Fractionated Stereotactic Radiosurgery Following Surgery for Brain Metastases: A Single Australian Centre Experience and Literature Review.

doi:10.21203/rs.3.rs-1429480/v1

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Fractionated Stereotactic Radiosurgery Following Surgery for Brain Metastases: A Single Australian Centre Experience and Literature Review.

https://doi.org/10.21203/rs.3.rs-1429480/v1

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Purpose

The aim of this study was to evaluate the efficacy and safety of adjuvant multifractionated stereotactic radiotherapy (SRS) for patients with resected brain metastases (BM).

Methods and Materials

We retrospectively assessed 54 patients with brain metastases who underwent surgery and postoperative SRS in a single institution between January 2016 and June 2021. All but one patient were treated with hypo fractionated stereotactic radiotherapy (HF-SRT) with doses ranging from 30 Gy in 5 fractions, 25 Gy in 5 fractions, or 27 Gy in 3 fractions. The primary outcome for this study was local control (LC) within the resection cavity. The secondary endpoints were overall survival (OS), distant brain failure (DBF), leptomeningeal disease (LMD), and brain radionecrosis (RN).

Results

The median follow-up was 14.9 months. Local control was 90.6% at 6 months and 82.1% at 12 months. The six and twelve-month estimates of DBF were 19.2% and 25.9%, respectively. Seven patients (12.9%) experienced both local and distant failures, including 2 cases with leptomeningeal disease. At the time of final analysis, median times to local failure, DBF and LMD were not reached. OS rates at 6 months and 12 months were 80.8% and 56.6%, respectively. RN was present in 4 cases (7.4%).

Conclusions

This single-institution retrospective study shows that postoperative HF-SRT in patients with BM seems to be associated with favourable outcomes for LC and relatively low-risk of RN.

Stereotactic radiosurgery

Brain metastases

Radiotherapy

Surgery

SRS

Distant brain failure

Radionecrosis

Brain metastases (BM) are the most frequent type of intracranial malignant tumour and constitute a significant source of morbidity and mortality worldwide [1]. It is estimated that between 20-40% of cancer patients will develop BM in their lifetime, and the prevalence is rising due to advances in systemic therapy and superior imaging techniques [2,3]. Unfortunately, the prognosis remains poor with a median survival time of only 6-12 months for BM cases [4].

The contemporary management of BM is multidisciplinary and often includes corticosteroids, surgery, systemic therapy, radiotherapy or a combination of modalities [5]. Options for radiotherapy include whole brain irradiation (WBRT) with or without hippocampal sparing or stereotactic radiosurgery (SRS).

Patchell et al. demonstrated in a phase III-controlled trial that the addition of WBRT for resected solitary BM improved local control and reduced risk of neurologic death [6]. As a result, adjuvant WBRT was widely adopted as the standard treatment to improve intracranial control following resection of BM. However, randomized evidence showed that WBRT was associated with worse cognitive function preservation compared to SRS, with no survival differences between modalities [7].

Due to lack of prospective data, there is no current consensus on the optimal dose-fractionation for postoperative SRS in patients with resected BM. Hypofractionated stereotactic radiotherapy (HF-SRT) in 3-5 fractions is an important strategy to reduce the risk of radionecrosis (RN) in patients with large surgical cavities or those located nearby critical structures compared with single SRS. In addition, HF-SRT has the potential advantage to allow normal tissue repair between fractions [8].

In the following analysis, we retrospectively reviewed rates of overall survival, local failure, distant brain failure and RN in patients with brain metastases who had adjuvant HF-SRT to resection cavity at a single institution from 2016 to 2021.

Patients

This retrospective study was performed at the Crown Princess Mary Cancer Centre in Sydney, Australia. After receiving approval from our institutional review board, we identified 55 patients who underwent postoperative SRS to the surgical cavity for single or multiple BM without whole brain radiotherapy (WBRT) treated between January 1, 2016, and June 30, 2021. Patients were aged >18 years and had an ECOG performance status of 0-2. This analysis excluded one patient who had a histological diagnosis of small cell lung cancer. The collected data included patient demographics (age, sex, ECOG performance status), tumour characteristics (BM histopathology, location, number), as well as treatment data (extent of resection; SRS dose, fractionation, PTV volume and dosimetric data).

