Factors associated with the use of salvage whole brain radiation therapy versus salvage stereotactic radiosurgery after initial stereotactic radiosurgery for brain metastases

Abstract

Objectives

Patients undergoing stereotactic radiosurgery (SRS) for brain metastases require additional radiation for relapse. Our objective is to determine the factors associated with salvage SRS versus whole brain radiation therapy (WBRT) for salvage of first intracranial failure (ICF) after upfront SRS.

Method

We identified a cohort of 110 patients with brain metastases treated with SRS in the definitive or postoperative setting followed by subsequent salvage WBRT or SRS at least one month after initial SRS. Clinical and demographic characteristics were retrospectively recorded.

Results

78 Patients received SRS and 32 patients received WBRT at the time of first ICF. On multivariate analysis (MVA) factors associated with decreased use of salvage SRS were male gender (p=0.044) and local progression (p<0.001).

Conclusions

Local progression and male gender were the strongest factors associated with selection of salvage WBRT. Possible etiologies of this difference could be provider or patient driven, but warrant further exploration.

INTRODUCTION

An estimated 8-10% of cancer patients will develop brain metastasis as a result of their disease, making brain metastasis a significant contributor to disease burden and mortality in advanced stage cancer patients [1]. With targeted therapies increasing the efficacy of systemic treatment and disease control, controlling brain metastases is important for preserving patients’ quality of life [2]. Sperduto et al. reported a median overall survival (OS) across disease sites for patients after initial treatment of brain metastasis of 13 months [3]. Current treatments for brain metastasis continue to evolve with protocols including one or more of the following modalities: craniotomy for tumor resection, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and increasing numbers and types of systemic therapies [4]. The fundamental goal of brain metastasis treatment is to optimize disease control with neurocognitive preservation [5-8]. For example, omission of WBRT is increasingly favored in appropriate patients to prevent neurocognitive toxicity [6, 7]. However, withholding WBRT to preserve neurocognitive function leaves patients with a higher rate of distant central nervous system (CNS) failure, which may require salvage therapy [5, 9].

Salvage radiation therapy for CNS failure after initial SRS may consist of WBRT or repeat SRS. Rates of salvage treatment after initial SRS therapy without WBRT is reported in clinical trials, and ranges from 32% to 80%. Whereas salvage therapy after initial WBRT with SRS was 0% to 16% [7, 9-11]. Salvage SRS therapy in the appropriate population can provide excellent local control of 79% at one year and a median overall survival of 11.7 months [12]. Understanding which patients are appropriate candidates for salvage radiation therapy is an area of active research. For example, a higher brain metastasis velocity (BMV) after upfront SRS is associated with worse OS following salvage radiation therapy [13]. Although BMV predicts overall survival following salvage therapy, there are currently no prospective data to guide which modality of salvage radiation to use. The paucity of data may lead certain clinical factors to drive treatment with salvage SRS versus WBRT. Alternatively, socioeconomic factors or patient preferences may guide choice of salvage modality. In this study, we sought to analyze the clinical and socioeconomic factors associated with receipt of salvage SRS versus salvage WBRT after initial SRS in patients with brain metastasis. Given the absence of prospective trials guiding salvage reirradiation, we hypothesized that socioeconomic factors would have a significant impact on the salvage radiation modality used.

MATERIALS AND METHODS

This single-institution retrospective study was approved by the University of Miami Institutional Review Board (IRB). We identified 373 consecutive patients with brain metastasis treated with SRS using Gamma Knife (Eletka Instruments, Stockholm, Sweden) at our institution from August 2014 to July 2019. Patients eligible for inclusion in this study were at least 18 years of age with newly diagnosed brain metastasis who received SRS as definitive or post-operative treatment in their initial treatment course and received salvage intracranial radiotherapy a minimum of one month after initial SRS. Salvage radiotherapy could consist of SRS or WBRT, but patients were excluded if they received WBRT prior to or with their initial SRS treatment. Patients were also excluded if a second course of intracranial radiation therapy was started within one month of initial SRS in an effort to exclude patients with staged SRS procedures or adjuvant WBRT.

