Linac-based stereotactic radiosurgery and fractionated stereotactic radiotherapy with a micro-multileaf collimator for brain metastasis in the primary motor cortex.

This study aimed to assess the clinical outcomes of linear accelerators (linac)-based, stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator for brain metastasis in the primary motor cortex (BMPMC). Thirty-five consecutive patients with BMPMC who were treated by linac-based SRS or fSRT between January 2012 and March 2020 were analyzed. BMPMC was defined as a tumor located in the precentral gyrus on gadolinium-enhanced magnetic resonance imaging (MRI) and T2-weghted imaging (T2WI). In total, 35 patients with 37 metastases were analyzed. The median follow-up time was 13 (range: 1-97) months. The tumor volume was 0.05-26.5 (median: 0.62) cm3. All patients were treated with SRS or fSRT using 35 Gy with 7 Gy per fraction daily. The median survival time (MST) was 16.9 months. The pretreatment KPS and RPA class significantly differed in terms of MST on the log-rank tests. Seven symptomatic patients had hemiparesis before SRS or fSRT. All symptomatic patients, except one with facial paresis and one who died within 3 months, experienced improvement at a 3 month follow-up. None of the patients presented with persistent radiation injury at the final follow-up. Two patients presented with grade 3 radiation-related central nervous system necrosis, which was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In BMPMC, SRS and fSRT had good tumor control and did not cause serious complications. Therefore, they are suitable treatment options with an acceptable safety profile.

INTRODUCTION

Brain metastasis from systemic cancer is the most common neoplasm among intracranial brain tumors. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) for brain metastasis are associated with good tumor control and fewer complications [1-3]. In most cases, brain metastases are located in the frontal lobe [4]. Moreover, tumors in eloquent areas, compared to those in non-eloquent areas, are associated with a higher risk of neurologic deterioration after SRS and fSRT [5]. In particular, brain metastasis in the primary motor (BMPMC) area is a high-risk target of SRS and fSRT [6-8].

To the best of our knowledge, there are only three reports on BMPMC treated using SRS and fSRT. The local tumor control (LTC) and complication rates of lesions in eloquent areas, compared with those in non-eloquent area, were not satisfactory [6-8]. For symptomatic and large BMPMC, surgical resection is still challenging to perform [9-12].

In our previous studies, fSRT with a frameless fixation system for brainstem metastasis and large brain metastasis that cannot be managed with surgical resection had good tumor control with a lower risk of radiation necrosis [1, 2]. However, the optimal treatment for BMPMC remains controversial. This retrospective study aimed to assess clinical and radiographic outcomes and complication rates in 35 consecutive patients treated with linear accelerators (linac)-based SRS or fSRT for BMPMC.

MATERIALS AND METHODS

Patient characteristics

Clinical data were retrospectively collected to evaluate the efficacy and limitations of SRS and fSRT for BMPMC. This retrospective study was approved by the ethical committee of our hospital. Between January 2012 and March 2020, 35 consecutive patients with BMPMC were treated at our hospital. To determine the most appropriate therapy, each patient was evaluated prior to SRS or fSRT by tumor board review on brain tumors; a multidisciplinary team comprising neurosurgeons, neuro-oncologists, neuroradiologists and radiation oncologists. BMPMC was defined as a tumor located in the precentral gyrus on the axial images of gadolinium-enhanced magnetic resonance imaging (MRI) and T2-weighted imaging (T2WI). One patient lost to follow-up was excluded from the analysis. Two patients had two metastases in the primary motor cortex. In total, 35 patients with 37 metastases in the primary motor cortex were analyzed in this study.

