Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy

doi:10.21203/rs.3.rs-4850268/v1

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Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy

https://doi.org/10.21203/rs.3.rs-4850268/v1

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Purpose:

In patients with oligometastatic disease (OMD) treated with stereotactic body radiation therapy (SBRT), those who develop brain metastases (BrM) may have poor outcomes. We aimed to investigate variables associated with BrM development in this population.

Methods:

Patients with ≤ 5 extracranial metastases from solid tumors treated with SBRT from 2008–2016 at Sunnybrook Odette Cancer Centre were included. We investigated the association between covariates and CIBrM (cumulative incidence of BrM) using Fine-Gray analysis, and progression-free survival (PFS) and overall survival (OS) using Cox regression. We investigated the association between extracranial progression and CIBrM using time-based conditional analysis.

Results:

Among 404 patients, the most common primary sites were lung, colorectal, prostate, breast and kidney. Median follow-up was 49 months. Median PFS was 25 months. Median OS was 70 months. 58 patients developed BrM, and 5-year CIBrM was 16%. On multivariable analysis, number of extracranial metastases, location of metastases, total planning target volume (PTV), and time from primary diagnosis to OMD were not associated with CIBrM, although several of these variables were associated with extracranial PFS and OS. Primary site was associated with CIBrM, with colorectal and prostate cancer associated with lower CIBrM compared to lung cancer. Widespread extracranial progression (≥ 5 sites) within 24, 36, 48 and 60 months of OMD diagnosis was independently associated with higher CIBrM.

Conclusion:

In patients with OMD treated with SBRT, baseline variables related to extracranial disease burden and distribution were not associated with BrM development, while primary site and widespread extracranial progression were associated with BrM development.

Oligometastatic disease (OMD) is an intermediate state between localized and polymetastatic disease(1–3). Several recent trials have shown that SBRT (stereotactic body radiation therapy) improves overall survival (OS) and progression-free survival (PFS)(4–6) in patients with OMD, supporting the paradigm that such patients can be treated with the intent of long-term disease control or cure.

However, despite curative-intent treatment of OMD, a proportion of these patients go on to develop brain metastases (BrM), which is often an unexpected pivotal event associated with significant morbidity and mortality and finite treatment options. Between 10 and 40% of patients with cancer develop BrM, with common primary sites being non-small cell lung cancer (NSCLC), breast cancer, and melanoma(7–9). The median overall survival of patients with BrM is 7–12 months(10–12), although a small proportion of patients have long term survival(13).

Hence, there is a need to better understand the variables associated with the development of BrM in patients with OMD, in order to individualize treatment decisions and optimize patient selection and surveillance. In a retrospective Canadian cohort of patients with OMD treated with SBRT, we aimed to investigate clinical variables associated with development of BrM.

We investigated a retrospective cohort of 415 patients with OMD treated with SBRT between January 2008 and December 2016 at Sunnybrook Odette Cancer Centre (Toronto, Canada), as secondary use of local data originally part of a multi-institutional database that was previously described (14), with additional retrospective data collected on BrM. All patients were 18 years of age or older and had a pathologically confirmed diagnosis of a solid tumour malignancy. Patients with a primary diagnosis of hematological malignancy, primary central nervous system cancer or germ cell cancer, were excluded. All patients had ≤ 5 cumulative sites of metastatic disease seen on conventional staging investigations. Malignant lymph node(s), as defined by site-specific size criteria or PET avidity, were considered as site(s) of OMD. All patients had at least one site of OMD treated with SBRT. Patients with ≥ 1 site treated with conventional radical doses of radiation (> 60 Gy) were included as long as at least one site was treated with SBRT. Radiation therapy planning and treatment parameters were previously described(15). All patients underwent complete imaging within 4 months of first SBRT treatment, including either a CT scan of the head, chest, abdomen and pelvis or a full body PET scan, with an MRI of the brain being an acceptable substitute for a head CT. Eleven patients had BrM at the time of OMD diagnosis. These patients were excluded from subsequent analyses below (which will focus on the 404 patients without pre-existing BrM), and will be described separately.

