Neurocognitive Function of Patients with Brain Metastasis Who Received Either Whole Brain Radiotherapy Plus Stereotactic Radiosurgery or Radiosurgery Alone
In a prospective randomized trial between WBRT+SRS and SRS alone for patients with one to four brain metastases, we assessed the neurocognitive function using the Mini-Mental State Examination (MMSE). Of the 132 enrolled patients, MMSE scores were available for 110.
Results
In the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and Karnofsky performance status. Of the 92 patients who underwent the follow-up MMSE, 39 had a baseline MMSE score of ≤27 (17 in the WBRT+SRS group and 22 in the SRS-alone group). Improvements of ≥3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (p = 0.85) were observed. Of the 82 patients with a baseline MMSE score of ≥27 or whose baseline MMSE score was ≤26 but had improved to ≥27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free rate of the 3-point drop in the MMSE was 76.1%, 68.5%, and 14.7% in the WBRT+SRS group and 59.3%, 51.9%, and 51.9% in the SRS-alone group, respectively. The average duration until deterioration was 16.5 months in the WBRT+SRS group and 7.6 months in the SRS-alone group (p = 0.05).
Conclusion
The results of the present study have revealed that, for most brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effects of WBRT on neurocognitive function might not be negligible.
Introduction
Whole brain radiotherapy (WBRT) has long been a mainstay of treatment of brain metastases. The role of WBRT is to control radiologically visualized tumors, as well as nonvisualized micrometastases. Stereotactic radiosurgery (SRS) is a method of delivering high doses of focal irradiation to a tumor while minimizing the irradiation to the adjacent normal tissue 1, 2. Beginning in the 1990s, it has become increasingly used worldwide for patients with no more than a few brain metastases. A recent prospective randomized trial from the Radiation Therapy Oncology Group (RTOG) showed a small, but significant, improvement in the survival of patients who had had up to three metastases with good prognostic factors when SRS was used in conjunction with WBRT (2).
However, WBRT has several adverse effects. Acute adverse effects include nausea and headache, but they are generally limited in severity and duration. However, the late adverse effects are severe, progressive, and irreversible. They are caused by a syndrome called leukoencephalopathy, which is a structural alteration of cerebral white matter in which myelin suffers the most damage. Mild cases are typified by a chronic confusional state with inattention, memory loss, and emotional dysfunction. More severe cases produce major neurologic sequelae such as dementia, abulia, stupor, and coma. These symptoms usually develop 6–24 months after cranial RT. The degree of neurotoxicity resulting from WBRT correlates with the total dose received and with the time-dose-fractionation scheme (3). Because of the concern about leukoencephalopathy resulting from WBRT, treatment strategies relying on SRS alone have been increasingly used 4, 5, 6, 7. However, the omission of WBRT from the initial brain management has resulted in a significant increase in brain tumor recurrence 6, 7. Regine et al. (8) reported that brain tumor recurrence could also be a cause of neurocognitive functional deterioration.
The present study from the Japanese Radiation Oncology Study Group Protocol 99-1 is the first prospective randomized trial comparing SRS alone and WBRT combined with SRS. The details of the results have been previously published (1). In brief, it was a multi-institutional prospective randomized trial comparing WBRT+SRS and SRS alone conducted in Japan between 1999 and 2003. The 132 patients were randomized to receive WBRT+SRS (n = 65) or SRS alone (n = 67) for brain metastases. The primary endpoint was survival. No significant difference between the groups was observed in survival or cause of death; however, patients in the SRS-alone group developed brain tumor recurrences significantly more frequently than did those in the WBRT+SRS group. No difference in the functional observation rate (Karnofsky performance status ≥70) was observed.
We also monitored neurocognitive function serially using the Mini-Mental State Examination (MMSE) 8, 9, 10, 11, 12. We present the results of our detailed analysis of neurocognitive function for this trial. This is the first report to compare the neurocognitive function of patients who underwent either SRS alone or WBRT+SRS.
