Comparison of treatment outcomes of single-session and 2-stage gamma knife surgery for large brain metastases from lung adenocarcinoma

doi:10.21203/rs.3.rs-4964104/v1

PURPOSE

To compare the therapeutic outcomes of single-session gamma knife surgery (GKS) and 2-stage GKS for large (diameter ≥ 2 cm) brain metastases from lung cancer.

METHODS

For the first time, patients with brain metastases from a single primary tumor were selected, and the treatment data of patients with large lung brain metastases from lung adenocarcinoma treated with single-session or 2-stage GKS between January 2019 and June 2022 at our hospital were retrospectively analyzed. Seventy-seven patients (85 lesions) were in the single-session GKS group, while 62 patients (72 lesions) were in the 2-stage GKS group. Propensity score matching of cases was performed because of differences in the number of patients and clinical factors prior to GKS between the two groups. Finally, 90 patients (45 in each group) were included in the matched case-control study. Therapeutic outcomes were measured based on the Karnofsky performance status score, local tumor control, cumulative incidence of radiation necrosis, and overall survival of each patient.

RESULTS

In the overall patient cohort, the cumulative incidence of radiation necrosis was significantly lower in the staged GKS group than in the single-session GKS group (5.0% vs. 18.4% at 1 year, p = 0.028). In the case-matched cohort, the cumulative incidence of neurological death was significantly lower in the staged GKS group than in the single-session GKS group (2.4% vs. 4.9% at 1 year, p = 0.045). In both the overall and case-matched cohorts, the rate of tumor volume change after GKS was significantly higher in the staged GKS group (67.5%, 67.5%) than in the single-session GKS group (53.0, 51.1%) (p < 0.05). The local tumor control and rate of tumor volume change were also significantly better in the staged GKS group than in the single-session GKS group. No significant difference in overall survival was observed between the two groups. Besides, the rate of tumor volume change is a significant factor that influences the long-term efficacy of local tumor control. Additionally, the control of the primary tumor is an independent influencing factor for the overall survival of patients.

CONCLUSION

Our findings suggest that staged GKS is safer and more efficacious than single-session GKS for large brain metastases (≥ 2 cm in diameter) from lung adenocarcinoma, and that the rate of tumor volume change after treatment influences local tumor progression.

Health sciences/Oncology/Cancer/Cancer therapy

Health sciences/Oncology/Cancer/Metastases

gamma knife surgery

large brain metastasis

lung adenocarcinoma

2-stage

influencing factors

Brain metastasis is the most common intracranial malignancy in adults and causes high mortality in cancer patients. The incidence of brain metastasis in adult patients with solid tumors is 10–30%. ^{[1, 2]} Although brain metastasis may occur in almost all cancers, they are most common in lung adenocarcinoma, melanoma, and breast cancer, with an increased incidence in renal cell carcinoma and colorectal cancer. ^{[3, 4]} Brain metastasis more commonly arises from lung cancer in men and breast cancer in women. Brain metastasis is detected in 10–20% of patients with non-small cell lung cancer at the time of diagnosis and develops in 40–70% of patients during the course of disease. ^[5] This percentage is expected to increase with individualized cancer treatments with improvements in overall patient survival rates.

In the treatment of patients with brain metastasis from lung adenocarcinoma, the blood-brain barrier limits effective penetration of many systemic therapies into the brain. Although recently developed targeted therapies and immunotherapy-based systemic therapies have shown potential for intracranial disease control in some patients, ^{[6, 7]} localized treatment, such as stereotactic radiation therapy (SRT) or surgical resection, remains the most effective approach in most patients. ^[8-10] However, the application of SRT to brain metastasis is limited by tumor size, and the biologically effective dose of SRT must be adjusted depending on the size of the metastasis.