Cumulative incidence of brain metastases (CIBrM), overall survival (OS), and progression-free survival (PFS) were examined, starting at the date of diagnosis of OMD, and censored at the most recent follow-up date. Baseline covariates examined included: primary cancer site, time from primary cancer diagnosis to OMD diagnosis (measured as a continuous variable), total number of extracranial metastases, location of extracranial metastases, and total planning target volume (total PTV, defined as the sum of the PTVs of all lesions treated at the time of initial OMD presentation, as a surrogate measure of total disease burden). Kaplan-Meier curves were generated for PFS and OS; the log-rank test was used to ascertain any statistically significant differences between curves. Cox proportional hazards regression was employed to evaluate variables associated with PFS and OS. CIBrM was analysed with death prior to BrM development as a competing risk. Cumulative Incidence Function (CIF) curves were estimated, charted, and visually inspected. The Fine-Gray test was employed to test for differences between CIF curves. The effect of covariates on the CIF was modelled using Fine-Gray subdistribution regression. Modeling the effect of covariates on the CIF allows one to estimate the effect of covariates on the absolute risk of the outcome over time. Multivariable analysis (MVA) for CIBrM, PFS and OS was done using all covariates. Plots of Schoenfeld residuals were used to evaluate the proportional hazard subdistribution assumption.

Extracranial progression was not included as a covariate in the initial MVA as it was a temporal variable, rather than a baseline variable. We used conditional analysis to investigate the association between development of widespread extracranial progression (i.e. development of 5 or more sites of new extracranial disease) or any extracranial progression (i.e. widespread extracranial progression, extracranial oligoprogression, or extracranial local recurrence) within six pre-defined timeframes (i.e. within 6, 12, 24, 48 and 60 months from OMD diagnosis) and the CIBrM, after adjusting for the five baseline variables above. In this conditional analysis, all patients who died, were lost to follow-up, or developed BrM within each timeframe were excluded from that conditional analysis.

All testing used the traditional significance level of α = .05. Analyses were performed using R software package, version 4.3.1 (R Core Team 2023, R Foundation for Statistical Computing, Vienna, Austria)(16).

Baseline characteristics

In the full cohort of 415 patients, the median age was 71 years (range 32–94 years). 222 patients (53%) were male, and 193 patients (47%) were female. The five most common primary cancer sites were non-small cell lung cancer (NSCLC) (n = 136, 33%), colorectal cancer (n = 106, 26%), prostate cancer (n = 53, 13%), breast cancer (n = 43, 10%), renal cell carcinoma (n = 29, 7%). 126 patients (30%) presented with synchronous OMD (i.e. within 6 months of primary cancer diagnosis) and 289 patients (70%) presenting with metachronous OMD (Table 1).