Electronic medical records (EMR) of eligible patients were reviewed, and socioeconomic and clinical data were collected for each patient. This data was entered into a Research Data Electronic Capture database (REDCap). Karnofsky Performance Status (KPS) and insurance type were recorded from clinical documentation at the time of salvage treatment. Documentation from radiosurgery planning (GammaPlan software, Elekta Instruments) and MRI imaging was used to identify the volume and number of metastases or surgical cavities present at initial and salvage treatment. BMV was calculated as number of new intracranial lesions between initial and salvage treatment over time in years as described by Farris et al. [13]. Graded prognostic assessment (GPA) at the time of retreatment was calculated [14]. Overall survival was defined as time from salvage therapy to death and censored at last follow-up.

Statistical analysis was performed to determine association between clinical and socioeconomic factors with receipt of salvage WBRT versus salvage SRS. A survival analysis was performed to determine the factors associated with OS in this population. A subset analysis was done on patients only with distant brain metastasis failures. Patients who had salvage therapy for progressive lesions (local failure) were excluded from this ad-hoc analysis.

Statistical Methods

Clinical and demographic patient characteristics were summarized for the cohort using descriptive statistics. A univariate (UVA) and multivariate (MVA) logistic regression analysis was used to determine the association of clinical and demographic factors on salvage treatment modality. OS curves were estimated using the Kaplan Meier method and were compared between the patient groups using log-rank test. Findings were considered statistically significant if the P-value was ≤ .05. All statistical analyses were performed with statistical software package SAS ® version 9.4 (SAS Institute Inc., Cary, NC, USA).

RESULTS

A total of 110 patients were included in the study (Figure 1). A summary of baseline characteristics of the population is outlined in Table 1. A total of 68 females and 42 males were included. The median age of the cohort was 60, median time to salvage radiation was 5.85 months, and median follow-up from initial treatment was 1.47 years and 0.81 years from salvage treatment. 78 patients received salvage SRS and 32 patients received salvage WBRT at the time of first ICF. No patients received both salvage SRS and WBRT in the same treatment course.

Figure 1.

Consort diagram with inclusion and exclusion criteria.

Table 1.

Baseline characteristics by salvage therapy type for patients with loco-regional and distant failures

Variable	All Patients		Salvage Therapy Modality
	N	%	WBRT		SRS
			N	%	N	%
Total Patients	110	100.0	32	100.0	78	100.0
Age
Median	59.7	—	60.1	—	59.1	—
Primary malignancy
Lung	51	46.4	12	37.5	39	50.0
Breast	24	21.8	8	25.0	16	20.5
Melanoma	8	7.3	2	6.3	6	7.7
Other	27	24.5	10	31.3	17	21.8
Gender
Female	68	61.8	15	46.9	53	67.9
Male	42	38.2	17	53.1	25	32.1
Language
English	72	65.5	16	50.0	56	71.8
Spanish	37	33.6	15	46.9	22	28.2
Creole	1	0.9	1	3.1
Religion
None	19	17.3	6	18.8	13	16.7
Catholic	43	39.1	15	46.9	28	35.9
Christian/Protestant	19	17.3	5	15.6	14	17.9
Other	29	26.4	6	18.8	23	29.5
Ethnicity
Hispanic or Latino	52	47.3	19	59.4	33	42.3
NOT Hispanic or Latino	58	52.7	13	40.6	45	57.7
Race
Asian	5	4.5	1	3.1	4	5.1
Black or African American	10	9.1	4	12.5	6	7.7
Unknown / Not Reported	5	4.5			5	6.4
White	90	81.8	27	84.4	63	80.8
Ethnicity
Non-Hispanic White	46	41.8	10	31.3	36	46.2
Non-Hispanic Black	7	6.4	2	6.3	5	6.4
Hispanic	52	47.3	19	59.4	33	42.3
Asian/Other/Unknown	5	4.5	1	3.1	4	5.1
Income Level
1st quintile	—	—	—	—	—	—
2nd quintile	34	30.9	12	37.5	22	28.2
3rd quintile	53	48.2	14	43.8	39	50.0
4th quintile	20	18.2	5	15.6	15	19.2
5th quintile	2	1.8	1	3.1	1	1.3
Unknown	1	0.9	—	—	1	1.3
KPS
≤70	12	10.9	6	18.8	6	7.7
>70	98	89.1	26	81.3	72	92.3
Stable lesion
0	22	20.0	13	40.6	9	11.5
≥1	88	80.0	19	59.4	69	88.5
No. sites of DBF
0	8	7.3	4	12.5	4	5.1
1	37	33.6	3	9.4	34	43.6
2	20	18.2	6	18.8	14	17.9
>=3	45	40.9	19	59.4	26	33.3
Progressive lesion
0	84	76.4	15	46.9	69	88.5
1	19	17.3	12	37.5	7	9.0
≥2	7	6.4	5	15.6	2	2.6
Systemic therapy status
No active systemic therapy	23	20.9	9	28.1	14	17.9
Active systemic therapy	87	79.1	23	71.9	64	82.1
Extracranial disease
Not progressing	38	34.5	11	34.4	27	34.6
Progressing	71	64.5	21	65.6	50	64.1
Unknown	1	0.9			1	1.3
Brain metastasis velocity
<4 per year	49	44.5	11	34.4	38	48.7
≥4 per year	61	55.5	21	65.6	40	51.3
Vital status at last follow up
Alive	54	49.1	8	25.0	46	59.0
Dead	56	50.9	24	75.0	32	41.0

