Mean Brain Dose Remains Uninfluenced by Lesion Number for Gamma Knife Stereotactic Radiosurgery for Ten+ Metastases

doi:10.21203/rs.3.rs-887481/v1

Purpose:

Gamma Knife (GK) stereotactic radiosurgery (SRS) is increasingly used as an initial treatment for patients with ten or more brain metastases (BM). However, the clinical and dosimetric consequences of this practice are not well established.

Methods:

We performed a single institution, retrospective analysis of 30 patients who received GK SRS for ten or more BM in one session. We utilized MIM Software to contour the whole brain and accumulated the doses from all treated lesions to determine the mean dose delivered to the whole brain. Patient outcomes were determined from chart review.

Results:

Our cohort had a median number of 13 treated lesions (range 10 to 26 lesions) for a total of 427 treated lesions. The mean dose to the whole brain was determined to be 1.8 ± 0.91 Gy (range 0.70 to 3.8 Gy). Mean dose to the whole brain did not correlate with the number of treated lesions (Pearson r=0.23, p=0.21), but was closely associated with tumor volume (Pearson r=0.95, p<0.0001). There were no significant correlations between overall survival and number of lesions or aggregate tumor volume. Fourteen patients (47%) underwent additional SRS sessions and six patients (20%) underwent WBRT a median of 6.6 months (range 3.0-50 months) after SRS. Two patients (6.6%) developed grade 2 radionecrosis following SRS beyond earlier WBRT.

Conclusion:

The mean dose to the whole brain in patients treated with GK SRS for 10 or more BM remained low with an acceptable rate of radionecrosis. This strategy allowed the majority of patients to avoid subsequent WBRT.

Oncology

Surgery

Brain metastases

Gamma Knife

stereotactic radiosurgery

whole-brain radiation therapy

dosimetry

Brain metastases (BM) represent an unfortunately common occurrence as improvements in screening techniques, diagnostic imaging, and systemic therapeutics have lengthened patient survival after primary cancer diagnosis [1]. Radiotherapy plays an important role in the treatment of BM [2]. For patients with higher-burden intracranial disease, whole-brain radiotherapy (WBRT) has historically been the preferred therapeutic modality over stereotactic radiosurgery (SRS) [3]. However, SRS confers several advantages relative to WBRT, including significantly lower incidence and magnitude of neurocognitive decline [4], minimal hair loss, and completion in one to a few days as opposed to the 1-3 weeks needed for WBRT.

The decision to offer WBRT rather than SRS is sometimes driven by the belief that distant brain sites may be seeded with micrometastatic disease in patients with many BM. Therefore, irradiating the entire brain may theoretically confer a survival advantage [5]. However, the number of BM has been shown not to be a clinically meaningful prognostic indicator of overall survival [6]. Additionally, improvements in systemic therapy have prolonged overall survival after treatment of extensive intracranial disease [7]. Hence, to avoid the toxicity associated with WBRT, more radiation oncologists are offering upfront SRS rather than WBRT for extensive BM [8]. Despite this trend, the clinical and dosimetric consequences of treating ten or more BM with SRS are not well known. This study endeavored to determine cumulative radiation doses to the brain in patients who underwent gamma knife (GK) SRS for ten or more lesions in a single session and their associated clinical outcomes.

We performed a single institution, retrospective analysis of all patients who received GK SRS for ten or more BM in one session (not staged) at Northwestern Medicine between November 2014 and December 2018. The study was approved by the Northwestern University institutional review board to retrospectively evaluate radiation dose to the brain from Leksell GammaPlan (Elekta, Stockholm, Sweden) data and associated clinical outcomes. To perform the analysis, we imported Leksell GammaPlan patient data into MIM Software (Beachwood, OH, USA) and then utilized MIM to contour the whole brain. Then, we accumulated the doses from all treated lesions and exported corresponding dose-volume histogram data from the contoured whole brain. From these data, we determined the primary endpoint of mean dose delivered to the whole brain as well as volumes and percentages of brain receiving an aggregate dose of at least 3 Gy, 5 Gy, and 12 Gy. Patient information and outcomes were determined from retrospective chart review. Statistical analyses were performed using GraphPad Prism Version 9.1.0 (GraphPad Software Inc., San Diego, California, USA) including multiple unpaired t test function for grouped analyses with a p < 0.05 set for statistical significance. The Kaplan-Meier method was utilized to estimate survival and the log rank test was used to compute differences in survival. Pearson’s r was used to assess the correlation between variables, with a positive Pearson’s r indicative of a positive correlation between tested variables. Continuous features were summarized using medians and ranges.