Table 1

**Baseline and treatment characteristics.** Abbreviations: BrM (brain metastasis), NSCLC (non-small cell lung cancer), OMD (oligometastatic disease), mets (metastases), SRS (stereotactic radiosurgery).
	All patients		No BrM at diagnosis		BrM at diagnosis
	n = 415		n = 404		n = 11
	n	%	n	%	n	%
Age
Median (range)	71 (32–94)		71 (32–94)		58 (46–83)
Sex
Male	222	53%	215	53%	7	64%
Female	193	47%	189	47%	4	36%
Primary site
NSCLC	136	33%	131	32%	5	45%
Colorectal	106	26%	104	26%	2	18%
Prostate	53	13%	53	13%	0	0%
Breast	43	10%	42	10%	1	9%
Kidney	29	7%	28	7%	1	9%
Skin (melanoma)	6	1%	4	1%	2	18%
Endometrium	5	1%	5	1%	0	0%
Stomach	4	1%	4	1%	0	0%
Pancreas	4	1%	4	1%	0	0%
Skin (non = melanoma)	3	1%	3	0%	0	18%
Oropharynx	2	0%	2	0%	0	0%
Thyroid	1	0%	1	0%	0	0%
Nasopharynx	1	0%	1	0%	0	0%
Hypopharynx	1	0%	1	0%	0	0%
Cholangiocarcinoma	1	0%	1	0%	0	0%
Anal canal	1	0%	1	0%	0	0%
Other	19	5%	19	5%	0	0%
Primary to OMD (months)
Median (IQR)	18 (3.0–42)		18 (3.1–40)		40 (3.0–96)
≤ 6 months	126	30%	122	30%	4	36%
> 6 months	289	70%	282	70%	7	64%
Total number of mets
1	247	60%	247	61%	0	0%
2	100	24%	93	23%	7	64%
3	43	10%	42	10%	1	9%
4	19	5%	17	4%	2	18%
5	6	1%	5	1%	1	9%
Number of BrM at OMD diagnosis
0	404	97%	404	100%	0	0%
1	10	2%	0	0%	10	91%
2	1	0%	0	0%	1	9%
Location of mets
Bone only	111	27%	108	27%	3	27%
Lung or liver	273	66%	267	66%	6	55%
Other	31	7%	29	7%	2	18%
Total PTV (cc)
Median (IQR)	51 (25–112)		51 (24–109)		69 (46–163)
≤50	202	49%	197	49%	5	45%
> 50	213	51%	207	51%	6	55%
Systemic therapy change after MDT
Yes	134	32%	129	32%	5	45%
No	281	68%	275	68%	6	55%
Treatment of BrM present at diagnosis
SRS	NA	NA	NA	NA	2	18%
Craniotomy	NA	NA	NA	NA	9	82%

Clinical outcomes: Cumulative incidence of BrM, progression-free survival, and overall survival

Median follow-up was 49 (interquartile range [IQR]: 26–88) months. In total, 58 patients (14%) developed brain metastases. CIBrM was 5.3% (95% CI 3.4%-7.8%) at 24 months after OMD diagnosis, 12% (95% CI 9.0%-16%) at 60 months after OMD diagnosis, and 16% (95% CI 12%-21%) at 120 months after OMD diagnosis (Fig. 1A). 186 patients (46%) died without BrM, and 160 patients (40%) were alive without BrM at the time of last follow-up. Median OS was 70 months (95% CI 59–85 months) (Fig. 1C). Median PFS was 25 months (95% CI 22–28 months) (Fig. 1B). Among the 265 patients (66%) who had disease progression, 84 (32%) were alive at the time of last followup.

Fine-gray competing risks analysis of CIBrM

Patients with different primary cancer sites had significantly different incidence of BrM (p < 0.001), with CIBrM at 5 years after OMD diagnosis of 22% (95% CI 11%-36%) in patients with breast cancer, 15% (95% CI 9.5%-22%) in patients with NSCLC, 15% (95% CI 4.6–32%) in patients with renal cell carcinoma, 5.3% (95% CI 2.0–11%) in patients with colorectal cancer, 0% in patients with prostate cancer, and 23% (95% CI 9.4–39%) in patients with other primary sites (Fig. 2A).

Patients with synchronous OMD had a 5-year CIBrM of 15% (95% CI 9.0–22%) compared to 11% (95% CI 7.4–15%) in patients with metachronous OMD (p = 0.3). Patients with a solitary metastasis had a 5-year CIBrM of 12% (95% CI 7.8–16%) compared to 13% (95% CI 8.0–19%) in patients with multiple metastases (p = 0.5). Patients with isolated bone metastases had a 5-year CIBrM of 11% (6.0–19%) compared to 13% (95% CI 13–24%) in patients with lung or liver metastases, and 7.6% (95% CI 1.2–22%) in patients with other sites of metastases (p = 0.5). Patients with a total PTV of 50 cc or less had a 5-year CIBrM of 7.8% (95% CI 4.6–12%) compared to 17% (95% CI 13–25%) in patients with a total PTV above 50 cc (p = 0.11) (Fig. 2B-E).

