Abstract
Background and Purpose
To investigate the significance of the number of brain metastases in the treatment with stereotactic radiotherapy (SRT) with or without whole brain radiotherapy (WBRT).
Material and Methods
Between February 2003 and October 2010, 218 consecutive patients with brain metastases who underwent SRT alone or WBRT plus SRT were investigated. The prognostic factors affecting overall survival and brain progression-free survival were analyzed by multivariate and univariate analysis. By logistic regression analysis, factors associated with the number recurrences of brain metastasis after SRT were also investigated.
Results
The median overall and brain progression-free survivals were 7.2 months and 4.3 months, respectively. Significant prognostic factors for overall survival in multivariate analyses were performance status (hazard ratio [HR] = 1.71, 95% confidence interval [CI] 1.13–2.57, p = 0.01) and the number of brain metastases (HR = 1.75, 95% CI 1.08–2.83, p = 0.02). Cut-off line of the number of brain metastases was between 3 and 4, and 3 or fewer brain metastases were significantly better than 4 or more in prognosis by univariate and multivariate analysis (p < 0.01, p = 0.02).
Conclusions
The patients with 3 or fewer brain metastases were associated with brain progression free survival and 3 or fewer brain relapse. Repeated SRT without WBRT may be effective for patients with 3 or fewer brain metastases.
Keywords: oligometastases, brain metastases, stereotactic radiotherapy, stereotactic radiosurgery, whole brain radiotherapy
INTRODUCTION
Brain metastases are the most common brain malignancy in patients with systemic cancer, estimated at annual incidence rate of over 60,000 cases in Japan according to an autopsy series1. Brain metastases are severe conditions that cause not only death, but also deterioration in quality of life. Corticosteroid agents improve survival and quality of life for patients with brain metastases by reducing increased intracranial pressure due to brain edema2. Whole brain radiotherapy (WBRT) also leads to improvements by controlling tumors at a certain level. Borgelt et al. conducted a randomized trial to find an optimized dose and fraction schedule; however, no significant differences were observed3.
Stereotactic radiotherapy (SRT) can concentrate radiation doses to a limited volume and appears to be very effective when the tumor in the brain is small4,5. This treatment can also be performed repeatedly with a small burden on the brain. Thus, SRT was rapidly accepted in the US6 and later adopted in Japan in the 1990’s as a useful tool for patients with small brain metastases, although no clinical study had been performed. Kondziolka et al. conducted the first randomized trial to demonstrate the benefit of adding SRT when the primary endpoint was local control rate. This study was halted according to the trial’s predetermined stopping rule, because a group treated with WBRT plus single-fraction SRT achieved a significantly higher local control rate than those treated with WBRT alone in an interim analysis7. The RTOG 9508 trial showed that WBRT with single-fraction SRT prolonged overall survival over WBRT alone for patients with solitary brain metastasis8. The median overall survival for patients treated with WBRT and single-fraction SRT was 6.5 months, which was longer than those treated in previous RTOG trials3,9,10. In contrast, Aoyama et al. investigated the effect of WBRT when SRT was performed in patients with brain metastases on a multiinstitutional basis (Japanese Radiation Oncology Study Group Protocol [JROSG] 99-1)11. The trial showed the addition of WBRT enhanced the local control rates and brain control rates outside the irradiated volume, but not survival rates. Recently, neurocognitive function has been identified as a major concern when treating patients with WBRT for brain metastases.
In this communication, we investigated the significance of the number of brain metastases and various factors to identify patients who do not need WBRT when SRT is used to treat their brain metastases.
MATERIAL AND METHODS
Patient selection
Between February 2003 and October 2010, 226 consecutive patients with brain metastases who underwent SRT at Tokyo Medical University Hospital or its satellite hospital, Tsukuba Medical Hospital, were investigated. Eight patients who discontinued radiotherapy due to deterioration of performance status were excluded from this study. Thus, 218 consecutive patients were included. The median age was 64.2 (range, 33 to 87) years old. The patients’ characteristics are shown in Table 1. One hundred thirty one patients (60.1%) underwent SRT alone and 87 patients (39.9%) underwent WBRT plus SRT.
