Correlation between dimensions of brain metastases and therapeutic results after stereotactic radiosurgery.

doi:10.21203/rs.3.rs-1427975/v2

OBJECTIVE: Stereotactic radiosurgery (SRS) is an effective therapeutic method to treat brain metastases (BM). A current debate considers BM dimension as an important issue regarding SRS therapeutic result. The aim of this study was to evaluate the dimensional progression of BM after SRS and identify factors related to patients and BM leading to local recurrence.

METHODS: Patients eligible for this study were those with BM from non-small cell lung cancer (NSCLC) who had been consecutively treated with SRS in 2010-2015. The dimensions of BM were measured by volume and greater diameter by nuclear magnetic resonance imaging (MRI) in T1-weighted contrast weighting using the Elements software (Brainlab). Dimensional data of BM were collected before the performance of SRS and after performing them during the follow-up of outpatients. After identifying the dimensions of BM in time progression, lesions that presented therapeutic success (reduction of BM dimensions) and local recurrence (growth of BM after SRS) were identified. Next, statistical evaluations were performed by statistical analysis at 12 months, considering epidemiological features presented by patients as well as topographic characteristics and radiological aspects of BM.

RESULTS: There was no correlation, after 12 months of the performance of SRS, between initial volume of BM and local recurrence. The results obtained identify a non-cystic BM, and brain left sided BM as elements related to higher progression free survival after 12 months of SRS.

CONCLUSION: Considering therapeutics in patients presenting BM, the correlation between initial volume and failure within 12 months after SRS had no statistical significance, BM located on the right side of the brain showed therapeutic fail within 12 months after SRS. Longer time of observation may be useful to confirm such results.

radiosurgery

brain neoplasms

adenocarcinoma of lung

tumor burden

efficacy

radiation effects

Brain metastases (BM) are among the main causes of mortality and morbidity in cancer patients, corresponding to more than 50% of intracranial tumors. (1–2). The incidence of BM in recent years has decreased due to recent developments and technologic advances, and it has led to the increased survival of patients with malignant neoplasms. (2). Considering U.S. statistics, among 1.5 million patients expected to diagnose cancer in 1 year, approximately 70,000 patients will develop brain metastases. (3–4). BM account for an important share of morbidity and mortality in patients with non-small cell lung cancer (NSCLC) (5) and about 10–30% of lung cancer patients have BM (6–7). Other studies have shown that 15–20% of NSCLC patients with survival greater than 2 years will develop BM. (8–9). The prognosis of patients with BM is generally precarious; without treatment, median survival is estimated between 1 and 2 months. (10, 11, 12, 13).

Some studies have historically attributed survival around 4–6 months to patients with BM undergoing cerebral radiotherapy, a treatment instituted regardless of the tumor histological type. (12–13).

After the identification of BM, it is essential to indicate adequate treatment of the patient, considering that its progression tends to exert mass effect on adjacent structures leading to varying degrees of functional involvement of the nervous system.

In recent years, there has been debate about the most appropriate form of treatment of BM, considering therapies already instituted as conventional surgical approach, stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), chemotherapy, brachytherapy as well as new therapeutic techniques such as the use of laser (Laser Interstitial Thermal Therapy -LITT) and systemic treatments such immunotherapy. (14–15).

Multiple modalities of treatment modalities can be used by each patient and the definition of the best strategy involves individualized evaluation considering features, including clinical performance, life expectancy and those related to the characteristics of BM in terms of their number, size, location in the nervous system, response to chemotherapy and radiosensitivity. Regarding the important data on the use of SRS in the treatment of patients with BM, the literature review is inconclusive concerning data on the size of BM that may respond best to SRS treatment.

For BM smaller than 3 cm, SRS has been considered as a valid therapeutic option; in a previous study, however, it was shown in a previous study that the administration of SRS in BM greater than 3 cm in diameter is related with poor prognosis. (18). Another study indicated a better therapeutic result with surgical resection in BM > 3 cm in the largest diameter (19), whereas another study indicating benefits of the surgical approach (surgery + WBRT) with lower risk of local recurrence. (20).

In this scenario, the present research is based on the following question: is it possible to determine dimensional limits of BM that result in the best therapeutic response to SRS?