Large brain metastases (LBM) are usually defined as metastatic lesions with a maximum diameter of 2–4 cm or volume of 4–15 cm³. Patients with LBM usually have a poor prognosis if good tumor control is not achieved. The treatment of LBM presents some problems in balancing local control (LC) with treatment-related toxicity. Single-session SRT has gained popularity as a stand-alone therapy and is increasingly used to precisely deliver radiation to target lesions while minimizing radiation-related effects on nearby critical structures. However, results have been relatively unsatisfactory in the treatment of LBM, which involves the administration of high doses of targeted radiation in a single treatment session, as evidenced by a decreased remission rate and an increased risk of neurotoxicity. Studies on LBM treatment outcomes have demonstrated that treatment of LBM with single-session SRT at lower doses resulted in a 1-year LC rate of 66.6–84.6% but a higher incidence of radiation necrosis (RN) (38.8–48%). ^[11-13] Some studies have suggested that staged SRT for LBM reduces the risk of side effects such as post-treatment cranial hypertension, minimizes delays in systemic therapy, and reduces the incidence of delayed RN. ^[14-16] However, the efficacy of staged SRT with respect to local tumor control, neuroprotection, improvement of Karnofsky performance status (KPS) score, and prognosis remains unknown.

The present study selected patients with brain metastasis from a single primary tumor source for the first time, eliminating the possible effects of differences in the radiological response of different tumors. Patients with LBM from lung adenocarcinoma who underwent single-session gamma knife surgery (GKS) or 2-stage GKS strategies between January 2019 and June 2022 at our institution were retrospectively analyzed. The rate of change of brain metastasis volume, LC, treatment-related toxicity, KPS, and overall survival (OS) of the patients were evaluated before and after treatment.

1. Patient characteristics

Patients with LBM from lung adenocarcinoma who underwent single-session or 2-stage GKS between January 2019 and June 2022 were included. The inclusion criteria were 1) age ≥ 18 years, 2) brain metastases diameter of ≥2 cm, and 3) no contraindication to surgery or inability to tolerate surgical treatment. The exclusion criteria were 1) previous surgical resection of the target lesion, 2) systemic condition preventing tolerance of GKS, and 3) previous whole brain radiotherapy.

The sex, age, KPS, mutation type, whether systemic therapy (chemotherapy, targeted therapy, or immunotherapy) was administered, whether extracranial metastases were present, number of metastases, site of the largest metastatic lesion, diameter of the largest metastasis, volume of the largest metastasis, cumulative intracranial tumor volume (CITV), magnetic resonance imaging (MRI) follow-up data, therapeutic dose, radiation-related side effects, and OS of the patients were recorded.

2. Treatment modality

All patients underwent GKS. Patients were immobilized with a head frame during each planning and treatment session. Tumors were targeted and outlined using high-resolution T1-weighted enhanced MRI images on the Leksell Gamma Plan software (Elekta), and any other small metastases identified on imaging were treated simultaneously.

The interval between 2-stage GKS treatments was set at 4-6 weeks. Dose-volume histogram analysis was performed to ensure at least 99% coverage of the target area. The total treatment dose ranged from 24 to 30 Gy, with a standard prescription dose of 15 Gy for both treatments. For larger lesions or those located in the brain stem, the dose was adjusted to 12-13 Gy, while for other smaller lesions, 18 Gy was chosen. An isodose line of 45%-50% was used to encompass the lesion.

Volume and diameter data were obtained using the Gamma Plan treatment planning system, and the volume of the treated lesion was calculated at each stage.

3. Clinical outcomes

Various prognostic scales have been developed to predict survival and intracranial control in patients with brain metastasis. Three classes were formed using recursive partitioning analysis (RPA), and younger patients with higher KPS scores who had achieved control of the primary tumor and had no extracranial metastases had good median survival. ^[17] The graded prognostic assessment (GPA) scale classifies patients into four different groups according to age, KPS, extracranial metastasis, and number of brain metastases. ^[18] Further evaluation using GPA showed that different prognostic factors play major roles in different primary malignancies. Therefore, a lung cancer-specific GPA scale (Lung-mol GPA) was created to further update disease-specific prognostic factors by considering the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) status in addition to the four aforementioned factors mentioned above as molecular predictors in patients with lung adenocarcinoma. ^[19]