Treatment Delivery

SRS was delivered by a Varian TrueBeam STx (Varian Medical Systems, Palo Alto, CA) with high-definition 120-leaf MLCs using 6 MV beams. All patients were immobilised in an SRS frameless mask in supine with head in neutral position. A 1 mm slice thickness computer tomography (CT) simulation was performed through the entire head and fused with postoperative MRI scan of the brain (1mm T1-weighted with gadolium contrast and T2 flare sequences) to improve target delineation. The time interval between postoperative MRI scan and commencement of HF-SRT in within 1 week.

Cases were planned in Brainlab iPlan (BrainLAB Inc., Feldkirchen, Germany). The gross tumour volume (GTV) was defined as the surgical cavity plus any residual gross tumour. The planning target volume (PTV) was defined as the GTV plus a 2-mm expansion in all dimensions.

The prescription dose was based on tumour size and proximity to organs at risk. All but one patient were treated with HF-SRT, including doses of 30 Gy in 5 fractions, 25 Gy in 5 fractions, or 27 Gy in 3 fractions. The radiation therapy plan was prescribed to 80% isodose line and at least 98% of the PTV was covered with the prescription dose. Additionally, the biological effective dose (BED) was calculated according to the linear-quadratic (LQ) formula using an alpha-beta for tumour tissue of 12 Gy [9,10].

The delineated organs at risk (OARs) were whole brain (including PTV), brainstem, optic apparatus (including chiasm and optic nerves), cochlea and lenses. For the OARs, the original plan objectives were to minimize dose as much as possible to critical structures, following QUANTEC's recommendations [11]. Retrospectively, we also evaluated whole brain dose limits following the current recommendations generated from the recently published HyTEC report [12]. According to Milano et al, the recommended irradiated volume of brain plus PTV receiving 12 Gy (V12) in a single fraction is <5-10 cc for single fraction treatments. For patients treated with multifractionated SRS, the recommended brain including the PTV volume receiving 20 Gy (V20 in 3 fractions) and 24 Gy (V24 in 5 fractions) was <20cc.

Follow-up

All patients were assessed by a multidisciplinary team including radiation oncology and neurosurgery. Clinical and MRI brain follow-up examinations were completed at 3-month intervals.

The primary outcome for this study was local control (LC) within the resection cavity. The secondary endpoints were rates of overall survival (OS), distant brain failure (DBF), leptomeningeal disease (LMD) and brain radionecrosis (RN). Outcomes were calculated from the last day of SRS until death, local or distant failure or last follow-up, whichever happened first.

LC was defined as the absence of new, progressive nodular enhancement involving the resection cavity seen on contrast-enhanced MRI. DBF was defined as the presence of one or more new enhancing lesions or leptomeningeal enhancement distant from the surgical site. RN was based on pathological assessment or defined according to conventional imaging features, such as “soap bubble” or “swiss cheese” appearance [13], and modern imaging techniques, such as dynamic contrast-enhanced (DCE) perfusion MR imaging.

Statistical analysis

Methodological approaches to the analysis of the retrospective study comprised of time-to-event methods, primarily proportional hazards models. Cox proportional hazard models were used to explore the association of baseline factors female gender; age (< 60); primary diagnosis NSCLC; infratentorial index lesion; presence of extracranial disease; GTR/NTR/STR (0, 1, 2); SRS dose (Gy); number of fractions; BED₁₂ < 40; PTV size < 30 cc; interval between surgery completion and commencement of radiation therapy (weeks); ECOG performance status 0-1; presence of multiple brain metastases; GPA 0-2. Association of these variables with the risk of local recurrence, distant brain failure and development of radionecrosis were examined using the method of Fine and Gray [14,15] to account for the presence of competing risks associated with these endpoints. Cumulative incidence curves were calculated using the method of Gray [14] to provide estimates at 6 and 12 months. Survival curves were constructed according to the method of Kaplan-Meier, and the median follow-up time was obtained using the reverse Kaplan-Meier approach. No adjustments multiple comparisons have been performed and all tests are two-sided.

