Research ArticleClinical Studies

Predicting the Risk of Subsequent Distant Brain Metastases After Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy in Elderly Patients

DIRK RADES, TRANG NGUYEN, LIESA DZIGGEL, OLIVER BLANCK and STEVEN E. SCHILD
Anticancer Research July 2020, 40 (7) 4081-4086; DOI: https://doi.org/10.21873/anticanres.14406

Abstract

Background/Aim: Treatment for elderly patients with few brain metastases is controversial. A score was generated to predict distant brain metastases (DBMs) after stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). Patients and Methods: Ten characteristics were retrospectively analyzed for freedom from new DBMs in 104 elderly patients receiving SRS or FSRT alone for 1-3 brain metastases. Characteristics that were significant or showed a trend on multivariate analysis were used for the score. Results: On multivariate analysis, favorable histology (p=0.026) and single brain metastasis (p=0.006) showed significant associations with freedom from DBMs. A trend was found for supra-tentorial location only (p=0.065). Three groups were designed, 10-14, 16-20 and 21-25 points, with 6-month rates of freedom from DBMs of 10%, 54% and 95%, respectively (p<0.0001). Positive predictive values to predict DBMs and freedom from DBMs at 6 months were 91% and 94%. Conclusion: This new score provided high accuracy in predicting DBMs and freedom from DBMs.

Brain metastases can be found in up to 30-40% of adult cancer patients during the course of their malignant disease (1). Patients with a limited number of one to three lesions account for about 40% of these patients and often receive a local therapy such as neurosurgery, single-fraction stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT). The majority of patients with one to three brain metastases receive SRS or FSRT, whereas neurosurgery is mainly limited to one or two larger (>3-4 cm) lesions (2). Local therapies can be administered alone or in combination with whole-brain irradiation (WBI). More recently, local therapies have also been combined with novel systemic agents (3). The role of WBI in addition to a local therapy is controversial. In 2009, a randomized trial was stopped early, because WBI when added to SRS led to a significantly higher rate of cognitive decline after 4 months (4). Similar results were reported from another randomized trial published in 2016 (5). However, after one-year, intra-cerebral progression, mainly new distant brain metastases (DBMs) outside the irradiated sites, was significantly more common in the SRS alone groups of both trials (4-5). Since intra-cerebral progression can also be associated with cognitive decline, it may not be optimal to omit WBI in all patients with a few brain metastases (6, 7). Individualized approaches appear preferable. To select the optimal treatment for such a patient, a scoring system that allows the identification of patients with a high probability of developing new DBMs within a comparably short time, i.e. 6 months, will be helpful. These patients may benefit from the addition of WBI, particularly if a hippocampus-sparing approach (plus memantine) is used that can significantly reduce cognitive decline (8-10). On the contrary, WBI can be omitted in patients who have a low risk of experiencing new DBMs. Six years ago, we created a scoring instrument to predict the risk of new DBMs in a cohort of patients of any age (median age: 61 years) (11). It is generally accepted that elderly patients, often defined as 65 years and older, should be regarded as a separate group (12). Since in the previous score elderly patients were under-represented, it appeared reasonable to generate an additional score tailored to this age group (11). Therefore, the present study was conducted with the goal of providing such a specific tool for elderly patients.

Patients and Methods

One-hundred-and-four elderly patients (65 years or older) treated with SRS (n=81) or FSRT (n=23) alone for one to three brain metastases between 1999 and 2019 were included in this retrospective study. The study has received approval from the Ethics Committee of the University of Lübeck (reference 19-011A). Seventy-three patients were irradiated with linear accelerator-based SRS/FSRT and 31 patients with Cyberknife® radiosurgery. The patients generally had imaging data after about six weeks, three months, six months and twelve months, and if they experienced new or progressive symptoms. Ten characteristics were evaluated for associations with freedom from new DBMs including the dose of SRS/FSRT given as an equivalent dose in 2 Gy fractions (EQD2) (<50 Gy vs. 50 Gy vs. >50 Gy, using an alpha/beta value of 10 Gy for tumor cell kill, which was prescribed to the 75-90% isodose), age at SRS/FSRT (≤70 vs. ≥71 years, median age=70 years), gender (female vs. male), Karnofsky performance score (70-80% vs. 90-100%), histology of the primary tumor (breast cancer vs. lung cancer vs. kidney cancer vs. malignant melanoma vs. colorectal cancer vs. other histology), number of brain metastases (1 vs. 2 or 3 lesions), maximum cumulative diameter of the brain metastases (≤15 mm vs. ≥16 mm, median diameter=15.5 mm), location of the brain metastases (supra-tentorial location only vs. infra-tentorial with or without supra-tentorial involvement), extra-cerebral metastasis (presence vs. absence) and the time from tumor diagnosis until SRS/FSRT (≤18 vs. ≥19 months, median time=19 months). Other tumors included cancer of unknown primary (n=2) prostate cancer (n=2), oropharynx cancer (n=1), ovarian cancer (n=1) and pancreatic cancer (n=1).