The following outcomes were specifically documented: (1) KPS of patients before and after treatment. (2) OS determined using the Kaplan-Meier method, calculated as the time from first GKS to death or the last follow-up time point. Deaths were classified as neurological death or systemic death, with neurological death defined as death due to intracranial tumor progression and systemic death defined as death attributed to extracranial disease progression. (3) Response to treatment was evaluated, with the majority of patients undergoing MRI 1–3 months after completion of single-session GKS or staged GKS to compare the maximum volume of metastases with that at the time of initial GKS. Similar to the efficacy criteria in the Response Evaluation Criteria in Solid Tumors guidelines, ^[20] efficacy was defined as a ≥30% reduction in tumor volume, progression was defined as an increase in tumor volume of ≥20%, and LC was defined as tumor stability or shrinkage from the previous size. (4) Occurrence of RN. RN was distinguished from tumor recurrence by histopathological assessment or imaging manifestations such as MRI T1/T2 mismatch ^[21] and perfusion imaging findings. RN was classified according to the National Institutes of Health Common Terminology Criteria for Adverse Events (CTCAE). RN represents an inflammatory response caused by tissue death and dissociation and is usually associated with peripheral edema, which can be symptomatic or asymptomatic. Although the terminology for RN varies in the literature and includes necrosis, response to radiation therapy, and radiation side effects, ^[22] the term RN is used consistently throughout this article.

4. Statistics

The baseline characteristics and treatment parameters of patients were summarized and compared using the t-test (for continuous variables) and Fisher’s exact test (for categorical variables). The Kaplan–Meier method was used to evaluate OS and LC for primary endpoint events, whereas competing risk analysis with Fine-Gray subdistribution hazard models were used to determine the cumulative incidence rates to quantify the overall benefit or harm of exposure for secondary endpoint events. Death was considered a competing risk for RN, and systemic death was considered a competing event for neurological death.

Propensity score matching was performed to reduce the effect of selection bias and confounders. Patients were selected based on nine clinical factors: sex, age, systemic treatment, KPS, extracranial metastasis, CITV, maximum volume of metastases, lung cancer control, and site of the largest metastasis. Patients with meningeal metastases were excluded. A caliper width of 0.2 was selected. After matching, continuous and categorical variables were compared using the t-test and Fisher’s exact test, respectively. For the primary endpoint, OS and LC were analyzed after matching using the Kaplan–Meier method. The cumulative incidence of tumor progression and RN between the two groups was compared using Gray’s test. All statistical analyses were performed using SPSS Statistics version 26 and R version 4.3.1. Differences with p < 0.05 were considered statistically significant.

5.Ethics approval and consent to participate

This study was carried out in accordance with the principles of the Helsinki Declaration and approved by the First Affiliated Hospital, Zhejiang University School of Medicine.

1. Patient data

Seventy-seven patients (85 lesions) underwent single-session GKS, of which two LBMs were treated in six patients and three LBMs were treated in one patient, and 62 patients (72 lesions) underwent staged GKS. Thirty-five of the patients who underwent single-session GKS were women (45.5%). The mean age at the time of diagnosis of brain metastasis was 58.7 years (range: 27–83 years), and the mean age at the time of the first GKS was 59.4 years (range: 29–83 years). Twenty-eight of the patients who underwent staged GKS were women (45.2%). The mean age at the time of diagnosis of brain metastasis was 57.8 years (range: 31–89 years), and the mean age at the time of the first GKS was 58.4 years (range: 31–89 years).

No significant differences were observed between the two cohorts of patients in terms of male-to-female ratio, age at diagnosis of brain metastasis, age at the first GKS, KPS, RPA classification, lung-molGPA score, number of metastases, and site of metastases at the first GKS and at the first follow-up. The characteristics of the patients are summarized in Table 1.

2. Treatment data

In the single-session GKS group, the median peripheral dose was 16.4 Gy (range: 10–27 Gy) and the mean prescription isodose was 49.9% (range: 45%–52%). In the staged GKS group, the median peripheral dose was 15 Gy (range: 10–18 Gy) and the mean prescription isodose was 49.6% (range: 45%–50%) for the first treatment, whereas the median peripheral dose was 14 Gy (range: 10–18 Gy) and the mean prescription isodose was 50% (range: 45%–55%) for the second treatment. The mean interval between the two treatments was 34.4 days (range: 28–36 days) (Table 2).