Patient Demographics

A summary of patient and tumour characteristics are shown in table 1. A total of 54 patients with 58 surgical cavities were treated with postoperative SRS at our institution between January 2016 and June 2021. There were 31 females (57%) and 23 males, with a median age of 63 years (range: 33-79 years).

The most common primary tumour histologies included in this study were non-small cell lung cancer (n = 30) and breast cancer (n = 12). Other histologies included melanoma (n = 3), renal cell carcinoma (n = 3), and others (n = 6).

Table 1: Patient and tumour characteristics

	n	%
Sex
Female	31	57
Male	23	43
Age (years)
Median	63
Range	33-79
ECOG PS
0	17
1	30
2	7
GPA Score
0-1	13
1.5-2.5	35
3-4	6
Histology
NSCLC	30	55.5
Breast	12	22.2
Melanoma	3	5.6
CRC	2	3.7
RCC	3	5.6
Others	4	7.4
Number of brain metastases
1	30	55.5
2	9	16.6
3	8	14.8
4+	7	12.9
Index lesion location
Supratentorial	45	83.3
Infratentorial	9	16.7
Extracranial metastases
Yes	41	75.9
No	13	24

Treatment

A summary of treatment details is listed in Table 2. Gross or near total resection, based on surgical report and/or postoperative MRI, was achieved in 52 cases (96.2%) and two cases resulted in subtotal resection. Median time interval between surgical resection and postoperative SRS was 4.5 weeks (range 2-11 weeks). All cases completed the planned SRS schedule without delay or discontinuation. The median PTV volume was 10.9 cm3 (range, 3.7-87.2).

Table 2: Treatment characteristics

	n	%
Surgery
Gross tumour resection	49	91
Near total resection	3	5
Subtotal resection	2	4
Number of brain metastases treated
1	50	92.5
2	4	7.4
Planning target volume (cm³)
Mean	15.3
Range	3.77-87.24
Interval from surgery to SRS (weeks)
Median	4.5
Range	2-11
Total dose
Median	26 Gy
Range	20-30 Gy
BED₁₂ (n= Surgical Cavities)
Median	45.7
Range	26.7-53.3
Dose >40 Gy₁₂	28	51.8
Dose <40 Gy₁₂	26	48.1

The median SRS prescription was 25 Gy in 3 fractions (range, 1-5 fractions). The majority of patients (41.3%) were treated using a dose of 25 Gy in 5 fractions, while one patient was treated with a single fraction of postoperative SRS. Mean BED₁₂ dose was 45.75 Gy (range, 26.67-53.3). Twenty-eight patients received BED₁₂of at least 40 Gy (55%) to all surgical cavity volumes (52%).

Outcomes

With a median follow-up of 16.4 months (95% confidence interval: 12.6-23.7), local recurrence occurred in 10 patients (18.5%). The median time to local failure was not reached, and the 6-month and 12-month KM estimates for local control were 90.6% and 82.1%, respectively (Fig 1). On univariate analysis, there was a trend towards improved LC for patients receiving a radiotherapy dose with BED₁₂ ≥ 40 Gy (HR: 3.25, 95% CI 0.92-11.4, p=0.065) (Table 3).

Table 3: Univariate analysis for local and distant brain failure

	Local Failure		Distant Brain Failure		Reference
	HR (95% CI)	P value	HR (95% CI)	P value	Reference
Age ≥ 60	2.89 (0.65-12.8)	0.16	0.65 (0.23-1.59)	0.32	<60
Male	0.6 (0.15-2.28)	0.45	0.9 (0.33-2.48)	0.85	Female
ECOG PS >1	0.66 (0.09-4.59)	0.68	0.41 (0.04-3.59)	0.42	PS 0-1
GPA score: 3-4	0.88 (0.11-6.83)	0.91	1.45 (0.28-7.41)	0.65	0-2.5
Multiple brain metastasis	0.71 (0.21-2.35)	0.58	4.61 (1.45-14.6)	0.01	Single
Extracranial disease	0.84 (0.24-2.82)	0.78	0.66 (0.23-1.84)	0.43	Absent
PTV volume (Size ≥30 cc)	1.26 (0.26-5.94)	0.77	1.2 (0.31-4.62)	0.79	<30 cc
BED₁₂ <40 Gy	3.26 (0.92-11.43)	0.07	0.86 (0.33-2.24)	0.76	≥48 Gy

Distant brain failures were observed in twenty-three patients (42.5%). The six and twelve-month KM estimates of DBF were 19.2% and 25.9%, respectively (Fig 2). While there was a 28% reduction in the risk of DBF for each week delay to SRS, this reduction was not statistically significant and within the play of chance. Among distant recurrences, LMD recurrence was detected in 7 (12.9%) patients. Seven patients (12.9%) experienced both local and distant failures, including 2 cases with leptomeningeal disease. At the time of final analysis, median times to DBF and LMD were not reached.