Thirty patients were identified with a median of 13 tumors treated per patient (range 10-26 tumors) for a total of 427 tumors (Table 1). The median aggregate tumor volume was 4.70 cm³ (range 1.30-45.2 cm³). The median dose to the margin was 20 Gy (range 12-20 Gy) prescribed to the 50% percent isodose line. Histologic tumor types included non-small cell lung cancer (NSCLC, 14 patients), breast cancer (5 patients), gastrointestinal cancer (GI, 4 patients), melanoma (2 patients), salivary duct carcinoma (2 patients), neuroendocrine carcinoma (2 patients), and sarcoma (1 patient). Eleven patients (37%) had received prior WBRT.

The mean dose to the whole brain was 1.8 ± 0.91 Gy (range 0.70–3.8 Gy), and 83% of patients had a mean brain dose less than 3 Gy. The volume of brain receiving at least 12 Gy was a median of 7.71 cm³ (range 2.97-77.2 cm³), equivalent to 0.50% (range 0.17%-4.1%) of the brain volume (Table 2). The median volumes of brain receiving at least 5 Gy and 3 Gy were 32.9 cm³ (range 12.4-400 cm³) and 99.3 cm³ (range 33.2-821 cm³), respectively, equating to 2.3% (range 0.73%-22%) of brain receiving at least 5 Gy and 7.2% (2.0%-44%) of brain receiving at least 3 Gy. There was no correlation between the number of metastases and the volume of treatment (p=0.22). There was also no association between the number of metastases and the mean dose to the brain (p=0.21) (Figure 1, left). The number of metastases was not correlated to the volume of brain receiving at least 3 Gy (p=0.42), at least 5 Gy (p=0.31), or at least 12 Gy (p=0.35). However, aggregate tumor volume was significantly associated with a higher mean dose to the brain (Pearson r=0.95, p<0.0001) (Figure 1, right), as well as with volume of brain receiving at least 12 Gy (p<0.0001), 5 Gy (p<0.0001), and 3 Gy (p<0.0001). Tumor volume of GI cancer metastases was significantly larger than metastases from either NSCLC (p=0.033), or breast cancer (p=0.017) primaries, but no other significant differences between primary histologies were noted.

The median survival time after GK SRS was 10 months for all patients and 9.9 months, 3.5 months, and 14 months for breast cancer, GI cancer, and NSCLC, respectively (Table 3). There was a significant difference in overall survival between GI cancer and NSCLC (p=0.042) and between GI cancer and other diagnoses (p=0.040), but not between GI cancer and breast cancer (p=0.080). There was no significant correlation between overall survival and number of lesions (p=0.79) (Figure 2, left), aggregate tumor volume (p=0.94) (Figure 2, right), or mean dose to the whole brain (p=0.95). Fourteen patients (47%) underwent additional SRS sessions and six patients (20%) underwent WBRT a median of 6.6 months (range 3.0-50 months) after SRS.

Two patients (6.6%) developed grade 2 radionecrosis. One patient developed radionecrosis 5.0 months following SRS for 17 BM (tumor volume 11.8 cm³) with mean whole brain dose of 2.2 Gy and 12 Gy volume of 24.0 cm³; history was also notable for WBRT 11 months prior to SRS to total dose 37.5 Gy in 15 fractions. Another patient had developed pathologically-proven radionecrosis prior to SRS from previous WBRT to total dose 30 Gy in 10 fractions and CyberKnife radiosurgery to 3 lesions (including 20 Gy in single fraction to a left parietal tumor where necrosis developed). However, this patient subsequently survived 26 months after GK SRS treatment without developing additional radionecrosis after GK SRS treatment for 18 BM (tumor volume 11.3 cm³) with mean whole brain dose of 2.2 Gy and 12-Gy volume of 19.8 cm³.