Multivariable analysis of covariates associated with CIBrM

In a MVA for the outcome of CIBrM, among the five baseline covariates assessed, primary cancer site was the only variable that was independently associated with CIBrM (Likelihood ratio test (LRT) p < 0.001). Specifically, patients with colorectal cancer and prostate cancer had a significantly lower hazard ratio (HR) for CIBrM (HR 0.37 (95% CI 0.16–0.87, p = 0.022) and HR 0.00 (p < 0.001), respectively) compared to patients with NSCLC (Table 2).

Number of extracranial metastases, location of extracranial metastases, total PTV, and time from primary cancer diagnosis to OMD diagnosis were not significantly associated with CIBrM (Table 2).

Table 2

**Variables associated with cumulative incidence of brain metastases (CIBrM), progression free survival (PFS), and overall survival (OS).** Abbreviations: MVA (multivariate analysis), NSCLC (non-small cell lung cancer), OMD (oligometastatic disease), PTV (planning target volume), mets (metastases), LRT (likelihood ratio test).
			CIBrM MVA			PFS MVA			OS MVA
		n	HR (95% CI)	p	LRT p	HR (95% CI)	p	LRT p	HR (95% CI)	p	LRT p
Primary site
	NSCLC (ref)	131	1		< 0.001	1		< 0.001	1		< 0.001
	Colorectal	104	0.34 (0.14,0.82)	0.017		0.96 (0.71, 1.3)	0.81		0.60 (0.42, 0.84)	0.04
	Breast	42	1.8 (0.79, 4.2)	0.16		0.52 (0.34, 0.81)	0.004		0.29 (0.17, 0.50)	< 0.001
	Prostate	53	0.0 (0.0, 0.0)	< 0.001		0.30 (0.18, 0.48)	< 0.001		0.17 (0.090,0.33)	< 0.001
	Kidney	28	1.9 (0.82, 4.5)	0.13		0.48 (0.28, 0.82)	0.008		0.23 (0.11, 0.46)	< 0.001
	Other	46	1.2 (0.51, 2.9)	0.66		2.1 (1.4, 3.0)	< 0.001		1.5 (1.0, 2.3)	0.052
Primary to OMD (months)
		404	1.0 (0.99, 1.0)	0.22	0.26	1.0 (1.0, 1.0)	0.38	0.38	1.0 (0.99, 1.0)	0.013	0.013
Total number of mets
	1 (ref)	247	1		0.49	1		0.46	1		0.91
	> 1	157	1.22 (0.66, 2.3)	0.52		1.1 (0.86, 1.4)	0.46		1.0 (0.77, 1.4)	0.91
Location of mets
	Bone only (ref)	108	1		0.71	1		< 0.001	1		0.02
	Lung or liver	267	1.3 (0.59, 2.7)	0.56		0.44 (0.31, 0.62)	< 0.001		0.68 (0.46, 1.0)	0.065
	Other	29	0.86 (0.24, 3.0)	0.81		0.51 (0.30, 0.86)	0.011		0.39 (0.19, 0.80)	0.01
Total PTV (cc)
		404	1.00 (1.00, 1.00)	0.4	0.5	1.0 (1.0, 1.0)	0.03	0.042	1.0 (1.0, 1.0)	0.001	0.004

Multivariable analysis of covariates associated with PFS and OS

In a MVA for the outcome of PFS, primary cancer site (LRT p < 0.001), location of metastases (LRT p < 0.001) and total PTV (LRT p = 0.042) were independently associated with PFS (Table 2).

In a MVA for the outcome of OS, primary cancer site (LRT p < 0.001), location of metastases (LRT p = 0.02), total PTV (LRT p = 0.004) and time from primary cancer diagnosis to OMD (LRT p = 0.013) were independently associated with OS (Table 2).