Twenty-five patients (46.2%) patients were alive at last follow-up. The median survival time was 14.9 months (95% CI: 10.4-25.6). The six and twelve-month estimates of overall survival from radiation completion date were 80.8% and 56.6%, respectively (Fig 3). On univariate analysis, a trend in worse OS with extracranial disease was present (HR: 2.85, 95% CI: 0.86-9.4, p=0.08) (Table 4).

Table 4: Univariate analysis for Overall Survival

	Overall Survival
	HR (95% CI)	P value	Reference
Age ≥ 60	1.03 (0.48-2.19)	0.93	<60
Male	1.02 (0.47-2.18)	0.95	female
ECOG PS >1	1.53 (0.58-4.03)	0.39	PS 0-1
GPA score: 3-4	0.96 (0.27-3.29)	0.95	0-2.5
Multiple brain metastasis	0.58 (0.27-1.23)	0.16	single
Extracranial disease	2.85 (0.86-9.44)	0.09	absent
PTV volume: (Size ≥30 cc)	1.17 (0.46-2.91)	0.73	<30 cc
BED₁₂ <40 Gy	1.58 (0.75-3.29)	0.26	≥40 Gy

Dose constraints

We analysed dose volume constraints for OARS. For whole brain, only 13 patients (24.1%) achieved recommended dose constraints from HyTEC report [12] (For single fraction SRS, V12 <5-10cc for single fraction SRS; V20 and V24 <20cc for 3 and 5 fractions, respectively). The remaining OARs were all well within normal limits based on QUANTEC report [11].

Toxicity

At the time of last follow-up, four patients (7.4%) developed radiological evidence of RN, of whom one case was confirmed by biopsy. (The median time to occurrence of RN was 22.5 months). Two cases presented with RN before 12 months after SRS completion (8 and 11 months). One symptomatic patient with RN was managed with a combination of Avastin and steroids while another case required steroids alone.

The aim of this study was to evaluate the efficacy and safety of HF-SRT for patients with resected BM.

Brain metastases affect a significant percentage of cancer patients, and their prevalence is increasing as emerging systemic therapies keep improving long-term survival outcomes. Multiple treatment alternatives are available for patients with BM including surgery, WBRT, SRS, systemic therapy, or some combination of the above.

Surgery plays a vital role in the management of patients diagnosed with limited BM, improving overall survival, local control, and quality of life in patients with solitary brain mets [6]. In addition, surgery also offers the benefit of establishing a histological diagnosis, immediate mass reduction of large lesions and management of neurological symptoms refractory to steroids. Surgical resection alone, however, is associated with increased risk of local recurrence in the absence of adjuvant radiotherapy [16]. Although historically WBRT was a cornerstone therapy for patients with BM, new concerns regarding declines in neurocognitive toxicity and QOL led to the increasing use of SRS as a safer alternative in the definitive and postoperative setting [7, 17-18].

Brown et al [17] published a randomized trial comparing adjuvant SRS with WBRT for resected BM cases. At a median follow-up of 11 months, postoperative SRS showed no difference in OS compared to WBRT (median OS 3.2 months vs 3 months), with better 1-year cognitive deterioration free survival (median 3.7 months vs 3 months. Another randomized phase III trial compared gross total resection with or without SRS to surgical cavity in patients with 1–3 brain metastases [19]. 132 patients were randomized to receive either total resection of BM plus SRS boost (volume-based dosing, 12–16 Gy in a single fraction) or surgery alone. In this study, the addition of SRS led to a significant improvement in local control rate compared to observation (72% vs 43% at 12 months, respectively), while OS and neurological death were unchanged.