3. Tumor control

The median volume of the largest lesion was 5.82 cm³ (range: 1.0–23.0 cm³) in patients who underwent single-session GKS and 9.73 cm³ (range: 2.20–24.70 cm³) in patients who underwent staged GKS; the difference was statistically significant (p < 0.05). The CITV was 8.56 cm³ (range: 1.30–44.30 cm³) in patients who underwent single-session GKS and 12.74 cm³ (range: 2.80–28.80 cm³) in patients who underwent staged GKS (p < 0.05).

At the first follow-up after treatment, the median volume of the largest lesion was 3.04 cm³ (range: 0–19.3 cm³) in patients who underwent single-session GKS and 3.82 cm³ (range: 0–38.98 cm³) in patients who underwent staged GKS (p > 0.05). The median relative change in volume observed between the first GKS and follow-up was 53% in patients who underwent single-session GKS and 68% in patients who underwent staged GKS (p < 0.05). Seventy-seven of the 85 lesions (90.6%) exhibited LC at the first re-examination in patients who underwent single-session GKS, with 59 (69.4%) of these lesions exhibiting a volume reduction ≥ 30%. Fifty-nine of the 72 lesions (95.2%, 10 lesions lost to follow-up) exhibited LC at the first re-examination in patients who underwent staged GKS, with 50 (80.6%) of these lesions exhibiting a volume reduction ≥ 30% (Table 3).

Overall, distant failure occurred in 24 patients (31.2%) who underwent single-session GKS and 26 patients (41.9%) who underwent staged GKS (p > 0.05). Staged treatment resulted in better local tumor control than single-session treatment (p < 0.05) (Figure 1a).

4. Radiation necrosis

No patients in either treatment group had adverse events related to CTCAE grade 5 toxicity. Radiation-related side effects were defined as clinical and/or radiological findings associated with lesion enlargement but unrelated to actual tumor progression. Among patients who underwent single-session GKS, 14 cases (18.2%) developed RN, of which 6 were defined as CTCAE Grade 2 toxicity, 2 as CTCAE Grade 3 toxicity, and 3 as CTCAE Grade 4 toxicity. Among these 11 patients, all received salvage treatment for RN, including the use of steroid hormones and bevacizumab. In patients who underwent staged GKS, 4 cases (6.5%) developed RN, all classified as CTCAE Grade 2 toxicity, and 3 of them received salvage treatment. The cumulative incidence of RN was 9.9% at 6 months, 18.4% at 1 year, and 19.9% at 18 months in patients who underwent single-session GKS, and 3.3% at 6 months, 5.0% at 1 year, and 6.7% at 18 months in patients who underwent staged GKS (p < 0.05) (Table 4, Figure 2).

5. Treatment outcomes

KPS scores were recorded for all patients at the time of initial treatment and at follow-up re-examination. The median KPS score at initial treatment was 84 for patients who underwent single-session GKS, with 80% having KPS scores ≥ 70, and 82 for patients who underwent staged GKS, with 75.6% having KPS scores ≥ 70 (p > 0.05). At the first follow-up, the median KPS of patients who underwent single-session and staged GKS were 84.4 and 87.6, respectively (p > 0.05), and the median change in KPS was 0.44 and 5.56, respectively (p < 0.05). The improvement in KPS of patients who underwent staged GKS was significantly better than that of patients who underwent single-session GKS.

The median OS was 43.1 months (range: 3.6–84.2 months) in patients who underwent single-session GKS and 37.5 months (range: 2.5–116.7 months) in patients who underwent staged GKS; the difference was not statistically significant (p > 0.05) despite the longer OS of patients who underwent staged GKS than that of patients who underwent single-session GKS (Figure 1c). During the follow-up period, 33 (48.1%) patients who underwent single-session GKS died, with 11 cases of neurological death and 22 cases of systemic death, and 27 (51.6%) patients who underwent staged GKS died, with 5 cases of neurological death and 22 cases of systemic death. The cumulative incidence of neurological death was 1.4% at 6 months, 4.3% at 12 months, and 10.1% at 18 months in patients who underwent single-session GKS and 0 at 6 months, 3.4% at 12 months, and 5.1% at 18 months in patients who underwent staged GKS (p > 0.05).