Conditional analysis of association between extracranial progression and CIBrM

Development of widespread extracranial progression (i.e. five or more sites of new extracranial disease) within four of the six pre-defined time intervals, i.e. within 24, 36, 48 and 60 months of OMD diagnosis, was independently associated with higher CIBrM after that time interval, after adjusting for the five baseline covariates above (Table 3).

Development of any extracranial progression (i.e. widespread extracranial progression, extracranial oligoprogression, or extracranial local recurrence) within 48 months of OMD diagnosis, but not within any of the other five timepoints investigated, was independently associated with higher CIBrM after that time interval, after adjusting for the five baseline covariates (Table 3).

Table 3

**Conditional analysis of cumulative incidence of brain metastases, based on ECP (extracranial progression) and WSP (widespread progression) within various time intervals.** Abbreviations: MVA (multivariate analysis), LRT (likelihood ratio test). All time intervals are relative to date of diagnosis of oligometastatic disease. MVA adjusts for the five baseline variables investigated in Table 2.
	ECP or WSP	No ECP or WSP	UVA HR (95% CI)	LRT p	MVA HR (95% CI)	LRT p
ECP within 6 months	25	373	1.7(0.65–4.3)	0.31	1.4(0.43–4.6)	0.53
ECP within 12 months	76	293	1.6 (0.85-3.0)	0.16	1.7(0.84–3.5)	0.14
ECP within 24 months	102	207	1.2(0.59–2.3)	0.66	1.3(0.62–2.6)	0.54
ECP within 36 months	99	148	1.6(0.76–3.2)	0.24	1.8(0.76–4.1)	0.18
ECP within 48 months	87	118	2.8(1.2–6.5)	0.021	4.0(1.6–9.9)	0.0041
ECP within 60 months	63	100	1.7(0.60-5.0)	0.33	3.0(1.1–8.6)	0.083
WSP within 6 months	16	382	1.6(0.48–5.2)	0.47	1.3(0.32–5.4)	0.69
WSP within 12 months	31	338	2.1(0.93–4.6)	0.1	2.6(0.96–7.1)	0.053
WSP within 24 months	41	268	3.1(1.5–6.6)	0.0082	4.1(1.5–12)	0.0041
WSP within 36 months	38	209	3.0(1.3–6.8)	0.017	3.7(1.3–11)	0.013
WSP within 48 months	28	177	2.4(0.88–6.7)	0.11	5.9(1.7–20)	0.0094
WSP within 60 months	15	148	2.2(0.47-10)	0.36	23(1.6–340)	0.017

Characteristics and outcomes of patients with pre-existing BrM

In total, eleven patients had pre-existing BrM at the time of OMD diagnosis. Among these patients, ten had a single BrM, and one had two BrM. All patients had more than one site of OMD, and 4 patients had synchronous OMD. 5 patients had NSCLC, 2 had colorectal cancer, 2 had melanoma, 1 had breast cancer, and 1 had renal cell carcinoma. 9 patients underwent craniotomy: 4 underwent adjuvant whole brain radiotherapy, and 5 underwent adjuvant intensity modulated radiotherapy to the surgical cavity. Two patients were treated with stereotactic radiosurgery alone without surgery (Table 1). These eleven patients had poor prognosis, with median intracranial PFS of 6.2 months, median extracranial PFS of 13 months, and median OS of 23 months. Only two patients did not have intracranial progression, and they were also the only two patients alive at the time of last followup.

This is the first study to identify variables associated with development of BrM in a population consisting exclusively of patients with OMD treated with SBRT. We found that variables associated with baseline burden and distribution of extracranial disease were not associated with CIBrM. We also found primary cancer site and extracranial progression were independently associated with CIBrM.