Table 1.
Patients’ characteristics (n=218)
| All | SRT alone (n=131) | SRT plus WBRT (n=87) | P value | |
|---|---|---|---|---|
| Age (years) | 0.271 | |||
| <65 | 105 (48.1%) | 59 (45.0%) | 46 (52.9%) | |
| ≥65 | 113 (51.8%) | 72 (55.0%) | 41 (47.1%) | |
| Sex | 0.147 | |||
| Male | 142 (65.1%) | 80 (61.1%) | 62 (71.3%) | |
| Female | 76 (34.9%) | 51 (38.9%) | 25 (28.7%) | |
| Performance status | 0.080 | |||
| 0,1 | 176 (80.7%) | 111 (84.7%) | 65 (74.7%) | |
| 2-4 | 42 (19.3%) | 20 (15.3%) | 22 (25.3%) | |
| Active extracranial tumors | 0.213 | |||
| Presence | 159 (72,9%) | 100 (76.3%) | 59 (67.8%) | |
| Absence | 59 (27.1%) | 31 (23.7%) | 28 (32.2%) | |
| Number of brain metastases | 0.003 | |||
| 1-3 | 191 (87.6%) | 122 (93.1%) | 69 (79.3%) | |
| ≥4 | 27 (12.4%) | 9 (6.9%) | 18 (20.7%) | |
| Primary cancer | 0.128 | |||
| Lung | 138 (63.3%) | 76 (58.0%) | 62 (71.3%) | |
| Breast | 23 (10.6%) | 15 (11.5%) | 8 (9.2%) | |
| Others | 57 (26.1%) | 40 (30.5%) | 17 (19.5%) |
To count the number of tumors, axial, coronal, and sagittal views of gadolinium-enhanced brain magnetic resonance imaging (MRI) were taken within 1 month before treatment (1.5 T MRI, Siemens Co. Ltd. Germany). Patients were excluded from this study if they were diagnosed with leukemia, lymphoma, germ-cell tumors, small-cell lung cancer, or leptomeningeal disease, and if they previously underwent tumor resection or radiotherapy of the brain, including SRT or WBRT. Patients whose tumors were located in the brain stem were also excluded. Conditions of extracranial cancer were determined to be active when the cancer had clinically progressed for 3 months before SRT. The patients were stratified based on age, performance status (PS), the status of the extracranial disease, addition or absence of WBRT, and the number of brain metastases and Graded Prognostic Assessment (GPA) score. PS was classified according to Eastern Cooperative Oncology Group (ECOG) criteria.
Treatment
A rigid head immobilization plastic frame was custom-made for SRT (Mask-set, Brainlab AG, Feldkirchen, Germany or ESFOM, Engineering system Co., Ltd., Matsumoto, Japan). The clinical target volume (CTV) was determined as the contrast-enhanced tumor volume. The planning target volume (PTV) was determined as the CTV plus a 2–5 mm margin. An 80% isodose line of the prescribed doses was given to encompass the entire CTV. The median irradiated dose of 36 Gy (range, 12 to 52 Gy) was given daily at 12 Gy over 3 days. The detail of irradiated dose is shown in Table 2.
Table 2.
No. and total dose of SRT and WBRT
| SRT (n=218) | WBRT (n=87) | ||
|---|---|---|---|
| Total doses/Fraction | No. | Total doses/Fraction | No. |
| 36 Gy/3 fractions | 91 | 37.5 Gy/15 fractions | 44 |
| 20 Gy/1 fraction | 60 | 30 Gy/10 fractions | 39 |
| 42 Gy/7 fractions | 36 | other | 4 |
| 40 Gy/4 fractions | 13 | ||
| other | 18 |
WBRT was performed with a median of 30 Gy (range, 20 to 39 Gy) given daily at 3 Gy each over 2 weeks using 4–6 MV photons with parallel opposite ports. WBRT was performed within 1 week of completing SRT and vice versa. These patients were followed using a contrast-enhanced brain MRI every 2–4 months after the treatments.