6. The prognostic factors of treatment outcomes

Upon analyzing the prognostic factors, a tumor volume reduction rate exceeding 20% may serve as a predictor of improved LC (P < 0.05). Conversely, the maximum tumor volume, CITV, and the receipt of targeted therapy did not exhibit a significant association with LC.

Furthermore, patients with poorly controlled primary tumors emerged as independent adverse prognostic factors for OS. Notably, factors such as the administration of immune/targeted therapy, maximum tumor volume, intracranial tumor LC, CITV, age, and gender were not identified as significant predictors of OS in this study.

7. Propensity score matching

For propensity score matching, nine clinical factors that may influence prognosis were considered, and in the end, 90 patients (45 in each group) were selected. The baseline characteristics of the matched patients in the two groups are detailed in Table 5. The p-values for all matched clinical factors were greater than 0.3 (Table 5). The treatment parameters, response to treatment, and treatment outcomes for the 139 patients and the 90 matched patients are shown in Tables 2 and 3. The median rates of volume change between the first GKS and the first follow-up for patients in the staged and single-session groups were 68% and 51%, respectively (p < 0.05).

In the matched cohort, patients in the staged treatment group had a longer OS than patients in the single-session group, but the difference was not statistically significant (p > 0.05) (Figure 1d). The improvement in KPS was greater in the staged treatment group than in the single-session treatment group; the difference was statistically significant. Table 6 compares the cumulative incidence of RN and neurological death in the matched cohort. The cumulative incidence of neurological death was significantly higher in the single-session group than that in the staged group, at 2.4% and 0% at 6 months and 4.9% and 2.4% at 1 year, respectively (p < 0.05). LC of tumors in the staged group was significantly better than that in the single-session group (p < 0.05) (Figure 1b). No statistically significant difference was observed in the cumulative incidence of RN between the two groups.

Several studies ^{[23, 24]} have demonstrated the benefits of single-session GKS in patients with brain metastases, including excellent LC rates; however, single-session GKS is not as effective for LC of tumors in LBM. In the management of LBM, RTOG 90-05 ^[25] recommends prescription doses of 18 Gy and 15 Gy for brain metastases with diameters of 2–3 cm and > 3 cm, respectively, and a prescription dose of 20–24 Gy for smaller brain metastases with < 2 cm diameter. A lower prescription dose is associated with a lower biologically effective dose, which in turn leads to suboptimal LC rates in LBM. Therefore, the introduction of staged GKS is a major breakthrough. In 2009, Higuchi et al. ^[26] first introduced a three-staged SRT and confirmed that it resulted in a better tumor control rate and lower toxicity. Staged GKS attempts to deliver a higher total dose to the tumor in two or three separate sessions, allowing for repair of sublethal radiation damage to healthy tissues between sessions, ^[24] with the aim of improving patient outcomes while reducing neurotoxicity compared to single-session GKS. In addition, various studies have shown that staged GKS has a higher safety and efficacy profile than single-session GKS for the treatment of LBM. ^{[14, 16, 26-28]} The key clinical significance of staged GKS is that it improves safety and significantly reduces the incidence of RN without compromising tumor control.