We investigated several variables related to baseline metastatic burden and distribution at the time of OMD diagnosis, including: total number of metastases, total PTV (i.e. a surrogate measure of total metastatic burden), and location of extracranial metastases. While many of these variables were independently associated with PFS and OS, none of them were associated with CIBrM on univariable and multivariable analysis. These findings suggest that different underlying variables predict extracranial and intracranial progression. This calls for a need to investigate additional variables associated with the risk of developing BrM in this population. It is important to recognize that there were fewer events (n = 58) in the CIBrM analysis compared to the PFS and OS analyses, which reduced statistical power.

It is well known that the incidence of BrM varies greatly depending on primary tumor site, and we demonstrate that this holds true in the setting of oligometastatic disease. In a population-based study of over 16,000 patients, Barnholtz-Sloan et al(7) observed that the incidence of BrM was 9.6% for patients across all primary tumor sites, and highest among patients with lung cancer (19.9%), followed by melanoma (6.9%), renal cell carcinoma (6.5%), breast cancer (5.1%), and lowest among patients with colorectal (1.8%) cancer. Furthermore, is it known that patients with prostate cancer have an extremely low incidence of BrM (17). Our finding that patients with colorectal and prostate cancer had a significantly lower CIBrM compared to patients with NSCLC is consistent with what is known about these cancer types. Future studies will need to investigate variables associated with BrM development in individual cancer types by integrating histology-specific variables, such as receptor status and Ki67 index in breast cancer(18), pathological subtype in lung cancer(19), and primary location and mitotic rate in melanoma(20), in order to provide more accurate prognostication.

We observed that extracranial progression, particularly widespread extracranial progression (i.e. 5 or more sites of disease), was independently associated with CIBrM. A recent retrospective study had also identified an association between development of BrM and oligometastic-to-polymetastatic transition (21). Biologically, many of these cancers may exhibit an aggressive phenotype with a greater propensity to metastasize. Furthermore, these cancers may harbour more resistant clones to ongoing systemic therapies, or alternatively, the patient may no longer be actively receiving systemic therapy to control their disease. This calls for a need to investigate additional temporally dynamic variables when estimating the risk of developing BrM in patients with OMD. An example of a non-invasive dynamic variable is circulating tumour DNA (ctDNA), which has been shown to predict recurrence-free survival after curative-intent resection in oligometastatic colorectal cancer in a metanalysis of 23 studies(22), and further studies are underway to investigate the utility of ctDNA in patients with various cancer types treated with SBRT for OMD(4).

Although our cohort only included 11 patients with pre-existing BrM, it is important to consider the very short median intracranial PFS and OS of this subgroup. In a meta-analysis of 68 studies, Li et al(23) observed that patients with BrM with stable extracranial disease had a longer intracranial PFS compared to patients with disseminated or uncontrolled extracranial disease. In addition, in patients with oligometastatic NSCLC, Iyengar et al(6) observed that SBRT to extracranial sites was associated with a numerically lower rate of intracranial progression. There is a complex association between the dynamics of extracranial and intracranial disease, involving the intrinsic metastatic potential of the tumour and the timing and choice of systemic therapies. It is important for future trials regarding OMD to include patients with BrM, in order to identify substrates necessary for long term intracranial control.

Our study has a number of limitations. It is a single centre retrospective study, and the infrequent occurrence of BrM limited our statistical power. In addition, we chose to define temporal clinical outcomes in relation to the date of diagnosis of OMD rather than the end date of SBRT, as our primary objective was to investigate variables associated with development of BrM in patients with OMD, rather than to investigate the effect of SBRT on outcomes. When generalizing our findings, readers will need to be cognizant that all patients in our cohort received SBRT at some point.