Statistical analysis
The χ2 test or Fisher’s exact test were used to evaluate differences between the two groups. Overall survival was measured from the beginning of radiotherapy to the date of death or January 2011, whichever came first. Brain progression-free survival was calculated from the date of beginning radiotherapy to the date of relapse in the brain or the last follow-up. The survival curves were calculated using the Kaplan-Meier method and the differences were analyzed with the log-rank test. Cox proportional hazard regression analysis and univariate analysis were used to identify the most significant independent prognostic factors for survival. Logistic regression analysis was used to identify factors such as having small numbers of metastases of 3 or fewer after SRT. The variables included were age, PS, adding WBRT, number of brain metastases before SRT, and the presence or absence of active extracranial tumors. A p-value of 0.05 or less was considered significant. Statistical analyses were performed using SPSS ver. 11. (SPSS Inc., Chicago, IL).
RESULTS
The median overall survival and brain progressionfree survival were 7.2 months and 4.3 months, respectively. Univariate analysis showed significantly better overall survival in patients with a PS of 0 or 1 than those with a PS of 2 to 4 (p < 0.01), in patients with 3 or fewer brain metastases than in patients with 4 or more brain metastases (p < 0.01) (Table 3), and in patients with GPA of 0 to 1.5 than those with GPA of 2 to 4 (p < 0.01). The absence of an active extracranial tumor was marginally significantly better than the presence of one (p = 0.07). In multivariate analysis, significantly prognostic factors for overall survival were PS (hazard ratio [HR] = 1.71, 95% confidence interval [CI] of 1.13–2.57, p = 0.01) and the number of brain metastases (HR = 1.75, 95% CI 1.08–2.83, p = 0.02). Age, activate extracranial tumor and the addition of WBRT to SRT were not statistically significant for overall survival in univariate or multivariate analyses.
Table 3.
The prognostic factors for overall survival
| Univariate | Multivariate | P value | |||||
|---|---|---|---|---|---|---|---|
| MST | 95% CI (months) | P value | Hazard ratio | 95% CI | |||
| Age | < 65 | 9.1 | 7.2 - 11.0 | ||||
| 0.33 | 1.01 | 0.73 - 1.40 | 0.94 | ||||
| (years) | ≥65 | 8.0 | 7.5 - 10.2 | ||||
| PS | 0, 1 | 9.2 | 7.5 - 10.9 | ||||
| <0.01 | 1.71 | 1.13 - 2.57 | 0.01 | ||||
| 2 - 4 | 4.6 | 2.8 - 6.4 | |||||
| Active extracranial tumors | Absence | 10.1 | 8.2 - 12.0 | ||||
| 0.07 | 1.07 | 0.74 - 1.53 | 0.73 | ||||
| Presence | 8.0 | 6.5 - 9.5 | |||||
| WBRT | SRT alone | 9.0 | 7.1 - 10.9 | ||||
| SRT plus WBRT | 8.4 | 5.5 - 11.3 | 0.33 | 0.75 | 0.55 - 1.02 | 0.07 | |
| No. of brain metastases | 1 - 3 | 9.2 | 7.2 - 11.2 | ||||
| <0.01 | 1.75 | 1.08 - 2.83 | 0.02 | ||||
| ≥4 | 4.0 | 2.6 - 5.4 | |||||
| GPA | 0-1.5 | 11.4 | 8.2 - 14.6 | ||||
| <0.01 | 1.50 | 0.99 - 2.27 | 0.06 | ||||
| ≥2 | 7.1 | 5.8 - 8.4 | |||||
Abbreviations: CI, confidence interval; PS, performance status, WBRT; whole brain radiotherapy; MST, median survival time; GPA, Graded Prognostic Assessment.
Concerning brain progression-free survival, number of brain metastases of 4 or more was the only significant worse prognostic factor than 3 or fewer in prolonging brain progression-free survival with both of the univariate (p < 0.01) and multivariate analysis (HR = 3.37, 95% CI 2.02–5.62, p < 0.01) (Table 4). The addition of WBRT and age were not significant for the brain progression-free survival in univariate analysis.