SRS and fSRT

Planning SRS and fSRT was based on computed tomography (CT) scan with a slice thickness of 1 mm. All patients were immobilized in a thermoplastic mask. The gross tumor volume (GTV) for each lesion was delineated on MRI with a slice thickness of 1 mm. The planning target volume (PTV) was defined as GTV plus 1–2 mm for all dimensions. Treatment was provided within 1 week after planning the CT scan. Treatment planning was performed using BrainSCAN® or iPlan® RT (BRAINLAB AG, Munich, Germany). The irradiation dose was prescribed to confirm a dose coverage of 90% for the PTV. Dose calculations were performed using a pencil beam algorithm. SRS and fSRT were performed using linacs with a micro multi-leaf collimator: Novalis® (BRAINLAB AG, Munich, Germany) with a collimator width of 3 mm or TrueBeam® STx (Varian Medical Systems, Palo Alto, USA) with a collimator width of 2.5 mm. Twenty-four patients were treated with Novalis and 11 patients were treated with TrueBeam STx. Every patient was treated with X-rays of 6 MV beam energy.

Patient positioning and verification were performed using BrainLab ExacTrac® (BRAINLAB AG, Munich, Germany). This device comprises two infrared cameras and two dual diagnostic kV X-ray tubes, which can be moved automatically into treatment position to minimize setup errors [15, 16].

All patients were treated using Novalis or TrueBeam STx with 21–22.5 Gy in a single fraction for SRS or 35 Gy in 5 fractions for fSRT via non-coplanar multi-beams, non-coplanar multi-arcs, or both. The treatment methods in SRS or fSRT were conformal beams, dynamic conformal arcs, intensity-modulated radiotherapy (IMRT), or hybrid arcs. This is a novel treatment technique blending aperture-enhanced optimized arcs with discrete IMRT elements, thereby allowing arc selection with a set of static IMRT-beams [17].

Clinical and radiological follow-up

Follow-up contrast-enhanced MRI was performed every 3 months after the end of SRS or fSRT if possible. Five patients died due to primary cancer progression within 3 months, and one did not undergo follow-up MRI. Hence, these patients did not undergo follow-up MRI at 3 months. Tumor volumes were evaluated before and after SRS or fSRT using BrainSCAN or iPlan® RT. Each lesion was assessed for local tumor response, and tumors were graded according to the following categories: (i) complete remission (CR), defined as the disappearance of all enhanced lesions on MRI, (ii) partial remission (PR), defined as >50% reduction in the cross-sectional dimensions of tumors on MRI images, (iii) progressive disease (PD), defined as >25% increase in size, or (iv) stable disease (SD), defined as all other responses. LTC was defined as CR, PR or SD [18]. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. [19].

Statistical analysis

The MST was calculated using the Kaplan–Meier method. The log-rank test was used for univariate analyses. We analyzed prognostic factors including age (≥70 vs <70 years), sex, tumor volume (≥0.7 vs <0.7), extracranial metastasis, control of primary cancer, pretreatment Karnofsky Performance Status score (≥80 vs <80), treatment method (SRS vs SRT), RPA class (I + II vs III), metastatic zone, and tumor volume. The Cox proportional hazards model was used to identify factors associated with survival at the univariate levels. All analyses were performed with the EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [20], and a p value of <0.05 was considered statistically significant.