Few studies have directly compared the efficacy and safety of single-session GKS and staged GKS for treatment of LBM, and it is difficult to demonstrate in an objective manner that staged GKS achieves better clinical outcomes than single-session GKS in patients with similar conditions. In addition, a diagnosis-specific graded prognostic assessment study of 412 patients with brain metastases by Nieder et al. ^[29] revealed that the primary tumor type was associated with survival, and other studies found that primary tumor type might affect local tumor control. ^[30] Therefore, only patients with brain metastases from lung adenocarcinoma were selected for the present study to minimize the possible effect of primary tumor type on treatment outcomes. Our study demonstrated that 2-stage GKS has greater clinical efficacy and safety for the treatment of LBM compared to single-session GKS. With better local tumor control, the incidence of radiation-related adverse effects reduced, and a greater improvement in KPS was also observed, thus suggesting that patient quality of life was further improved. The 1-year OS of staged GKS was 35.2–69.1% according to previous reports; ^{[14, 16, 26-28, 31]} in our matched patient cohort, the 1-year OS of patients who underwent staged GKS was better than 75%, which was higher than that in previous studies. We believe that the major reasons might be that the mean volume of the largest metastasis in our cohort was less than that in other studies and the primary tumor in all patients was lung adenocarcinoma, a tumor with moderate radiosensitivity, which may have contributed to the better OS and tumor control in the present study. Oermann et al. ^[32] reported that fractionated SRT was less effective than single-session SRT treatment for radioresistant tumors. However, no studies have compared the efficacy of staging versus single-session treatment for tumors with different degrees of radiosensitivity. The present study found that staged GKS for lung adenocarcinoma was safer and more effective compared to single-session GKS.

Although there was some selection bias with respect to CITV and maximum tumor volume between the two groups, the patients in the staged group with higher intracranial tumor burden actually achieved a lower cumulative incidence of RN than patients in the single-session group; the difference was statistically significant. In most studies, RN developed months to years after SRT, with a median time of development of approximately 7–8 months after SRT. ^{[33, 34]} In the present study, the cumulative incidence of RN at 6 months after GKS was 9.9% and 3.3% in the single-session and staged treatment groups, respectively. Although there was no significant difference in the cumulative incidence of RN among patients in the matched cohort, we believe this is primarily due to loss of patient data during the matching process. Staged stereotactic radiotherapy was originally intended to mitigate radiation toxicity through longer treatment intervals, taking advantage of the reduction in tumor volume in the interval between treatments, thereby irradiating smaller volumes of normal brain tissue during subsequent stages of treatments and reducing the incidence of radiation-related adverse effects.

Few studies have compared the effects of single-session and staged treatments on the rate of tumor volume change. In our cohort, we found that the rate of tumor volume reduction was significantly greater in the staged treatment group than in the single-session treatment group, and that staged treatment was significantly more effective in the treatment of tumors than single-session treatment. The relationship between the rate of tumor volume change and local tumor progression was also analyzed. In a previous study of 1,194 patients who underwent SRT by Serizawa et al., ^[35] four factors affecting the local progression of tumors and associated with poor prognosis were identified based on Fine-Gray subdistribution hazard models: age ≤ 65 years, presence of neurological symptoms, large tumor volume, and low prescription dose (<22 Gy). The present study found that the rate of tumor volume change had better predictive value for local tumor progression than either maximum tumor volume or dose. Previous studies have similarly concluded that the rate of tumor volume change is predictive of therapeutic response; ^{[16, 30, 36]} however, no such correlation was found in a study by Ito et al. ^[28] The effect of the rate of tumor volume change on local tumor progression should be validated in future large-sample studies. In terms of predicting OS, we found that the control of the primary tumor played a large role, and a stable primary tumor predicted longer OS.

The results of the present study suggest that 2-stage GKS has higher safety and efficacy than single-session GKS for LBM from lung adenocarcinoma ≥ 2 cm in diameter, and that the rate of volume change before and after treatment of metastatic tumors is predictive of long-term local tumor control, and poorly controlled primary tumor serves as an independent adverse prognostic factor for predicting patients' OS. However, these results must be validated through future large-sample studies

Authors contributions: X.W. and Y.W. wrote the main manuscript text, K.H., Q.X., K.Y. and F.W. prepared figures. Y.Z., Y.T., L.Z., R.Z. and H.Z. prepared tables. All authors reviewed the manuscript.

Competing interests: The authors declare that they have no competing interests.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request

Acknowledgements: Not applicable.

Funding: Health Department of Zhejiang Province, 2022510274; Natural Science Foundation of Zhejiang Province, LGF22H160002

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Due to the retrospective nature of the study, (full name of IRB) waived the need of obtaining informed consent.