In patients treated with SBRT for OMD, it is crucial to identify and integrate biomarkers to predict an individual patient’s risk of developing BrM, which are associated with significant morbidity and mortality. Our study shows that although variables related to baseline burden and distribution of extracranial disease are associated with extracranial progression, they are not associated with intracranial progression. Furthermore, as expected, primary cancer site and extracranial progression are independently associated with the development of BrM. This calls for a need to explore beyond traditional clinical variables and to investigate histology-specific and/or dynamic biomarkers that better reflect the underlying biology of intracranial metastogenesis, in order to identify patients with OMD at high risk of developing BrM who may benefit from screening and preventative treatment.

Ethics approval and consent to participate:

Ethics approval was obtained from the Sunnybrook Research Institute (REB SUN-5942). This study was performed in accordance with the Declaration of Helsinki.

Consent for publication:

Not applicable

Competing Interests

KJJ serves as a consultant and advisory board member for: Amgen, Astra-Zeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Gilead Sciences, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Seagen, Novartis, and Viatris. HC has received speaker's honoraria from Novartis. These organizations had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. No competing interests from other authors of this manuscript.

Funding information:

None

Author Contribution

KYF and KJJ contributed equally and are co-first authors of this manuscript. KYF, KJJ and HC conceptualized the study. KYF, and VM contributed to software development and implementation. Analyses were performed by KYF, KJJ, VM and HC. Data were collected by KYF, SK and BIS. Curation of data was conducted by KYF, KJJ, SK, VM and HC. The original draft was written by KYF, KJJ and HC. Reviewing and editing of the manuscript was performed by KYF, KJJ, SK, VM, BIS, SD, AVL, HS, AS and HC. Data visualization was conducted by KYF and VM. Project management and coordination was performed by KYF, KJJ and HC.

Acknowledgement

We acknowledge Hold’em for Life Oncology Fellowships for trainee support.

Data availability:

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Hellman S, Weichselbaum RR, Oligometastases (1995) J Clin Oncol Off J Am Soc Clin Oncol 13(1):8–10
Beckham TH, Yang TJ, Gomez D, Tsai CJ (2021) Metastasis-directed therapy for oligometastasis and beyond. Br J Cancer 124(1):136–141
Guckenberger M, Lievens Y, Bouma AB, Collette L, Dekker A, deSouza NM et al (2020) Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol 21(1):e18–28
Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C et al (2020) Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 38(25):2830–2838
Gomez DR, Tang C, Zhang J, Blumenschein GR, Hernandez M, Lee JJ et al (2019) Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non–Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol 37(18):1558–1565
Iyengar P, Wardak Z, Gerber DE, Tumati V, Ahn C, Hughes RS et al (2018) Consolidative Radiotherapy for Limited Metastatic Non–Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol 4(1):e173501
Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol Off J Am Soc Clin Oncol 22(14):2865–2872
Mazzola R, Corradini S, Gregucci F, Figlia V, Fiorentino A, Alongi F (2019) Role of Radiosurgery/Stereotactic Radiotherapy in Oligometastatic Disease: Brain Oligometastases. Front Oncol 9:206
Lupattelli M, Tini P, Nardone V, Aristei C, Borghesi S, Maranzano E et al (2022) Stereotactic radiotherapy for brain oligometastases. Rep Pract Oncol Radiother J Gt Cancer Cent Poznan Pol Soc Radiat Oncol 27(1):15–22
AlTamimi JO, AlJohani HA, Naaman N, Johar RA, Allam TA, Lary DAI (2022) Brain Metastases in Adults: A Five-Year Observational Study From King Abdulaziz Medical City. Cureus 14(11):e31197
Lamba N, Catalano PJ, Bi WL, Wen PY, Haas-Kogan DA, Cagney DN et al (2022) Predictors of long-term survival among patients with brain metastases. Neuro-Oncol 24(3):494–496
Nieder C, Haukland E, Mannsåker B, Pawinski AR, Yobuta R, Dalhaug A Presence of Brain Metastases at Initial Diagnosis of Cancer: Patient Characteristics and Outcome. Cureus [Internet]. 2019 Feb 21 [cited 2024 Jan 6]; https://www.cureus.com/articles/16541-presence-of-brain-metastases-at-initial-diagnosis-of-cancer-patient-characteristics-and-outcome
Sperduto PW, Mesko S, Li J, Cagney D, Aizer A, Lin NU et al (2020) Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient. J Clin Oncol 38(32):3773–3784
Poon I, Erler D, Dagan R, Redmond KJ, Foote M, Badellino S et al (2020) Evaluation of Definitive Stereotactic Body Radiotherapy and Outcomes in Adults With Extracranial Oligometastasis. JAMA Netw Open 3(11):e2026312
Redmond KJ, Lo SS, Dagan R, Poon I, Foote MC, Erler D et al (2017) A multinational report of technical factors on stereotactic body radiotherapy for oligometastases. Future Oncol Lond Engl 13(12):1081–1089
R Foundation for Statistical Computing. R: A Language and Environment for Statistical ## Computing [Internet]. Vienna, Austria (2023) https://www.R-project.org/
Hatzoglou V, Patel GV, Morris MJ, Curtis K, Zhang Z, Shi W et al (2014) Brain metastases from prostate cancer: an 11-year analysis in the MRI era with emphasis on imaging characteristics, incidence, and prognosis. J Neuroimaging Off J Am Soc Neuroimaging 24(2):161–166
Koniali L, Hadjisavvas A, Constantinidou A, Christodoulou K, Christou Y, Demetriou C et al (2020) Risk factors for breast cancer brain metastases: a systematic review. Oncotarget 11(6):650–669
Wu B, Zhou Y, Yang Y, Zhou D (2023) Risk factors and a new nomogram for predicting brain metastasis from lung cancer: a retrospective study. Front Oncol 13:1092721
Haydu LE, Lo SN, McQuade JL, Amaria RN, Wargo J, Ross MI et al (2020) Cumulative Incidence and Predictors of CNS Metastasis for Patients With American Joint Committee on Cancer 8th Edition Stage III Melanoma. J Clin Oncol Off J Am Soc Clin Oncol 38(13):1429–1441
Christ SM, Thiel GW, Heesen P, Mayinger M, Willmann J, Ahmadsei M et al Influence of brain metastases on the classification, treatment, and outcome of patients with extracranial oligometastasis: A single-center cross-sectional analysis [Internet]. 2024 [cited 2024 Jul 26]. https://www.researchsquare.com/article/rs-4559627/v1
Chidharla A, Rapoport E, Agarwal K, Madala S, Linares B, Sun W et al (2023) Circulating Tumor DNA as a Minimal Residual Disease Assessment and Recurrence Risk in Patients Undergoing Curative-Intent Resection with or without Adjuvant Chemotherapy in Colorectal Cancer: A Systematic Review and Meta-Analysis. Int J Mol Sci 24(12):10230
Li AY, Gaebe K, Zulfiqar A, Lee G, Jerzak KJ, Sahgal A et al (2023) Association of Brain Metastases With Survival in Patients With Limited or Stable Extracranial Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 6(2):e230475

Competing interest reported. KJJ serves as a consultant and advisory board member for: Amgen, Astra-Zeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Gilead Sciences, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Seagen, Novartis, and Viatris. HC has received speaker's honoraria from Novartis. These organizations had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. No competing interests from other authors of this manuscript.

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Predictors of brain metastases in patients with oligometastatic solid tumours treated with stereotactic body radiation therapy

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Abstract

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Introduction

Materials and Methods

Results

Baseline characteristics

Clinical outcomes: Cumulative incidence of BrM, progression-free survival, and overall survival

Fine-gray competing risks analysis of CIBrM

Multivariable analysis of covariates associated with CIBrM

Multivariable analysis of covariates associated with PFS and OS

Conditional analysis of association between extracranial progression and CIBrM

Characteristics and outcomes of patients with pre-existing BrM

Discussion

Conclusions

Declarations

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References

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Version 1