RESULTS

Radiological and clinical response

In total, 35 patients underwent SRS and fSRT for 37 lesions during the study period. Table 1 shows the characteristics of all patients. There were 20 men and 15 women, with a median age of 71 years (range: 51–90). BMPMC originated from the lung (n = 30, 86%), stomach (n = 2, 5.7%), pancreas (n = 1, 2.8%), and skin (n = 1, 2.8%) and from unknown origin (n = 1, 2.8%). The primary motor cortex was divided into three zones, as defined by Magill et al. Zone 1 included the leg/torso cortex or the medial portion of the motor cortex adjacent to the falx and the sagittal sinus. Zone 2 comprised the hand cortex underlying the cerebral convexity and the hand knob. Zone 3 included the face cortex, which was the anterior and lateral portion of the motor cortex [13]. In this study, 17 lesions were located in zone 1, 18 in zone 2, and two in zone 3. In total, 26 patients had no symptoms, and seven presented with motor weakness. Three patients had symptomatic epilepsy, and one had sensory disturbance. Based on the recursive partition analysis (RPA), there were 2, 27, and 6 patients in classes I, II, and III, respectively [14]. The maximum diameter ranged from 1 to 41 (median: 7) mm. The tumor volume ranged from 0.05 to 26.5 (median: 0.62) cm3 (Table 1). All patients were treated with 35 Gy in 5 fractions for 27 lesions or 21–22.5 Gy in a single fraction for 10 lesions. Basically, patients with neurological symptoms and patients with brain metastases larger than 10 mm in size underwent fSRT. Asymptomatic patients with brain metastases smaller than 10 mm were treated with SRS or fSRT, and the decision was based on tumor size, surrounding edema, and other reasons.

Table 1

The characteristics of all patients with BMPMC

Characteristic	Number
Sex
	Male/female 20/15
Age (years)
	Median (range) 71(51–90)
Pretreatment KPS
	Median (range) 100(50–100)
Tumor origin
lung/pancreas/skin/unknown	30/2/1/1/1
Tumor number
	single/multiple 10/25
Side
	right/left 18/19
Tumor location
	Zone 1/2/3 17/18/2
Control of primary tumor
	yes/no 10/25
Extracranial metastasis
	yes/no 15/20
RPA class
	I/II/III 2/27/6
Maximum tumor diameter (mm)
	Median (range) 7(1–41)
Tumor volume (cm3) (N = 37*)
	Median (range) 0.62(0.05–26.50)
Initial symptom
asymptomatic/motor weakness/seizure/sensory disturbance	26/5/3/1

*Two patients had two metastases in the primary motor cortex.

Eventually, 31 lesions in 29 patients were evaluated on follow-up MRI conducted after 3 months. CR was observed in 9 (29%) patients, PR in 14 (45%), SD in 7 (23%), and PD in one (3.2%). During the follow-up period, six patients were diagnosed with distant brain metastasis; hence, additional SRS or fSRT was performed. Then, four patients received whole-brain radiation therapy. In symptomatic patients, seven had hemiparesis before SRS or fSRT. All symptomatic patients, except one with facial paresis and one who died within 3 months, experienced improvement in hemiparesis at a 3 month follow-up. One patient with facial paresis had intratumoral hemorrhage from melanoma before fSRT and this facial paresis did not improve after fSRT.

Survival rate and prognostic factors

At the final follow-up after radiotherapy, 22 patients had died due to worsening of systemic cancer. No patient died due to brain metastasis. The MST of all patients with BMPMC and those with BMPMC originating from the lung were 16.9 and 20.7 months, respectively (Fig. 1). The pretreatment KPS ≥80 and good RPA class I + II, were significantly associated with longer MST calculated using the Kaplan–Meier method on the log-rank tests (Table 2).

Fig. 1

Overall survival time of all patients with BMPMC (A) and the patients with BMPMC from the lung (B) with estimated using the Kaplan–Meier method.

Table 2

Log-rank tests and Cox proportional hazard model for prognostic factors affecting overall survival

Factor	P-value (log-rank test)	HR	95%CI	reference
Gender: male	0.94	0.97	0.42–2.26	female
Age: <70 years	0.55	0.76	0.31–1.89	≥ 70 years
Tumor volume: <0.7 cc	0.27	1.61	0.67–3.85	≥ 0.7 cc
Number of metastasis: single	0.06	2.4	0.95–6.04	multiple
Pretreatment KPS: <80	0.002	3.83	1.51–9.68	≥ 80
RPA class: I + II vs III	<0.001	13.44	4.02–44.95	RPA I + II
Control of primary cancer: Yes	0.33	0.63	0.24–1.62	No
Extracranial metastasis: Yes	0.29	1.56	0.67–3.62	No
Zone of metastasis
1 vs 2	0.09	2.19	0.85–5.61	Zone 1
1 vs 3	0.89	1.07	0.37–3.07	Zone 1
2 vs 3	0.36	0.39	0.05–3.23	Zone 2
Fractionation: fSRT	0.6	1.28	0.50–3.30	SRS