WBRT: whole brain radiation therapy; SRS: stereotactic radiosurgery; DBF: distant brain metastasis failure; KPS: Karnofsky performance status scale

The results of factors associated with salvage therapy modality on UVA and MVA are shown in Table 2. The following factors were associated with receiving salvage SRS on UVA: having a single new lesion (OR 9.86, p=0.012), and ≥1 stable lesions (OR 5.06, p=0.001). On UVA the following factors were associated with decreased use of salvage SRS: male gender (OR 0.42, p=0.044), patient primary language of Spanish (OR=0.42, p=0.050), and local progressive lesions (1 lesion OR 0.13, p<0.001; ≥ 2 lesions, OR 0.10, p=0.008). On MVA, male gender (OR=0.35, p=0.044) and local progressive lesions (1 lesion OR 0.11, p<0.001; ≥ 2 lesions, OR 0.11, p=0.038) remained associated with decreased use of salvage SRS. An analysis of GPA showed no significant effect on use of salvage SRS on UVA (OR 1.35, p=0.215) or MVA. Median OS from time of salvage SRS was 1.56 years for the entire cohort. Factors associated with increased survival on MVA (Table 3) included KPS >70, stable/absent systemic disease, and receipt of salvage SRS.

Table 2.

Effect of selected variable on receipt of salvage SRS or salvage WBRT (WBRT = reference) for patients with loco-regional and distant brain failures

Variable	Category	Univariate Analysis		Multivariate Analysis
		OR (95% CI)	P-value	OR (95%)	P-value
Primary Cancer	Lung	Reference
	Breast	0.61 (0.21, 1.77)	0.368
	Melanoma	0.82 (0.15, 4.39)	0.820
	Other	0.53 (0.19, 1.45)	0.214
Gender	Female	Reference		Reference
	Male	0.42 (0.18, 0.98)	0.044	0.35 (0.13, 0.97)	0.044
Language	English	Reference		Reference
	Spanish	0.42 (0.18, 1.00)	0.050	0.52 (0.18, 1.46)	0.213
	Creole	NE	NE	NE	NE
Religion	None	Reference
	Catholic	0.89 (0.28, 2.78)	0.835
	Christian/Protestant	1.27 (0.32, 5.10)	0.737
	Other	1.74 (0.47, 6.42)	0.405
Ethnicity	Hispanic or Latino	Reference
	NOT Hispanic or Latino	1.96 (0.85, 4.51)	0.113
Race	White	Reference
	Asian	1.30 (0.16, 10.33)	0.805
	Black or African American	0.63 (0.16, 2.39)	0.492
	Unknown / Not Reported	4.77 (0.19, 117.45)	0.339
Race/Ethnicity	Non-Hispanic White	Reference
	Non-Hispanic Black	0.63 (0.11, 3.61)	0.607
	Hispanic	0.49 (0.20, 1.21)	0.122
	Asian/Other/Unknown	0.86 (0.10, 7.33)	0.892
Income Level	2nd Quintile	Reference
	3rd Quintile	1.51 (0.60, 3.83)	0.381
	4th Quintile	0.87 (0.17, 4.52)	0.471
	5th Quintile	0.20 (0.01, 3.91)	0.687
	Unknown	NE	NE
KPS	≤70	Reference
	>70	0.91 (0.10, 8.45)	0.937
Stable Lesion	0	Reference		Reference
	≥1	5.06 (1.89, 13.60)	0.001	2.40 (0.71, 8.14)	0.159
No. sites of DBF	0	Reference		Reference
	1	9.86 (1.67, 58.36)	0.012	1.10 (0.12, 9.79)	0.934
	2	2.23 (0.42, 11.96)	0.349	0.29 (0.03, 2.55)	0.263
	≥3	1.36 (0.30, 6.13)	0.690	0.19 (0.02, 1.50)	0.114
Loco-regional failure	0	Reference		Reference
	1	0.13 (0.05, 0.39)	<.001	0.11 (0.03, 0.39)	<0.001
	≥2	0.10 (0.02, 0.55)	0.008	0.11 (0.01, 0.88)	0.038
Extracranial Disease	Not progressing	Reference
	Progressing	0.98 (0.41, 2.33)	0.968
Systemic therapy status	No active systemic therapy	Reference
	Active systemic therapy	1.80 (0.69, 4.70)	0.231
Brain metastasis velocity	< 4 per year	Reference		Reference
	≥4 per year	0.56 (0.24, 1.32)	0.184	0.45 (0.15, 1.34)	0.149
Age		Every one unit increased
		1.01 (0.98, 1.05)	0.477
GPA		Every one unit increased
		1.35 (0.85, 2.22)	0.215
Time to Salvage Therapy		Every one unit increased
		1.00 (0.94, 1.05)	0.910