For all 10 characteristics, univariate analyses were performed regarding freedom from new DBMs by applying the Kaplan-Meier method and the log-rank test. If characteristics were significantly associated with freedom from new DBMs (p<0.05) or showed a trend (p<0.07), they were additionally included in a multivariate analysis with the Cox proportional hazard model. Those characteristics that were significant or showed a trend also in the multivariate analysis were used for creating the prognostic instrument designed to predict the 6-month probability of freedom from new DBMs. The 6-month rates of freedom from new DBMs, referenced from the day of SRS or the first fraction of FSRT, were divided by 10 for each characteristic to obtain the corresponding scoring points. These points were added, and the resulting sum represented the total score for an individual patient.

The new instrument was compared to an existing score regarding correct identification of patients who developed new DBMs within 6 months after SRS/FSRT and patients achieving freedom from new DBMs for 6 months or longer following SRS/FSRT. These comparisons were performed based on the corresponding positive predictive values (PPVs) that were calculated by dividing the number of true positives with the number of all patients (true positives plus false positives).

Results

On univariate analyses, a favorable histology (breast cancer, lung cancer, kidney cancer and colorectal cancer) (p<0.001), a single brain metastasis (p<0.001), a maximum cumulative diameter of all lesions ≤15 mm and supra-tentorial location only (p=0.018) showed significant associations with higher rates of freedom from new DBMs (Table I). In the additional multivariate analysis (Table II), histology (p=0.026) and number of brain metastases (p=0.006) achieved significance, and a trend was found for location of the brain metastases (p=0.065). Therefore, these characteristics were taken to create the prognostic score.

View this table:
Table I.

Freedom from distant brain metastases at 6 and 12 months after SRS/FSRT.

Using the procedure described above, scoring points between 10 and 25 were obtained (Table III). The rates of freedom from new DBMs at 6 months are shown in Figure 1. Based on these rates, three groups were designed: 10-14 points (n=11), 16-20 points (n=50) and 21-25 points (n=43). The 6-months of freedom from new DBMs of these groups were 10%, 54% and 95%, respectively (Figure 2, p<0.0001).

View this table:
Table II.

Results obtained from the Cox proportional hazard model.

For the calculations of the PPVs regarding the identification of patients developing new DBMs within 6 months (least favorable group=10-14 points) and patients without new DBMs after 6 months (most favorable group=21-25 points), patients who had a follow up of less than 6 months and did not experience new DBMs during this period were excluded. The PPV to correctly predict new DBMs within 6 months was 91% (10 of 11 patients), and the PPV to correctly predict freedom from DBMs after 6 months was 94% (32 of 34 patients). In the previous score developed from patients of any age with one to three brain metastases (Table IV), the PPVs were 73% (16 of 22 patients) in the least favorable of three groups (16-17 points) and 92% (12 of 13 patients) in the most favorable group (21-22 points), respectively (11).

Discussion

SRS and FSRT are very often used to treat limited numbers of brain metastases, since these therapies are less invasive than surgical resection and may even result in better control of the metastases (13-18). When SRS and FSRT are administered, controversy still exists whether they should be combined with WBI. For a long time, it was considered very important to avoid intra-cerebral progression including new DBMs, since such a progression could be associated with significant cognitive deficits (6, 7, 19). In 2001, the authors of a secondary analysis of a Radiation Therapy Oncology Group trial, which compared accelerated WBI and accelerated hyper-fractionated WBI, stated that the only factor associated with poor neuro-cognitive function was an intra-cerebral recurrence (19). In 2004, a similar statement was given in an article reporting the neuro-cognitive outcomes of a randomized trial that compared WBI alone to WBI plus motexafin gadolinium (6). In a report of neuro-cognitive findings of a third randomized trial, the time to cognitive decline (decrease by 3 or more points in the Mini-Mental State Examination) was 16.5 months after SRS plus WBI compared to 7.6 months after SRS alone (p=0.05) (7).

View this table:
Table III.

Rates of freedom from new distant brain metastases (in %) at 6 months after stereotactic radiosurgery/fractionated stereotactic radiotherapy of the characteristics used for the prognostic tool and the related scoring points.

View this table:
Table IV.

Scoring points of the previous score (11).