HR: hazard ratio

CI: confidence interval

Complications

None of the patients presented with persistent radiation injury. Two patients had a transient new symptom after SRS and fSRT. They had grade 3 radiation-related central nervous system necrosis, and they were treated with steroid and antiepileptic drugs. One patient presented with hemi-facial seizure six months after fSRT. MRI revealed significant perifocal edema. He then received antiepileptic and oral steroid drugs, and his symptom eventually improved. This case is described in illustrative case 2. Another patient presented with hemiparesis in the lower limb 15 months after fSRT. She then received antiepileptic and oral steroid drugs, and her symptom eventually improved.

Illustrative case 1

A 72-year-old woman with adenocarcinoma in the lung, which was positive for epidermal growth factor receptor mutation, was treated using conventional cytotoxic chemotherapy (see Fig. 2). This patient presented with symptomatic epilepsy 1 year and 6 months after treatment. MRI revealed multiple brain metastases. The largest metastatic tumor was located in the left primary motor cortex. The maximum tumor diameter and volume were 17 mm and 4.10 cm3, respectively. Before treatment, the patient presented with motor weakness in the right upper and lower limbs. Then, she was treated with linac-based fSRT using 35 Gy in 5 fractions. Three months after SRT, erlotinib was commenced, but was eventually discontinued because of serious skin rashes. The patient subsequently refused additional chemotherapy. After 3 and 9 months of SRT, MRI revealed significantly decreased tumor size. MRI revealed multiple small metastases and then she underwent whole brain radiotherapy 7 months after SRT. Osimertinib was commenced 2 months after whole brain radiotherapy. The primary tumor and brain metastasis were stable, and the patient is still alive 2 years and 6 months after fSRT.

Fig. 2

Illustrative case 1: A 72-year-old woman with adenocarcinoma in the lung presented symptomatic epilepsy. MRI revealed the presence of multiple brain metastases. The largest metastasis was located in the left primary motor cortex. The maximum tumor diameter and volume was 17 mm and 4.10 cm3, respectively. (A) The patient was treated with linac-based fSRT using 35 Gy in 5 fractions for this lesion. (D) After 3 months (B) and 9 months (C) of treatment, MRI revealed that the tumor size decreased significantly.

Illustrative case 2

A 70-year-old man with non-small cell lung cancer was treated using conventional cytotoxic chemotherapy and radiotherapy (see Fig. 3). Eight months after treatment, MRI revealed brain metastasis in the right primary motor cortex. The maximum tumor diameter and volume were 23 mm and 5.54 cm3, respectively. The patient was treated with linac-based fSRT using 35 Gy in 5 fractions. Three months after treatment, MRI revealed that the tumor size decreased. The patient presented with hemi-facial seizure 6 months after SRT. MRI revealed significant perifocal edema. He then received antiepileptic and oral steroid drugs, and his symptom eventually improved. The patient was prescribed erlotinib treatment as fourth-line chemotherapy for 3 months, but was discontinued because of enlargement of adrenal metastasis. The patient was treated with nivolumab as fifth-line chemotherapy. The patient is still alive 5 years and 6 months after fSRT.

Fig. 3

Illustrative case 2: A 70-year-old man with non-small cell lung cancer presented without any symptom. MRI revealed the presence of a brain metastasis in the right primary motor cortex. The maximum tumor diameter and volume was 23 mm and 5.54 cm3, respectively. (A) The patient was treated with linac-based fSRT using 35 Gy in 5 fractions for this lesion. (E) After 3 months of treatment, MRI revealed that the tumor size decreased. (B) The patient presented with hemi-facial seizure 6 months after SRT. MRI revealed the significant perifocal edema. (C) The patient was administered the antiepileptic drug and oral steroid. Eventually, the patient improved the symptom. The patient is still alive 5 years and 6 months after SRT, and MRI revealed no recurrence. (D).