Table 4.
The prognostic factors for intracranial progression-free survival
| Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|
| MST | 95% CI (months) | P value | Hazard ratio | 95% CI | P value | ||
| Age | < 65 | 4.9 | 3.1 - 6.7 | 0.60 | 1.06 | 0.77 - 1.46 | 0.71 |
| (years) | ≥65 | 5.4 | 3.8 - 7.0 | ||||
| PS | 0, 1 | 5.8 | 4.5 - 7.2 | <0.01 | 1.49 | 0.97 - 2.27 | 0.68 |
| 2 - 4 | 3.5 | 1.8 - 5.2 | |||||
| Active extracranial tumors | Absence | 7.2 | 5.2 - 9.2 | <0.01 | 1.37 | 0.91 - 2.06 | 0.13 |
| Presence | 4.4 | 3.1 - 5.7 | |||||
| WBRT | SRT alone | 5.6 | 4.2 - 7.0 | 0.43 | 0.74 | 0.55 - 1.01 | 0.06 |
| SRT plus WBRT | 4.7 | 3.3 - 6.1 | |||||
| No. of brain metastases | 1 - 3 | 5.9 | 4.7 - 7.1 | <0.01 | 3.37 | 2.02 - 5.62 | <0.01 |
| ≥4 | 2.1 | 0.9 - 3.3 | |||||
| GPA | 0 - 1.5 | 10.0 | 5.8 - 14.2 | <0.01 | 1.19 | 0.77 - 1.84 | 0.44 |
| ≥2 | 4.3 | 3.3 - 5.4 | |||||
Abbreviations: CI, confidence interval; PS, performance status, WBRT; whole brain radiotherapy; MST, median survival time; GPA: Graded Prognostic Assessment.
Fifty-five patients who previously underwent SRT alone had brain relapse (Fig. 1). The statistically significant factor associated with having 3 or fewer brain metastases after the first SRT was the number of brain metastases before the first SRT (HR = 2.93, 95% CI 1.00–8.59, p=0.05) by logistic regression analysis (Table 5).
Figure 1.
Schematic showing the number of patients receiving each treatment and their treatment outcomes.
Table 5.
The factor associated 3 or less brain relapse after SRT by logistic regression analysis
| Relative ratio | 95% CI | P value | |
|---|---|---|---|
| Performance status (0,1 : 2-4) | 0.66 | 0.22 - 2.01 | 0.47 |
| Active extracranial tumors (Presence : Absence) | 1.97 | 0.61- 6.40 | 0.26 |
| WBRT SRT plus WBRT : SRT alone | 0.97 | 0.42 - 2.27 | 0.95 |
| Number of brain metastases (1-3 : ≥4) | 2.93 | 1.00 - 8.59 | 0.05 |
| GPA (0-1.5 : ≥2) | 0.85 | 0.28 - 2.57 | 0.77 |
Abbreviations: SRT, stereotactic radiotherapy; CI, confidence interval; GPA, Graded Prognostic Assessment.
And the addition of WBRT to SRT was not significant for the brain progression-free survival and overall survival (95% confidence interval [CI] 7.95-13.65, p = 0.20, 95% CI, 6.88-9.92, p = 0.33) (Fig. 2). In 131 patients who underwent SRT alone, 3 or fewer brain metastases before SRT alone had a significant propensity for 3 or fewer brain relapse (p = 0.045) (Fig. 3).
Figure 2.
Kaplan-Meier analysis of overall survival (A) and brain progression-free survival (B) comparing patients stereotactic radiotherapy (SRT) alone with SRT with whole brain radiotherapy (WBRT) (95% confidence interval [CI] 6.68 9.92, p = 0.33, 95% CI, 7.95 13.65, p = 0.20).
Figure 3.