WBRT: whole brain radiation therapy; NE: not estimatable; KPS Karnofsky performance status scale;

DBF: distant brain metastasis failure: GPA: graded prognostic assessment

Table 3.

Effect of selected variable on receipt of salvage SRS or salvage WBRT (WBRT = reference) for patients with distant brain failures

Variable	Category	Univariate Analysis		Multivariate Analysis
		OR (95% CI)	P-value	OR (95%)	P-value
Primary Cancer	Lung	Reference
	Breast	0.86 (0.23, 3.29)	0.826
	Melanoma	NE	NE
	Other	2.12 (0.41, 10.95)	0.371
Gender	Female	Reference
	Male	0.47 (0.15, 1.44)	0.186
Language	English	Reference
	Spanish	0.66 (0.21, 2.08)	0.474
Religion	None	Reference
	Catholic	1.10 (0.27, 4.50)	0.900
	Christian/Protestant	4.67 (0.46, 47.63)	0.194
	Other	2.22 (0.42, 11.68)	0.346
Ethnicity	Hispanic or Latino	Reference
	NOT Hispanic or Latino	1.95 (0.63, 6.08)	0.250
Race	White	Reference
	Asian	1.02 (0.11, 9.84)	0.988
	Black or African American	NE	NE
	Unknown / Not Reported	NE	NE
Race/Ethnicity	Non-Hispanic White	Reference
	Non-Hispanic Black	NE	NE
	Hispanic	0.56 (0.17, 1.85)	0.339
	Asian/Other/Unknown	0.67 (0.06, 7.25)	0.739
Income level	2nd Quintile	Reference
	3rd Quintile	0.97 (0.25, 3.74)	0.966
	4th Quintile	0.87 (0.17, 4.52)	0.865
	5th Quintile	0.20 (0.01, 3.91)	0.289
	Unknown	NE	NE
KPS	≤70	Reference
	>70	0.91 (0.10, 8.45)	0.937
# sites of DBF	1	Reference		Reference
	2	0.22 (0.02, 2.62)	0.230	0.28 (0.03, 2.39)	0.244
	≥3	0.06 (0.01, 0.49)	0.009	0.10 (0.01, 0.81)	0.031
Extracranial Disease	Not progressing	Reference
	Progressing	0.78 (0.22, 2.72)	0.693
Systemic therapy status	No active systemic therapy	Reference
	Active systemic therapy	0.31 (0.04, 2.55)	0.275
Brain metastasis velocity	< 4 per year	Reference		Reference
	≥4 per year	0.17 (0.04, 0.80)	0.025	1.04 (0.16, 6.71)	0.971
Insurance	Private	Reference
	Medicaid	NE	NE
	Medicare	1.31 (0.37, 4.64)	0.680
	Uninsured	NE	NE
Age		Every one unit increased
		0.99 (0.94, 1.04)	0.713
Time to salvage therapy		Every one unit increased
		1.00 (0.93, 1.08)	0.940