DISCUSSION

Brain metastasis in the primary motor cortex

Due to advancements in chemotherapy and radiotherapy against cancer in the modern era, physicians have more options in treating brain metastases. This condition is the most common intracranial malignant tumor in adults. That is, it occurs in up to 8% of 35% of cancer patients [21].

Treatment for brain metastasis includes whole-brain radiotherapy, surgical resection and SRS and fSRT. In particular, SRS is the first-line treatment for small brain metastases and lower number of metastatic tumors. In contrast, surgical resection is the first-line treatment in patients with good general condition who presented with large brain metastasis. Wolf et al. showed the use of gamma knife radiosurgery (GKRS) for the management of brain metastasis [3]. In 31.3% of cases, brain metastasis was located in the frontal lobes [4]. In this area, the primary motor cortex is the essential region as it controls contralateral motor function. Motor function should be preserved, and maximum tumor resection must be achieved. Hence, surgeries for metastatic tumors in the primary motor cortex are still challenging to perform [7, 11, 12, 22]. By contrast, some studies reported that metastatic tumors in the primary motor cortex are considered a high-risk target of SRS and fSRT [6-8].

Surgical resection of brain metastasis in the primary motor cortex

In large brain metastasis, surgical resection is the only method that immediately achieve cerebral decompression, relieve the effects induced by the mass, and rapidly reduce intracranial pressure [21]. In symptomatic and large BMPMC, surgical resection is still challenging to perform [9-12]. With advancements in intraoperative neuro-monitoring, deterioration in motor function after surgery can be prevented. The main cause of motor deterioration is direct injury in the primary motor cortex, corticospinal tract and vascular injury. The incidence of worsened motor function after surgery ranged from 11% to 21% [9-12]. However, the optimal treatment in BMPMC patients remains controversial.

Stereotactic radiosurgery and radiotherapy for brain metastasis in the primary motor cortex

Dea et al. conducted a retrospective study on GKRS for metastatic lesions located in eloquent areas. Transient new or worsening motor deficits occur after radiosurgical treatment involving the primary motor cortex [5]. In the study of Luther et al., 94 patients were treated with GKRS for brain metastases (diameter: ≥1. 5 cm) located in the motor cortex. Further, 19% of patients experienced worsened motor function. Tumor volumes >9 cm3 were associated with a higher risk of worsening motor function [6].

Park et al. showed that 51 patients were treated with GKRS for brain metastases located in the motor cortex. The LTC rates at 6 and 12 months after GKRS were 89.7% and 77.4%, respectively. However, 38% of patients experienced new or worsened neurologic deficits with a median onset time of 2.5 ± 0.5 months. The prescription dose (> 20 Gy) was significantly correlated with neurological deterioration after GKRS [10]. Previous studies on SRS or fSRT for BMPMC are summarized in Table 3 [5, 6, 10].

Table 3

SRS and radiotherapy for BMPMC

Author(year)	Modality	Tumor size	Number of pts	Treatment	Clinical results in motor function	Complication	Others
Luther(2013)	GK	>1.5 cm(volume: NA)	94	12–20 Gy/1 fraction(median: 18 Gy)	Improved 31%Stable 50%Worsened 19%	5 pts	Surgical resection in 2 pts
Park(2016)	GK	3.2 cm3 (median)	51	12–24 Gy/1 fraction(median: 18.6 Gy)	New or worsened 35.3%	NA	Re-radiation in 5 ptsSurgical resection in 3 pts
Pintea(2017)	NA	4.9 cm3 (mean)	41	SRS: <4.5 cm3, 10 Gy volume of <10 cm3SRT: >4.5 cm3, 10 Gy volume > 10 cm3	Worsened 4.8%	35.8%	Surgical resection in 1 pt
This study(2021)	Linac-based	0.62 cm3(median)	35	SRS 21–22.5 Gy orSRT 35 Gy/5 fractions	Worsened 2.8%	2 pts (5.7%)(transient)	Surgical resection: none