In an effort to avoid known neurocognitive side effects of WBRT, radiation oncologists are increasingly choosing SRS over WBRT for treatment of high-burden intracranial disease. In a recent survey of American radiation oncologists, 42.4% of physicians stated their willingness to treat up to ten intracranial lesions without WBRT, while 17.2% were willing to treat more [9]. As studies of patients treated with SRS for extensive BM continue to demonstrate the safety and efficacy of such an approach, these percentages will likely rise [10-14]. With a median dose to the whole brain of 1.4 Gy and over 83% of patients receiving less than 3 Gy while treating up to 26 tumors, our data provide additional dosimetric evidence for the safety and feasibility of treating ten or more BM in a single GK SRS session. Furthermore, 11 of the 19 patients (58%) who had not received prior WBRT did not require post-SRS WBRT, permitting many to avoid the neurocognitive side effects of WBRT.

Our data compare similarly to a study performed by Bowden and colleagues which included patients with 15 or more BM (range 15-39 BM) treated in a single SRS session in which their median dose to the whole brain was 2.58 Gy and 79% of patients received a dose less than 3 Gy [14]. Bowden and colleagues reported no significant relationship between number of metastatic lesions and dose to the whole brain or volume of brain receiving at least 3 Gy, 5 Gy, or 12 Gy, but found a meaningful association between tumor volume and these dosing parameters. Analogously, we did not detect a significant relationship between number of intracranial lesions and corresponding dose to the whole brain (Figure 1 (left), p=0.21) or volume of brain receiving at least 3 Gy (p=0.42), 5 Gy (p=0.31), or 12 Gy (p=0.35); likewise, we found highly significant associations between aggregate tumor volume and dose to the whole brain (Figure 1 (right), p<0.0001) and volume of brain receiving at least 3 Gy, 5 Gy, or 12 Gy (p<0.0001). These data highlight the importance of tumor volume, not number of metastatic lesions, on brain dosimetry.

Studies have also shown that total number of metastatic brain tumors is not predictive of tumor control or brain-related survival [6, 15-18]. In a study of 1921 patients with BM who received SRS, Karlsson and colleagues demonstrated that median overall survival did not significantly differ in patients with two, three to four, five to eight, or more than eight metastases [19]. Additionally, Chang and colleagues showed that median survival did not significantly differ between patients with one to five, six to ten, eleven to fifteen, or more than fifteen brain metastases among 323 patients receiving SRS for BM [20]. In line with these studies, we did not find a significant correlation between overall survival and number of metastatic lesions (Figure 2 (left), p=0.79).

While greater aggregate tumor volume has been associated with worse overall survival [17, 21-23], we did not find a significant correlation in our data (Figure 2 (right), p=0.94). We did find a greater tumor volume in patients with primary histology of GI cancer compared to NSCLC (Table 1, 25.0 cm³ versus 4.50 cm³, p=0.033, respectively) and correspondingly worse overall survival post-SRS for GI cancer versus NSCLC (Table 3, 3.5 months versus 14 months, p=0.042, respectively), but no other significant links between both tumor volume and overall survival amongst other primary histologies. While unclear if these differences would persist with a larger cohort, it is noteworthy that GI cancer has been associated with some of the worst survival outcomes following development of brain metastases [24, 25].

Two patients (6.6%) in our cohort developed radionecrosis following SRS, which is lower than other reported incidences of 11.4% by Varlotto et al. and 30% by Korytko et al. for patients undergoing GK for brain metastases [26, 27]. However, our median survival post-SRS for all patients was 10 months, less than the median time of 1-2 years to develop radionecrosis after radiotherapy [28]. The lone patient who developed radionecrosis after GK for 10+ lesions had also received prior WBRT (to total dose 37.5 Gy in 15 fractions) and had a tumor volume greater than 2 cm³ (11.8 cm³), all of which likely contributed to an increased risk for radionecrosis development following SRS [26, 27].

This study is limited by its retrospective design and inherent selection bias. Ongoing prospective trials include the single institution, randomized phase III clinical trial for patients with four to 15 BM which randomizes to SRS versus WBRT (ClinicalTrials.gov identifier: NCT01592968) at MD Anderson Cancer Center, as well as a comparable trial (ClinicalTrials.gov identifier: NCT02353000) in the Netherlands which is currently enrolling patients with four to 10 brain metastases. In addition, there is the multi-institutional National Cancer Institute of Canada - Canadian Cancer Trials Group (NCIC - CCTG) CE7 trial comparing SRS with WBRT for five to 15 BM (NCT03550391). These prospective trials will ideally provide level 1 evidence regarding optimal management of patients with ten or more BM and further elucidate dosimetric and clinical outcomes for this patient population.