One significant disadvantage of postoperative SRS is difficulty of accurate delineation of the surgical cavity. This seems to translate into a relatively high rate of local recurrence, especially in large lesions compared with adjuvant WBRT [7, 19]. Indeed, Choi et al. demonstrated that a small PTV expansion of 2 mm improved local control without increasing toxicity [20].

Rationale for postoperative hypofractionated SRS

Currently, there is an ongoing debate whether single fraction SRS or HF-SRT should be the preferred radiation approach for patients with resected BMs. Potential advantages of hypofractionation include beneficial radiobiological effects (repair of normal tissues, reoxygenation and redistribution), reducing the risk of radiation necrosis (ref) and allowing for safe total dose escalation in candidates with large operative cavities or target volumes close to critical structures.

Overall, there is scarce literature comparing postoperative single vs hypofractionated stereotactic radiotherapy, although the published retrospective data suggests improved LC and lower risk of RN with HF-SRT versus single fraction SRS to risk cavity. A recent meta-analysis of over 3400 patients reported an improvement of 12-months LC and decreased risk of RN for patients treated with HF-SRT compared with single fraction SRS [21]. In addition, there is a phase III trial (Alliance A071801) currently randomizing patients with HF-SRT versus single fraction SRS to treat postoperative resection cavities.

A summary of selected studies of hypofractionated SRS for resected brain metastases is presented in Table 5. In our series, 12-month LC, DBF and RN rates were comparable to other HF-SRT studies reported in the literature. It was worth noting that the 12-month LC of 82.1% in our cohort exceeded the 12-months LC of the SRS arms of the two phase 3 randomised controlled trials, 72% in Mahajan et al. [19] and 61.8% in Brown et al [17], both of which employed single fraction SRS to the resection cavities.

The optimal dose fractionation protocol for HF-SRT for resected BM remains unknown. Kumar et al. reported that BED10 ≥48 Gy to the resection cavity is associated with improved LC for multifractionated SRS [39]. Meanwhile, Wiggenraad et al. published a systematic review recommended a BED12 of at least 40 Gy for local control rates above 70% [9]. In our trial, we achieved good LC result, despite only 52% patients (n=28) receiving at least 40 Gy BED₁₂. One explanation is that our results reflect a lower median PTV volume of our series of 15.3cc which falls in the lower end of the range reported in Table 1.