Section snippets
Randomization and treatment
Eligible patients had one to four brain metastases detected on enhanced magnetic resonance imaging, each <3 cm, and a good systemic performance status (Karnofsky performance status of ≥70). A total of 132 patients were randomized to receive WBRT+SRS (65 patients) or SRS alone (67 patients) for brain metastases. Each patient provided written informed consent before entry into the study. Randomization was performed at the Hokkaido University Hospital Data Center. A permuted-blocks randomization
Baseline MMSE
The pretreatment MMSE was available for 99 patients. MMSE data during the treatment were obtained for 11 additional patients. Those data, from 110 (83%) of the 132 patients enrolled in the study, constituted the “baseline” MMSE data and were used for the analysis (Fig. 1). The characteristics of those 110 patients are listed in Table 1 by treatment group. No statistically significant differences were found between the two groups. A comparison of the MMSE scores according to the patient
Discussion
The MMSE is the most frequently used and established tool for assessing the neurocognitive function of patients with brain tumors 7, 8, 9, 10, 11, 12, 13. The importance of MMSE in the treatment of patients with brain metastases, as well as in those with low-grade glioma, has been reported by Murray et al. (9) and Brown et al. (10). Murray et al. (9) assessed the MMSE scores of 182 patients with brain metastases who were treated with WBRT to 30 Gy in 10 fractions among 445 patients enrolled in
Conclusion
The results of the present study have revealed that the control of brain tumors is the most important factor in stabilizing neurocognitive function for most brain metastatic patients. However, the long-term adverse effect on neurocognitive function might not be negligible. Therefore, the development of a method to identify those patients who are less likely to experience brain tumor recurrence, as well as additional investigation to establish an optimal schedule of WBRT when combined with SRS,
Stereotactic radiosurgery plus whole-brain radiation therapy vs. stereotactic radiosurgery alone for treatment of brain metastases: A randomized controlled trial
JAMA
(2006)
C.M. Filley et al.
Toxic leukoencephalopathy
N Engl J Med
(2001)
T. Hasegawa et al.
Brain metastases treated with radiosurgery alone: An alternative to whole brain radiotherapy?
To evaluate the clinical feasibility of single-isocentre non-coplanar volumetric modulated arc therapy (NC-VMAT) with non-coplanar cone beam computed tomography (NC-CBCT) in hypofractionated stereotactic radiotherapy (HSRT) for five or fewer multiple brain metastases.
Ten patients with multiple brain metastases who underwent single-isocentre NC-VMAT HSRT with limited couch rotations (within ±45°) and NC-CBCT with a limited scanning range (150–200°) were included in the current analysis. Conventional single-isocentre coplanar VMAT (C-VMAT) plans were generated and compared with NC-VMAT plans. The intracranial response and toxicities of single-isocentre NC-VMAT HSRT were also evaluated.
Compared with C-VMAT, NC-VMAT generated better target conformity (P < 0.05), a lower gradient index (P < 0.05) and better normal brain tissue sparing, especially for volume ≥12 Gy, with a median reduction of 12.65 cm3. For 45° couch rotation, NC-CBCT produced sufficient image quality to differentiate bony anatomy, even with a 150° scanning range, which could be successfully used for patient set-up correction. After NC-CBCT, 57.1% of the measured non-coplanar set-up errors exceeded the threshold value. The median gamma passing rate of NC-VMAT was higher than that of C-VMAT plans (P < 0.05). The non-coplanar beam of NC-VMAT with NC-CBCT corrections exhibited superior gamma passing rate to that without NC-CBCT corrections. The intracranial objective response rate and disease control rate for all patients were 80% (8/10) and 100% (10/10), respectively, and the most common toxicities were headache (20%) and dizziness (20%).
NC-VMAT with limited couch rotation (within ±45°) combined with NC-CBCT with a limited scanning range (150–200°) markedly improves the plan quality and set-up accuracy in single-isocentre multiple-target HSRT.