Many radiation oncologists are offering SRS as an initial treatment for patients with many BM in an effort to avoid the toxicity associated with WBRT. The data from this clinical and dosimetric analysis suggest that the mean dose to the whole brain in patients treated with GK SRS for 10 or more BM remains low, does not approximate WBRT dosing, and is associated with acceptable rates of radionecrosis. Ongoing randomized trials will provide prospective evidence for this challenging clinical scenario.

Funding: No funding was received to conduct this study.

Conflicts of interest/competing interests: The authors report no relevant conflicts of interest or competing interests.

Availability of data and material: All data generated or analyzed during this study are included in this published article.

Code availability: Not applicable

Authors’ contributions: TLS and SS conceived and designed the study; TLS, MG, MKR, AMS, MCT, JPC, MSK, TJK, JAK, SS collected the data; TLS, MG, MKR, RS, AH, AMS, MCT, JPC, MSK, TJK, JAK, and SS analyzed and interpreted the data; TLS, AH, and SS wrote the original manuscript; TLS, MG, MKR, RS, AH, AMS, MCT, JPC, MSK, TJK, JAK, and SS reviewed the manuscript; and TLS and SS approved the final version of the manuscript.

Ethics Approval: This study was approved by the Northwestern University institutional review board (IRB approval number STU00208333).

Consent to participate: Not applicable

Consent for publication: Not applicable

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Table 1. Patient characteristics at time of radiosurgery.

				Median (range)
	No. of pts	Age at SRS (years)	No. of lesions	Margin dose (Gy)	Aggregate tumor volume (cm3)	No. of patients with prior WBRT
Breast	5	49 (33-80)	12 (11-17)	20 (16-20)	3.20 (1.30-11.8)	2 (40%)
Gastrointestinal	4	66 (45-80)	17 (10-25)	18 (12-20)	25.0 (7-40.7)	1 (25%)
NSCLC	14	66 (48-78)	13 (10-19)	20 (12-20)	4.50 (1.50-45.2)	6 (43%)
Other	7	66 (23-80)	13 (11-26)	20 (12-20)	4.00 (2.20-35.5)	2 (29%)
Total	30	65 (24-81)	13 (10-26)	20 (12-20)	4.70 (1.30-45.2)	11 (37%)

Table 2. Dosimetric parameters to whole brain.

				Median (range)
	Whole brain dose (Gy)	Volume receiving 12 Gy (cm³)	% Brain receiving 12 Gy	Volume receiving 5 Gy (cm³)	% Brain receiving 5 Gy	Volume receiving 3 Gy (cm³)	% Brain receiving 3 Gy
Breast	1.3 (0.70-2.2)	6.65 (2.97-24.0)	0.49% (0.17%-1.6%)	30.9 (12.4-132)	1.9% (0.73%-8.6%)	87.7 (33.2-302)	5.5% (2.0%-20%)
GI	2.9 (1.2-3.4)	38.1 (7.53-64.2)	2.3% (0.38%-4.1%)	172 (28.5-338)	10% (1.5%-22%)	433 (73.4-576)	26% (3.8%-37%)
NSCLC	1.4 (0.90-3.8)	7.45 (3.50-77.2)	0.47% (0.24%-4.1%)	32.6 (14.5-400)	2.1% (0.98%-21%)	97.3 (39.8-821)	6.3% (2.7%-44%)
Other	1.4 (1.0-3.5)	9.45 (4.49-58.7)	0.61% (0.26%-3.5%)	44.4 (19.1-300)	2.9% (1.1%-18%)	121 (50.3-641)	7.7% (3.1%-38%)
Total	1.4 (0.70-3.8)	7.71 (2.97-77.2)	0.50% (0.17%-4.1%)	32.9 (12.4-400)	2.3% (0.73%-22%)	99.3 (33.2-821)	7.2% (2.0%-44%)

Mean Brain Dose Remains Uninfluenced by Lesion Number for Gamma Knife Stereotactic Radiosurgery for Ten+ Metastases

Status:

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Abstract

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Introduction

Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Status:

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