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Table 1 Patient characteristics of main cohort

Factors	Single-session	2-stage	p Value
No. of patients	77	62
Sex (%)			0.972
Male	42（54.5%）	34（54.8%）
Female	35（45.5%）	28（45.2%）
Age at diagnosis (years)	58.7	57.8	0.601
Age at first GKS (years)	59.4	58.4	0.594
KPS at first GKS (%)			0.281
≥70	65（84.4%）	47（75.8%）
<70	12（15.6%）	15（24.2%）
KPS at first GKS	83.51	79.84	0.19
KPS at first follow-up (%)			1
70-100	67（87.0%）	54（87.1%）
<70	10（13.0%）	8（12.9%）
KPS at first follow-up	83.64	84.84	0.629
KPS_follow-up-KPS_GKS	0.13	5	0.00
RPA class (%)			0.477
I	27（35.1%）	26（41.9%）
II	39（50.6%）	25（40.3%）
III	11（14.3%）	11（17.8%）
Lung-mol GPA score (%)			0.901
0-1.0	3（3.9%）	2（3.2%）
1.5-2.0	21（27.3%）	16（25.8%）
2.5-3.0	38（49.3%）	33（53.2%）
3.5-4.0	15（19.5%）	11（17.8%）
No. of lesions at initial GKS (%)			0.974
1-3	42（54.5%）	34（54.8%）
4-6	16（20.8%）	12（19.4%）
≥7	19（24.7%）	16（25.8%）
Location of the largest metastatic tumor (%)			0.479
Frontal	38(44.7%)	22(30.5%)
Parietal	19(22.4%)	20(27.8%)
Temporal	10(11.8%)	10(13.9%)
Occipital	11(12.9%)	11(15.3%)
Cerebellum	6(7%)	9(12.5%)
Brainstem	1(1.2%)	0(0)
Extracranial metastases (%)			0.385
Yes	34（44.2%）	22（35.5%）
No	43（55.8%）	40（64.5%）
Systemic therapy (%)			1
Yes	69(89.6%)	55(88.7%)
No	8(10.4%)	7(11.3%)
Status of lung cancer (%)			0.607
Controlled	31(40.3%)	28(45.2%)
Uncontrolled	46(59.7%)	34(54.8%)
Leptomeningeal metastases (%)			0.548
Yes	8（10.4%）	4（6.5%）
No	69（89.6%）	58（93.5%）
Steroids therapy (%)			0.600
Yes	49(63.6%)	36(58.1%)
No	28(36.4%)	26(41.9%)

GKS gamma knife surgery, KPS Karnofsky performance status, RPA recursive partitioning analysis, GPA graded prognostic assessment

Table 2 Treatment parameters and treatment effects of main cohort and case-matched subsets of patients

Covariates	Entire Cohort				Case-Matched Subsets
	Single-session	2-stage		p Value	Single-session	2-stage			p Value
	Single-session	First time	Second time	p Value	Single-session	First time		Second time	p Value
No. of patients	77	62		/	45	45			/
Peripheral dose (Gy)	16.4	15.0	14.0	/	16.3	15.0	13.8		/
Associated isodose line (%)	49.9	49.6	50.0	/	49.8	49.8	50.1		/
Treatment interval (days)	/	34.4		/	/	35.0			/
CITV (cm³)	8.56	12.74		0.000	9.63	10.87			0.397
Volume of the largest metastatic tumor (cm³)	5.82	9.73		0.000	6.83	7.69			0.371
Volume of the largest metastatic tumor at first follow-up (cm³)	3.04	3.82		0.342	4.02	3.83			0.882
Relative change from 1^st GKS to 3-mo MRI^*	-0.53	-0.68		0.030	-0.51	-0.68			0.028

CITV cumulative intracranial tumor volume, GKS gamma knife surgery, MRI magnetic resonance imaging