Thus, the present study presents a series of patients diagnosed with single BM in a homogeneous sample. The study examines the histological type of BM (NSCLC) treated by SRS Additionally, it analyzes the dimensional variation of BM. This analysis used magnetic resonance imaging (MRI) of the brain after the therapeutic procedure during radiological follow-up.

A retrospective study of 185 patients presenting with a single NSCLC BM treated with SRS (Elekta Gamma Knife Perfexion system) from 01/01/2010 to 12/31/2015. Inclusion criteria was single NSCLC BM, 18 year-old or older and no previous treatments. Patients who underwent previous treatments such as surgery or WBRT, incomplete follow up (at least 27 days of follow up), or those without MRI during follow up were excluded from the analysis resulting in 135 patients treated with SRS for single BM.

Data acquisition was performed through the Department of Neurosurgery database and electronic medical records. The study was approved by the Institutional Review Board and due to its retrospective nature, a waiver of informed consent was obtained. Clinical, demographic, histopathological and radiological information was manually collected from the patients’ electronic medical records. Tumors were classified into one of three categories based on proximity to functional cortex (non-eloquent [Grade I], near-eloquent [Grade II], and eloquent [Grade III]). (32). BM characterized by contrast uptake throughout its extent were classified as non-cystic, whereas lesions characterized by the existence of hypointense areas were classified as cystic. Using pretreatment contrast-enhanced MRI, volumetric analysis was calculated by performing manual segmentation of the lesion using BrainLab Elements (BrainLab, Munich, Germany), where the volume between two slices is calculated following Cavalieri's Principle Gundersen et al. (21). It is equivalent to the problem of a cut cone volume using the areas of the two slices at the top and the bottom. The maximum tumor diameter was also calculated using the same software. Both calculations were performed by a neurosurgeon and reviewed by the senior author. Clinical and radiological data were collected from different time points: pre-treatment, one month after the treatment and on every follow-up.

Local recurrence was defined as persistent increase in BM volume when compared to before SRS treatment.

STATISTICAL ANALYSIS

For descriptive purposes, categorical variables are presented as relative and absolute frequencies. Normally distributed continuous data are presented as mean and standard deviations and, otherwise, by median and quartiles. The normality assumption was assessed by means of skewness and kurtosis values as well as graphical methods.

For the outcome of 1-year progression free survival (PFS), categorical potential predictors were identified through the Kaplan-Meier method, using the Log-rank (Mantel-Cox) test for the comparison of the survival functions. Continuous variables were analyzed through a univariate Cox regression. Variables with a univariate p value under 0.10 were included in a multivariate Cox regression model and the results presented as hazard ratios and 95% confidence intervals. The proportionality and linearity assumptions were verified using graphical methods and the Schoenfeld and Martingale residuals, respectively.

All tests were two-tailed and final p values under 0.05 were considered to be statistically significant. All analyses were conducted with the software Statistical Package for Social Sciences (IBM SPSS Statistics for Windows, version 24.0. Armonk, NY: IBM Corp.).

A total of 135 patients presenting with single NSCLC BM treated by SRS were included in the study. The mean age was 61.8 years (SD ±10.6) and the male gender was predominant. Median pretreatment volumes of BM were 1.0 (quartiles 0.4–2.3) and 1.1 cm3 (quartiles 0.4–2.3) in no failure and failure groups respectively. Most BM were supratentorial and location at frontal lobe, left sided BM, non cystic BM, BM in non eloquent area of the brain were predominant findings. Regarding areas of eloquence in which BM were found, 69 patients had BM in a non-eloquent area. Considering proximity to an eloquent cortex, there was no statistical significance in local recurrence (p = 0.395). (Table 1)