Table 5: Summary of published HF-SRT studies

Reference	n	GTR	Total dose/ Fractionation	Margin (mm)	Median PTV/Range (cc)	1yr-LC	1yr-DBF	LMD	Median OS (months)	RN
Choi et al.[20]	112	90%	20 Gy/1-5#	0-2	11.1 (0.1-66.8)	90.5%	54%		17	3.6%⁵
Wang et al.[22]	37		24 Gy/3#	2-3	28.84 (11.07-81)	80%²	20%³		5.5	2.9%⁵
Steinmann et al.[23]	33		30-40 Gy/5-10#	4	25.59 (4.87-93.56)	71%	33%		20.2	0
Minniti et al.[24]	101	100%	27 Gy/3#	2	29.5 (18.5-52.7)	93%	50%		17	9%⁶
Brömme et al.[25]	42	83.3%	24-40 Gy/1-10#	3	22 (14–44)	77%	67%	4.7%	15.9	2.4%⁵
Al-Omair et al.[26]	20	80.9%	25-37.5 Gy/5#	2	34.5 (5-179.8)	71%	37%		23.6	0%
Ahmed et al.[27]	65		20-30 Gy/5#	1-2	16.88 (4.8-128.4)	87%	50.9%	9.2%	10.1	1.5%⁶
Ammirati et al.[28]	36		30 Gy/5#	3	20.1 (1.1-109.2)¹	84%³	44%³		16	7.7⁵
Ling et al.[29]	99	81%	10-28 Gy/1-5#	0-1	12.9 (0.6-51.1)	71.8%	64.1%	6%	12.7	9%^5,6
Eaton et al.[30]	36	55.6%	21-30 Gy/3-5#	1-10	37.7 (12.7-80)	74.4%			11.2	13.8%⁶
Vogel et al.[31]	30	58%	15-35 Gy/1-5#	2-3	25.1 (4.7–90.9)	76%³	62%³	34%³	10.1	10%⁶
Dore et al.[32]	95	94.8%	23.1 Gy/3#	2	12.9 (0.8–64.7)	84%	56%	28%	25	20.6% ⁶
Lima et al.[33]	41	100%	20-30 Gy/5-10#	2	26.4 (14.1-38.4)	89.4%	10.4%		28.2	0%
Specht et al.[34]	46	63%	35 Gy/7#	2	26.19 (3.45-63.9)	88%	52%		25	0%
Pessina et al.[35]	69	100%	30 Gy/3#	3	55.2 (17.2-282.9)	100%	19.6%		24	0%
Abuodeh et al.[36]	75	94.8%	25 Gy/5#	1-2	13.8 (1.9-128.4)	88.8%	42.9% ³	2.7%		3%^5,6
Keller et al.[37]	181	94.2%	33 Gy/3#	2	14.15 (0.8-65.8)	88%	61%	14.4%	17	18.5%^5,6
Lockney et al.[38]	143	83.9%	30 Gy/5#	2-5		84%³	45*		5.4	11.8%
Kumar et al.[39]	39	100%	18-30 Gy/3-5#			77%²	7.7%³	13%		0
Navarria et al.[40]	101	64.4%	30 Gy/3#	3	52.9 (7.6-282.9)	98.9%	31.4%	13.9%	22	25.7%
Bilger et al.[41]	60	11.6%	30 Gy/5#	2	34.5 (3.6-307)	81.5%	55.8%³		15	0%
Martinage et al.[42]	160	92%	25-30 Gy/3-5#	2	15.2 (2.2-129.8)	88%	52%	20%	15.2	8.9%
Soliman et al.[43]	122	89%	25-35 Gy/5#	2¹		84%	45%	22%	17	6%^5,6
Minniti et al.[44]	95		27 Gy/3#	1	22.4 (6.3-67.4)	83%	50%	7%	13.5	15%⁷
Eitz et al.[45]	558	46%	18-35 Gy/2-7#		23.9 (13.5-36.3)	84%		13.1%	21.2	8.6%⁶
Our Study	54	91%	21-30 Gy/1-5#	2	15.3 (3.7-87.2)	82.1%	25.9%	13.8%	14.93	7.4%
1: 5-10 mm expansion for dura contact 2: LC at 6 months 3: Crude rate 4: Only for postoperative fractionated stereotactic radiotherapy 5: RN confirmed by histology 6: RN radiological rate 7: 1-year cumulative incidence rates of RN

Toxicity

Brain radiation necrosis is one of the most concerning late adverse effects in the treatment of brain malignancies and can have a significant impact in patient's quality of life. RN usually occurs 6 months to 2 years after radiotherapy and risk factors include large target volume, increased fraction size, previous brain irradiation and concomitant use of systemic therapy/immunotherapy [46].

One of the main concerns of adjuvant SRS is that a PTV margin expansion around the surgical cavity can lead to higher rates of neurotoxicity. Although Choi et al reported that adding a 2 mm PTV expansion was not correlated with an increase in late toxicity [20], recent retrospective studies have linked margin expansion to worsening number of RN events [47, 48].

Postoperative HFSRS is one of the strategies to mitigate this problem, allowing DNA damage repair between fractions while delivering a smaller biological effective dose for normal brain tissue. However, a recent meta-analysis showed no significant reduction of RN rates with the use of adjuvant HF-SRT [49].

In our series, we observed a RN crude rate of 7.4% (n=4), which is in line with previously published results (As per table 5). This relative low rate of RN occurred despite 75% of our patients exceeded the recently published HyTEC threshold for brain including PTV (V20 and V24 <20cc for 3 and 5 fractions) [12]. Among the 4 patients with RN, 2 cases were symptomatic and required low dose steroid administration (n=2) and bevacizumab (n=1).

In this study, we reported a single centre experience utilizing multifractionated SRS in the management of resected brain metastases. We report favourable rates of LC, OS with low rates of late toxicity.

Conflict of Interest:

Dr Hau is an advisory panel member, research funding and honoria from Astra Zeneca.

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Fractionated Stereotactic Radiosurgery Following Surgery for Brain Metastases: A Single Australian Centre Experience and Literature Review.

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