncol. 2025;43:2011-2011. 10.1200/JCO.2025.43.16_SUPPL.2011 [DOI] [Google Scholar]
- 18. Tariq R, Aziz HF, Paracha S, et al. Cognitive rehabilitation of brain tumor survivors: a systematic review. Brain Tumor Res Treat. 2025;13:1-16. 10.14791/BTRT.2024.0033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Weyer-Jamora C, Brie MS, Luks TL, Smith EM, Hervey-Jumper SL, Taylor JW. Postacute cognitive rehabilitation for adult brain tumor patients. Neurosurgery. 2021;89:945-953. 10.1093/NEUROS/NYAA552 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Coomans MB, van der Linden SD, Gehring K, Taphoorn MJB. Treatment of cognitive deficits in brain tumour patients: current status and future directions. Curr Opin Oncol. 2019;31:540-547. 10.1097/CCO.0000000000000581 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All datasets are available through the National Clinical Trials Network (NCTN) Data Archive of the National Cancer Institute’s (NCI’s) NCTN. The link for the archive is https://nctn-data-archive.nci.nih.gov/.