WBRT: whole brain radiation therapy; NE: not estimatable; KPS Karnofsky performance status scale;

DBF: distant brain metastasis failure

In the subsequent analysis done on the cohort of patients with distant brain metastasis failure alone, 84 patients were included after removing patients with local failure at a site of initial SRS. In this cohort, 69 patients received salvage SRS and 15 patients received salvage WBRT at the time of first DBF. The median age was 59.6, median time to salvage radiation was 5.4 months, and median follow-up from initial treatment was 1.45 years (0.84 years from salvage treatment).

UVA and MVA were done in this cohort to identify factors associated with salvage radiation therapy modality after distant brain failure. On UVA, the factors associated with decreased use of salvage SRS were ≥3 sites of DBF (OR 0.06, p=0.009) and brain metastasis velocity ≥4 (OR=0.17, p=0.025). On MVA, ≥3 sites of DBF was associated with decreased use of salvage SRS (OR 0.10, p=0.031). There were no socioeconomic or other clinical factors associated with receipt of salvage SRS versus WBRT on UVA or MVA in this sub-cohort. Median overall survival from retreatment in this cohort was 1.75 years. On MVA, progressing extracranial disease was associated with decreased survival (HR 2.96, p=0.018), while salvage SRS versus WBRT was associated with increased survival (HR 0.30, p=0.006).

DISCUSSION

In this retrospective analysis, which included 110 patients with local and distant brain failures who received salvage intracranial irradiation after upfront SRS, the strongest factor associated with receipt of salvage WBRT versus SRS was local progression. Male gender was also independently associated with receipt of salvage WBRT. The strongest factor associated with receiving salvage SRS was having a single site of distant brain failure. These findings suggest that although demographic factors may influence salvage treatment modality, the decision is primarily guided by appropriate clinical factors.

In a subset analysis of 84 patients receiving salvage radiation for distant brain failure without local progression, patients were more likely to receive salvage WBRT if they had 3 or more sites of distant brain failure. Patients with a BMV of at least 4 per year were more likely to receive salvage WBRT than salvage SRS. Therefore, the rate at which new metastases are occurring is also a factor involved in the choice of salvage modality used. As in the full cohort, in this subset analysis salvage SRS was associated with increased overall survival compared to patients receiving salvage WBRT.

Overall survival of the entire cohort was 1.56 years for patients with loco-regional and distant failures and 1.75 years for the subset of patients in the cohort with only distant failures. In both cohorts, independent predictors of poor overall survival were similar including progressive systemic disease, and treatment with salvage WBRT versus SRS. Brain metastasis velocity of at least 4 lesions per year predicted for worse survival, although this was not significant on multivariable analysis.

The strongest factor predicting receipt of salvage WBRT was local progression of a previously treated brain metastasis lesion. Although repeating SRS for a locally progressing brain metastasis has been poorly studied, it remains an acceptable treatment modality for salvage of locally progressing lesions after upfront SRS [15]. A study of 47 patients with local failures treated with salvage repeat SRS reported a local control of 83.6% with a median OS of 9.2 months [16]. Another report of 31 patients with local failure after SRS showed similar results with a 1-year local control rate of 79.5% [17]. However, repeat SRS to a locally progressing lesion results in high toxicity with approximately 20% of patients developing symptomatic radiation necrosis [16]. Therefore, other modalities such as WBRT, surgery or chemotherapy may be favored [15, 18]. Although McTyre et al. confirmed BMV as a useful prognostic factor in determining survival outcomes in patients treated with SRS for brain metastases[19], our study did not find BMV to be a significant, independent predictor of salvage radiation modality on MVA.