Brain metastases (BM) occur in the natural course of malignant tumors in 18–40% of cases. Their management has changed considerably over the past decade thanks to the advent of Gamma knife Stereotactic Radiosurgery (GKSR).
We report our experience on Single Brain metastasis treated with (GKSR).
Patients treated by Gamma Knife stereotaxic radiosurgery (GKSR) in our institution between 2009 and 2021 for Single BM were recorded retrospectively.
A total of 103 patients (n = 52; 50.5% females) were included, with a mean age of 56.33 ± 11.33. Breast (n = 39, 37.9%) and lung (n = 36, 35%) were the common original location for the primary tumors. GKSR alone without prior surgery, radiotherapy, or chemotherapy was achieved in 81.5% (n = 84). Thirteen patients (15.1%) progressed in BM volume while finding the appearance of de novo BM in 5 (5.8%) patients. The median percentage of tumor control after radiosurgery treatment was 70% (IQR: 65–78) and only 26.2% (n = 27) of patients had > 80% tumor control and stability over the median follow-up time of 5 (95% CI, 4–6) months. We found only two cases of radionecrosis (1.9%). The median survival time was 5.21 (IQR, 3–8) months. Retreatment, recursive partitioning analysis (RPA) class, and tumor stability influenced the overall survival of BM respectively (Hazard Ratio adjust (HRa)= 5.610,p = 0.045; HRa= 6.133,p = 0.031; HRa= 22.463, p = 0.036).
Stereotaxic Radiosurgery provides good results in terms of Overall survival with fewer neurocognitive disorders.RPA class and tumor control (stability) influenced the overall survival of single BM.
The HyperArc technique is known for generating high-quality radiosurgical treatment plans for intracranial lesions or hippocampal-sparing whole-brain radiotherapy (WBRT). However, there is no reported feasibility of using the HyperArc technique in hippocampal-sparing WBRT with a simultaneous integrated boost (SIB). This study aimed to compare dosimetric parameters of 2 commercially-available volumetric-modulated arc radiotherapy techniques, HyperArc and RapidArc, when using hippocampal-sparing WBRT with a SIB to treat brain metastases.
Treatment plans using HyperArc and RapidArc techniques were generated retrospectively for 19 previously treated patients (1 to 3 brain metastases). The planning target volumes for the whole brain (excluding the hippocampal avoidance region; PTVWB) and metastases (PTVmet) were prescribed 25 and 45 Gy, respectively, in 10 fractions. Each plan included homogeneous and inhomogeneous delivery to the PTVmet. Dosimetric parameters for the target (conformity index [CI], homogeneity index [HI], target coverage [D95%]), and nontarget organs at risk were compared for the HyperArc and RapidArc plans.
For homogeneous delivery, dosimetric parameters, including mean CI, HI, and target coverage in PTVWB and PTVmet, were superior for HyperArc than RapidArc plans (all p < 0.01). The PTVWB and PTVmet target coverage for HyperArc plans was significantly greater than for RapidArc plans (96.17% vs 93.38%, p < 0.01; 94.02% vs 92.21%, p < 0.01, respectively). HyperArc plans had significantly lower mean hippocampal Dmax and Dmin values than RapidArc plans (Dmax: 15.53 Gy vs, 16.71 Gy, p < 0.01; Dmin: 8.33 Gy vs 8.93 Gy, p < 0.01, respectively). Similarly, inhomogeneous delivery of hyperArc produced a superior target and lower hippocampal dosimetric parameters than RapidArc, except for the HI of PTVmet (all p < 0.01).
HyperArc generated superior conformity and target coverage with lower hippocampal doses than RapidArc. HyperArc could be an attractive technique for hippocampal-sparing WBRT with an SIB.
Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient.
Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12 Gy isodose at the first SRT and the 18 Gy isodose of the following SRT (V18-12Gy).
At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3–20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2–14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6–18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P < 0.001) and the number of SRTs (P < 0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P = 0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5 ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5 ml. The sum of all V18-12Gy larger than 1.5 ml was associated with a 74% specificity and 53% sensitivity of RN (P < 0.001).
Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6 ml in the case of local reirradiation or larger than 1.5 ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.
Dix à 40 % des patients atteints de cancer seront atteints d’une ou plusieurs métastases cérébrales. La radiothérapie en conditions stéréotaxiques fait partie de l’arsenal thérapeutique dans le traitement des métastases cérébrales de novo ou récidivantes. Son principal intérêt est de retarder la radiothérapie de l’encéphale en totalité, pourvoyeuse de toxicité cognitive. Cependant, la radiothérapie en conditions stéréotaxiques n’est pas exempte de toxicité à long terme, la plus connue étant la radionécrose. L’objectif de cette étude était d’analyser la fréquence de la radionécrose chez les patients pris en charge par radiothérapies en conditions stéréotaxiques répétées.
Entre 2010 et 2020, les données de 184 patients traités pour 915 métastases cérébrales par deux à six séances de radiothérapie en conditions stéréotaxiques pour une récidive cérébrale locale ou distante sans irradiation de l’encéphale en totalité préalable ou intercurrente ont été examinées rétrospectivement. La radionécrose a été étudiée sur l’IRM de suivi trimestriel et potentiellement confirmée par la chirurgie ou des examens de médecine nucléaire. Pour chaque métastase et à chaque session de radiothérapie en conditions stéréotaxiques, les V12Gy, V14Gy, V21Gy et V23Gy (VxGy : volume recevant × Gy) ont été collectés. Des volumes d’intersections ont été créés entre l’isodose 12 Gy de la première radiothérapie en conditions stéréotaxiques et l’isodose 18 Gy des radiothérapies en conditions stéréotaxiques suivantes (V18-12Gy).
À la fin du suivi, une radionécrose a été notée chez 3,0 % des patients et 6,3 % des métastases cérébrales. Le suivi médian des métastases cérébrales était de 13,3 mois (IC95 % [intervalle de confiance à 95 %] 18,3-20,8). L’intervalle médian entre l’irradiation de la métastases cérébrales et la survenue de la radionécrose était de 8,7 mois (IC 95 % : 9,2-14,7). Les taux de survie sans radionécrose à 6, 12 et 24 mois par métastase cérébrale étaient respectivement de 75 %, 54 % et 29 %. La médiane de survie sans radionécrose par patient était de 15,3 mois (IC 95 % : 13,6-18,1). En analyse multifactorielle par métastase cérébrale, la survenue de radionécrose était statistiquement associée à la réirradiation locale (p < 0,001) et au nombre de radiothérapies en conditions stéréotaxiques (p < 0,001). En analyse unifactorielle par patient, l’apparition de radionécrose était statistiquement associée à la somme de tous les V18-12Gy (p = 0,02). Aucune association statistique n’a été trouvée en analyse multifactorielle. Une somme de tous les V 18-12Gy inférieure à 1,5 ml était associée à un risque de radionécrose de 14,6 %, contre 35,6 % lorsque cette somme était supérieure à 1,5 ml. Une somme des V18-12Gy supérieure à 1,5 ml était associée à une spécificité de 74 % et à une sensibilité de 53 % de radionécrose (p < 0,001).
La radiothérapie en conditions stéréotaxiques était peu pourvoyeuse de radionécrose lors des irradiations répétées de métastases cérébrales de novo, en récidive locale ou cérébrale. La réirradiation locale était le facteur le plus prédictif de radionécrose cérébrale. Un V18-12Gy supérieur à 7,6 ml en cas de réirradiation locale ou supérieur à 1,5 ml en cas de réirradiation de proximité étaient des facteurs pronostiques de radionécrose. Le risque individuel de radionécrose par patient était plus élevé chez les patients survivant longtemps après l’irradiation et ceux ayant reçu de nombreuses sessions de radiothérapie en conditions stéréotaxiques.
Partly supported by a grant-in-aid for scientific research (Grant 18209039) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