GK: Gamma Knife, OS: overall survival, pt: patient, NA: not available

Fractionated stereotactic radiotherapy for brain metastasis

To prevent adverse effects caused by single-session radiosurgery, multi-session radiosurgery and fSRT were used for the treatment of large lesions and those located in near critical structures.

Minniti et al. conducted a retrospective analysis on SRS and SRT for large brain metastasis (>2 cm). Results showed that fSRT was superior to SRS in terms of LTC and the risk of radiation necrosis [23]. Navarria et al. presented the advantages of fSRT compared to other treatment modalities, which are as follows: (i) Compared with single-dose SRS, this procedure may treat large brain lesions with a lower risk of radiation-induced neurotoxicity, (ii) few fractions of radiotherapy can be used for the treatment of lesions located near critical structures, (iii) it has a theoretical advantage due to re-oxygenation of hypoxic tumor cells between fractions, (iv) it has a lower risk of brain radiation necrosis than SRS, and (v) it has a shorter treatment time than whole-brain radiotherapy [24].

Our previous study showed the clinical outcomes of fSRT for large brain metastasis that cannot be managed with surgical resection. Large brain metastasis (>30 mm) is well controlled with less complications [1]. SRT is an alternative treatment option for eloquent areas including the primary motor cortex.

Adverse events after radiosurgery and radiotherapy for brain metastasis in the primary motor cortex

In the study of Luther et al., five patients (5.3%) presented with worsened neurological function, and two underwent surgical resection because of intratumoral hemorrhage and cyst formation [6]. Pintea et al. showed that compared with surgery, SRS/SRT for tumors in the primary motor cortex was associated with the use of dexamethasone at higher dose and longer duration [8].

In this research, two patients presented with symptomatic radiation necrosis after fSRT. They received dexamethasone and antiepileptic drugs and eventually recovered from symptomatic radiation injury at the final follow-up. Although this study included the smaller brain metastases, we demonstrated the good tumor control and low complication rate.

The fractionation schedule of 35 Gy in 5 fractions was used for the present fSRT. EQD2 is the dose delivered in 2Gy fractions that is biologically equivalent to a total dose and often utilized to evaluate dose fractionation schedules. Alpha/beta ratios 2 or 3 in linear-quadratic model are generally used to evaluate late adverse events like radiation-induced brain necrosis. EQD2 of 35 Gy in 5 fractions are 78.75 Gy (alpha/beta ratios 2) and 70 Gy (alpha/beta ratios 3) and these are more than the tolerant dose of brain. However, marginal dose of the PTV is 31.5 Gy (90% of the prescribed dose), and EQD2 of 31.5 Gy in 5 fractions are 65.36 Gy (alpha/beta ratios 2) and 58.59 Gy (alpha/beta ratios 3) and these are comparable to the tolerant dose.

Limitations

The current study had several limitations. That is, it included a small sample size. Further, since this is a retrospective analysis, different treatment modalities for BMPMC could not be compared. In this study, multivariate analysis was not performed due to the small number of cases. Although similar clinical studies have been conducted recently, each involved different criteria, such as those for treatment modalities, dose fractionations, and tumor volume. Results showed that SRS and fSRT have potential benefits in terms of good tumor control and reduced toxicity in this setting.

CONCLUSION

SRS or fSRT using 35 Gy with 7 Gy per fraction daily for BMPMC had good tumor control and did not cause serious complications. Therefore, they are suitable treatment options with an acceptable safety profile that may prevent the development of neurological symptoms and the need for surgical resection.

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.