Interestingly, gender was the only demographic characteristic found to have a significant, independent association with salvage radiation modality. Male patients were more likely to receive salvage WBRT over salvage SRS. Multiple studies have shown a significant association between male gender and less likelihood of receiving SRS for brain metastasis treatment compared to other modalities [20, 21]. A study by Schüttrumpf et al. identified that males had a significantly shortened overall survival compared to females after receiving SRS therapy for brain metastases independent of other clinical factors [22]. The authors suggested higher rates of smoking in males and relatively favorable breast cancer primaries in females may have resulted in males with more advanced systemic disease. The gender disparities reported in the present study could be due to similar reasons, with males having more advanced systemic disease relative to females which favoring salvage treatment with WBRT. However, the disparity between salvage modalities persisted in our analysis despite controlling for progression of systemic disease and primary disease site. Further evaluation on gender disparities should be investigated with regards to patient preferences and other potential confounders.

Socioeconomic factors such as income, race, ethnicity, insurance status and age were not found to have an association with salvage WBRT versus SRS in this cohort. This is in contrast to two National Cancer Database (NCDB) analyses of patients treated with RT for brain metastasis [20, 21]. The NCDB analyses reported lower rates of upfront SRS utilization in patients who were nonwhite, without private insurance and lower income [20, 21]. It is likely that local progression and SRS feasibility (i.e size, number and/or volume of brain metastases), the latter of which was not assessed in the current analysis, outweigh socioeconomic factors in the salvage setting. An unexpected finding was that KPS score and GPA at time of salvage therapy was not significantly correlated with receipt of salvage SRS versus WBRT. Given that patients with poor KPS and low GPA tend to have poor overall survival after RT to brain metastasis, salvage SRS might be expected in patients with a high KPS score and/or low GPA score [23]. However, the etiology of poor KPS is varied. Patients with a poor KPS due to brain metastasis have a markedly better prognosis after SRS than patients with poor KPS due to extracranial disease [24].

The overall survival of 1.56 years after salvage radiation reported in this study compares favorably with previously published series. Studies have shown various overall survival ranging from 5.2 months to 22 months [25-28]. The present study found receipt of salvage SRS to be an independent predictor of survival compared to salvage WBRT, which is congruent with outcomes reported in the literature [21, 25-27]. Given that most patients in this population will die of extracranial disease, this is likely due to bias from unreported confounding factors [18]. Performance status and extracranial disease were correlated with OS, highlighting their role in predicting survival in agreement with historical data [3].

The appropriateness of the clinical practice patterns revealed in the present study may be answered by an accruing trial launched by NRG Oncology, NRG-BN009. This phase III randomized trial is studying the effects of salvage SRS alone vs SRS + salvage hippocampal avoidant WBRT after distant brain failure in patients with a BMV of 4 or more after initial SRS therapy for brain metastasis treatment. The results of this trial are eagerly awaited and are likely to change current clinical practice with regards to salvage brain metastasis radiation treatment. Additional prospective work on the role of local progression vs distant failures should be conducted to analyze if its influence on salvage radiation treatment modality is warranted.

There are several limitations to the findings reported this study. First, the study’s retrospective nature yields inherent bias. Second, patients with CNS failure who did not receive salvage intracranial irradiation were not included in the present study. Patients with poor performance status and brain metastasis may not benefit from intracranial radiation as concluded in the Quartz trial, and this may explain why performance status was not found to be a significant factor in this study [29]. Third, this study was limited to a single institution and may not be reflective of clinical practice at other institutions. Institutional variation is evident by the differences in salvage therapy rates reported in published studies [9, 10, 18]. However, the patients included in this study were cared for by seven different radiation oncologists specializing in stereotactic radiosurgery. Furthermore, the balance between patients’ prioritiesand physicians’ preferences in the treatment decision-making process is not elucidated with this analysis.

Overall, the determination of which salvage therapy to use for distant or loco-regional brain failures is a patient-specific decision. However, clinical factors which were found to be significant in this study, such as local failure and new lesions, play a large role in determining whether to use WBRT or SRS for salvage therapy. Although KPS was not significantly associated with either modality of treatment, other studies have shown that effective salvage SRS therapy may rely on a higher KPS. Male gender was associated with receiving salvage WBRT in our study and further investigation regarding the underlying reasons for this should be performed given the reproducibility of this in the literature. As we await results of the NRG BN009 trial, salvage intracranial re-irradiation guidelines after upfront SRS based on clinical characteristics can make choosing a specific salvage modality a more standardized process.