The comparison between the number of brain metastases before radiotherapy and brain relapse in 131 patient who underwent SRT alone. Patients with 3 or fewer brain metastases before SRT alone had a significant propensity for 3 or fewer brain relapse (p = 0.045)
DISCUSSION
In summary, overall and progression-free survival were 7.2 and 4.3 months after SRT, respectively, in our study, which were almost the same as that found in other studies8,11,12. PS and number of brain metastases were significant prognostic factors for overall survival both by multi- and uni-variate analyses. Three or fewer number of the brain metastases was the only prognostic factor for progression-free survival. We treated patients with brain metastases, assuming that SRT is standard when the number of brain metastases is 4 or fewer. In this communication, we investigated factors for which WBRT could be reasonably omitted.
Many studies have been performed to determine what adequate radiotherapy is for patients with brain metastases. However, whether WBRT is meaningful or not is still controversial. Aoyama et al. concluded that the addition of WBRT had limited effects for reducing recurrence rates, but did not increase survival rates11. Sneed et al. compared a group of 268 patients treated with SRT alone with a group of 301 patients treated with SRT plus WBRT. Although 24% of patients needed salvage therapy with WBRT, the median survivals were 14.0 and 15.2 months for recursive partitioning analysis (RPA) class I, 8.2 and 7.0 for RPA class II, and 5.3 and 5.5 for RPA class III, respectively, with no significant differences. They concluded that WBRT did not compromise overall survival13. Our results showed that adding WBRT did not prolong survival but also not reduce intracranial relapse. This results support the notions that adding WBRT does not prolong survival rates when SRT was performed in patients with few brain metastases.
Neurocognitive function is a major concern with WBRT in patients with brain metastases. Cheng et al. conducted a randomized clinical trial that compared SRT with SRT plus WBRT to identify neurocognitive function changes in learning and memory function using Hopkins Verbal Learning Test–Revised14. They showed that learning and memory function significantly declined in the SRT plus WBRT group 4 months after treatment. This trial was stopped after 58 patients were recruited according to the trial’s predetermined stopping rule. Aoyama et al. further analyzed the data from JROSG 99-1 to confirm the effect of WBRT in terms of neurocognitive function15. They concluded that the most important factor for stabilizing neurocognitive functions was control of brain tumors. WBRT was not negligible as a factor associated with deterioration of neurocognitive function. Welzel et al. concluded that deterioration of neurocognitive functions due to WBRT is limited in verbal memory, but not in visual memory16. Thus, WBRT should not be avoided in the treatment of brain metastases. In our study, we focused on identifying patients who do not need WBRT to avoid possible treatment-associated deterioration.
In 1995. Hellman and Weichselbaum proposed the concept of oligometastases17. This concept states that it is possible to cure some patients who have only a few metastases with a curative therapeutic strategy. The question remains how many brain metastases are oligometastases. Serizawa et al. analyzed 778 patients treated with gamma knife alone18. They showed that prognostic factors for overall survival were no active extracranial diseases, pretreatment Karnofsky performance status of 70 or more, and female sex, and that prognostic factors for brain metastases-free survival were 3 or fewer brain metastases at the initial diagnosis and no active extracranial disease. In our study, a prognostic factor of brain progression-free survival and overall survival was patients with fewer brain metastases. In addition, logistic regression analysis showed that 3 or fewer brain metastases was the only prognostic factor for 3 or fewer newly-developed brain metastases. This data supports that patients with 3 or fewer brain metastases had a propensity to have 3 or fewer brain metastases recurrences. Thus, we defined brain oligometastases as 3 or fewer metastases, and recommend treating these patients with SRT alone. Although absence of extracranial disease was not related with brain progression-free survival by multivariate analysis in our study, the absence of extracranial disease did not enhance the propensity to have brain oligometastases when they recurred. Further data is needed to clarify these results.
A limitation of this study is that it was a retrospective study, that primary lesions were inhomogeneous, and that there were no data on neurocognitive function. However, the clinical results were comparable with other major studies, which suggests that the treatment methods were reasonable.
In conclusion, the patients with 3 or fewer brain metastases were associated with prolonged brain progression free survival and propensity of having 3 or fewer brain relapse after SRT. Repeated SRT without WBRT may be effective for patients with 3 or fewer brain metastases. The concept of brain oligometastases was proposed in this article. Oligometastases may be useful for identifying patients who do not need WBRT.
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