However, in 2009, a randomized trial, which was stopped by the data safety monitoring board after 58 patients, suggested that the addition of WBI to SRS resulted in a significantly higher rate of cognitive decline (4). At 4 months following treatment, cognitive decline was observed in 24% of patients receiving SRS alone and in 96% of patients receiving SRS plus WBI, respectively (p<0.001). After the publication of this trial, radiation oncologists became more reluctant regarding the addition of WBI. Similar findings were reported from another randomized trial of 213 patients in 2016 (5). In this trial, the rates of cognitive progression after 3 months compared to baseline were 92% with SRS plus WBI and 64% with SRS alone (p<0.001). However, in both trials, long-term intra-cerebral control was significantly better in the SRS+WBI groups (4-5). In the first trial, 1-year intra-cerebral control rates were 73% after SRS+WBI and 27% after SRS alone (p<0.001) (4). In the second trial, intra-cerebral progression at 1 year was observed in 50% of the patients after SRS alone and 15% after SRS+WBI (p<0.001) (5). It remains unclear, whether the higher rates of intra-cerebral progression were associated with increased cognitive impairment. In the first trial, cognitive function was evaluated only after 4 months (4). However, in the second trial, cognitive decline was assessed up to 12 months (5); the incidence after 12 months was lower after SRS alone than after SRS+WBI (60% vs. 94%). However, only 10 and 18 patients, respectively, were evaluable resulting in a very low statistical power. Moreover, both trials did not use the newer approaches of hippocampus-sparing WBI and memantine. These two approaches and their combination were demonstrated to lead to a significant reduction in WBI-associated cognitive decline (8-10). In the study of Gondi et al., cognitive decline occurred in 7% of 42 patients treated with hippocampus-sparing WBI within the study compared to 30% of patients belonging to a historical control group (p<0.001). In a randomized trial of 554 patients, the addition of memantine to WBI (37.5 Gy in 15 fractions) led to a prolongation of the time to decline in cognitive function (p=0.01) (9). Moreover, in a recent randomized trial including 518 patients, hippocampus-sparing WBI plus memantine resulted in a significantly lower risk of neuro-cognitive decline when compared to non-hippocampus-sparing WBI plus memantine (adjusted hazard ratio=0.74, p=0.02) (10).

Figure 1.
Figure 1.

Scoring points for individual patients and corresponding rates of freedom from new distant brain metastases (DBMs) after 6 months.

Certainly, the best option to avoid cognitive decline is the omission of WBI. Therefore, it is important to have a clear understanding of an individual patient's risk to experience intra-cerebral progression such as new DBMs. To support physicians with this matter, a scoring tool that included three groups with different probabilities of developing new DMBs within 6 months following radiosurgery alone was already introduced (11). However, this previous tool was developed in a cohort of patients of any age with one to three brain metastases. The majority of patients were younger than 65 years. It is generally agreed that patients aged ≥65 years must be regarded a specific group that often requires adjustments of treatment protocols administered to younger patients, considering the higher rate of underlying diseases, reduced organ functions and differences in physiology.

Figure 2.
Figure 2.

Kaplan-Meier curves of the prognostic groups 10-14 points (n=11), 16-20 points (n=50) and 10 points (n=43) for freedom from new distant brain metastases (DBMs). Calculation of the p-value was performed using the log-rank test.

Therefore, it appeared reasonable to create an additional score tailored to this patient group, as done in the present study. Considering the 6-month rates of freedom from new DBMs, three groups were formed. Since only 10% of the patients of the 10-14 points group did not develop new DBMs within 6 months after SRS or FSRT alone (high risk group), these patients would likely benefit from the addition of WBI in terms of improved intracerebral control. On the contrary, the rate of freedom from new DBMs in the 21-25 points group was very high (95%, low risk group). Therefore, WBI may be omitted in this group. For patients of the intermediate risk group with a probability of freedom from new DBMs with 6 months of 54%, WBI may be considered for selected patients, depending on several factors including the patient's preferences and social situation as well as the estimated survival time, co-morbidities and general condition. It is also critical to integrate memantine and radiotherapy with hippocampal sparing to provide the best neurocognitive outcomes (8-10).

Our new score was compared to the previous score for accuracy in predicting new DBMs within 6 months and freedom from DBMs after 6 months (11). The corresponding PPVs were higher for the new score. It was particularly superior to the previous tool regarding the correct prediction of new DBMs within 6 months. However, one should be aware that, since the new score was created from retrospective data, the risk of hidden biases existed. Moreover, nowadays, several systemic agents are available, particularly for patients with lung cancer and melanoma that can control small brain metastases (3). This aspect was not considered for the development of the score, since systemic treatment was not considered a true pre-treatment factor. However, systemic treatments potentially effective in the brain that were administered following SRS or FSRT would likely have had an influence on the occurrence of DBMs.

In conclusion, this new score included three groups with significantly different probabilities of developing new DBMs after SRS or FSRT alone. It showed high accuracy in predicting both the development of new DBMs within 6 months and freedom from DBMs after 6 months. This score was superior to an existing tool, particularly regarding the correct prediction of new DBMs. It can help physicians when selecting the treatment for elderly patients with few brain metastases.

Footnotes

  • Authors' Contributions

    D.R., T.N. and S.E.S. designed the study. T.N., L.D., O.B. and D.R. collected or provided data. D.R. and S.E.S. analyzed the data and drafted the article, which was reviewed and approved by all Authors.

  • Conflicts of Interest

    On behalf of all Authors, the corresponding Author states that there are no conflicts of interest related to this study.

  • Received May 28, 2020.
  • Revision received June 15, 2020.
  • Accepted June 16, 2020.

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Predicting the Risk of Subsequent Distant Brain Metastases After Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy in Elderly Patients
DIRK RADES, TRANG NGUYEN, LIESA DZIGGEL, OLIVER BLANCK, STEVEN E. SCHILD
Anticancer Research Jul 2020, 40 (7) 4081-4086; DOI: 10.21873/anticanres.14406
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