*The data of radiation necrosis were deleted

Table 3 Treatment outcomes of cohort and case-matched subsets of patients

Covariates	Entire Cohort			Case-Matched Subsets
Covariates	Single-session	2-stage	p Value	Single-session	2-stage	p Value
Local control^*(%)	77（90.6%）	59（95.2%）	0.357	46（95.8%）	43（93.5%）	0.674
Local efficacy^*(%)	59（69.4%）	50（80.6%）	0.133	32（66.7%）	34（73.9%）	0.503
RN (%)			0.045			0.677
Yes	14（18.2%）	4（6.5%）		2(4.4%)	4(8.9%)
No	63（81.8%）	58（93.5%）		43(95.6%)	41(91.1%)
Salvage treatment after RN			1			1
Yes	11（78.6%）	3（75.0%）		1（50.0%）	3（75.0%）
No	3（21.4%）	1（25.0%）		1（50.0%）	1（25.0%）
Distant failure^#	24（31.2%）	26（41.9%）	0.216	16	19	0.666
Status (%)			/			/
Alive	37（48.1%）	32（51.6%）		18（40.0%）	26（57.8%）
Neurologic death	11（14.3%）	5（8.1%）		6（13.3%）	1（2.2%）
Systemic death	22（28.5%）	22（35.5%）		17（37.8%）	15（33.3%）
NA	7（9.1%）	3（4.8%）		4（8.9%）	3（6.7%）
OS (months)	43.1	37.5	0.791	31.5	47.8	0.088

RN radiation necrosis, NA not available, OS overall survial

^*Results at first follow-up after GKS

^#Results at the end of follow-up

Table 4 Cumulative incidence of treatment outcomes of main cohort

	Cumulative incidence					p Value
	6 months	12 months	18 months	24 months	30 months
Radiation necrosis						0.028
Single-session	0.099	0.184	0.199	0.199	0.199
2-stage	0.033	0.050	0.067	0.067	0.067
Neurologic death						0.196
Single-session	0.014	0.043	0.101	0.101	0.160
2-stage	0.000	0.034	0.051	0.051	0.074

Table 5 Patient characteristics of case-matched subsets

Factors	Single-session	2-stage	p Value
No. of patients	45	45
Sex (%)			1
Male	26（57.8%）	25（55.6%）
Female	19（42.2%）	20（44.4%）
Age at first GKS (years)	58.18	57.47	0.742
KPS at first GKS (%)			0.800
≥70	36（80.0%）	34（75.6%）
<70	9（20.0%）	11（24.4%）
KPS at first GKS	84.00	82.00	0.581
KPS at first follow-up (%)			0.739
≥70	39	41
<70	6	4
KPS at first follow-up	84.44	87.56	0.290
KPS_follow-up-KPS_GKS	0.44	5.56	0.000
No. of lesions at initial GKS	4.44	4.09	0.618
Location of the largest metastatic tumor (%)			0.504
Frontal	20（41.6%）	16（29.6%）
Parietal	14（29.2%）	17（31.5%）
Temporal	5（10.4%）	6（11.1%）
Occipital	7（14.6%）	8（14.8%）
Cerebellum	1（2.1%）	7（13.0%）
Brainstem	1（2.1%）	0（0%）
Extracranial metastases (%)			1
Yes	16（35.6%）	17（37.8%）
No	29（64.4%）	28（62.2%）
Systemic therapy (%)			1
Yes	38（84.4%）	39（86.7%）
No	7（15.6%）	6（13.3%）
Status of lung cancer (%)			0.832
Controlled	24（53.3%）	26（57.8%）
Uncontrolled	21（46.7%）	19（42.2%）
Steroids therapy (%)			0.831
Yes	27（60%）	25（55.6%）
No	18（40%）	20（44.4%）

GKS gamma knife surgery, KPS Karnofsky performance status

Table 6 Cumulative incidence of treatment outcomes of case-matched subsets

	case-matched subsets					p Value
	6 months	12 months	18 months	24 months	30 months	p Value
Radiation necrosis						0.444
Single-session	0.024	0.024	0.049	0.049	0.049
2-stage	0.047	0.070	0.093	0.093	0.093
Neurologic death						0.045
Single-session	0.024	0.049	0.100	0.100	0.172
2-stage	0.000	0.024	0.024	0.024	0.024

No competing interests reported.

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Comparison of treatment outcomes of single-session and 2-stage gamma knife surgery for large brain metastases from lung adenocarcinoma

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