Table 1

Analysis of therapeutic failure in 1 year follow up
Variable	General (135)	1-year fail		p value *
Variable	General (135)	No (83)	Yes (52)	p value *
Age (mean ± SD)	61.8 ± 10.6	61.8 ± 9.9	62.0 ± 11.6	0.867
Male	82 (60.7)	49 (59.0)	33 (63.5)	0.706
BM dimensions
Volume (median and quartiles)	1.1 (0.4–2.3)	1.0 (0.4–2.3)	1.1 (0.4–2.5)	0.835
Diameter (median and quartiles)	12 (7.3–16.6)	12.2 (8.4–16.9)	9.9 (5.5–12.4)	0.722
Location				0.459
Frontal	47 (34.8)	31 (37.3)	16 (30.8)
Temporal	16 (11.9)	7 (8.4)	9 (17.3)
Parietal	22 (16.3)	14 (16.9)	8 (15.4)
Occipital	16 (11.9)	11 (13.3)	5 (9.6)
Cerebellum	24 (17.8)	14 (16.9)	10 (19.2)
Brainstem	5 (3.7)	2 (2.4)	3 (5.8)
Thalamus	2 (2.4)	1 (1.9)	3 (2.2)
Other	2 (2.4)	0 (0.0)	2 (1.5)
Side				0.039
Right	56 (41.5)	29 (34.9)	27 (51.9)
Left	72 (53.3)	51 (61.4)	21 (40.4)
Midline (BS or Cerebellum)	7 (5.2)	3 (3.6)	4 (7.7)
Non cystic BM	76 (56.3)	51 (61.4)	25 (48.1)	0.082
Eloquence				0.395
Non eloquent	69 (51.1)	46 (55.4)	23 (44.2)
Near eloquent	16 (11.9)	8 (9.6)	8 (15.4)
Eloquent	49 (36.3)	28 (33.7)	21 (40.4)
SRS dose (median and quartiles)	20 (18–20)	20 (18–20)	20 (18–20)	0.549
* Survival analysis (log-rank test or Cox regression) BM: Brain Metastasis;BS: Brainstem; SRS: Stereotactic radiosurgery.

BM located in left hemisphere presented statistical significance in PFS in 1 year (p = 0.039).

A Receiver Operating Characteristic (ROC) curve was designed and there was no correlation between initial BM volume and SRS therapeutic success. (Table 2)

Table 2. AUC ROC for initial volume and SRS fail up to 1 year:

0.519 ± 0.051, 95% CI 0.420 – 0.619, p = 0.706

There was a predominance of BM in the frontal lobe among the treated patients, and there was no statistical significance relating the topography of the BM and local recurrence in 1 year after SRS (p = 0.459).

There was statistical significance regarding left sided BM and longer PFS in 1 year after SRS (p = 0.039).

Considering contrast enhancement MRI images, BM were divided in cystic (partial BM contrast enhancement) and non-cystic (complete BM contrast enhancement). Contrast enhanced MRI analysis showed that 76 patients presented non-cystic BM, while 59 patients had cystic BM. In the group where there was no local recurrence within 1 year, 51 patients had non-cystic BM. There was no statistical relevance considering radiologic features of BM (p = 0.082).

The dose of SRS presented a median of 20 Gy (quartiles 18–20 Gy). There was no significant correlation between dose delivered during treatment by SRS and local recurrence in 1 year (p = 0.549). SRS dose, age, BM eloquence area are related in Fig. 1.

SRS is considered an effective form of treatment in the treatment of patients with BM. Studies evaluating local control with the use of SRS indicate rates between 70–90% in 12 months (22–26). In a study conducted by Sharma et al. (27), a 38% rate was recorded in the occurrence of radiation necrosis (RN) occurring up to 5 years after SRS, an index higher than that historically recorded in the literature. Several other authors have reported local control between 70%-90% in patients treated with SRS for BM. (1). The local control rates reported in the literature indicate local control in BM between 70–90% of patients treated by SRS and around 38% of the presence of RN after SRS. The present study showed local recurrence around 38% in 1 year, considering local recurrence a volumetric increase in BM above the value measured at the time of the SRS.

The volume evaluation criterion was discussed in response assessment in neuro-oncology brain metastases (RANO-BM) working group. It was considered that the cost and complexity of volumetric analysis could be unavailable in all treatment centers and that the volume verification associated with one-dimensional criteria in future trials could define the importance of the role of volumetric measurement of BM. (28). This verification was performed in the present study and the discrepancy between the failure rates found at 12 months compared to the indexes recorded in the literature may indicate that the volumetric measurement may correspond to an identification method that leads to a greater number of patients who present with disease in progression associated or not with RN, enabling the use of appropriate therapeutic methods with improvement of the quality of life and survival of patients.

In a study conducted by Goethe et al. (29) showed a median BM volume of 0.8 cm3 in a heterogeneous sample of NSCLC, breast, melanoma and renal cell carcinoma BM. In this study, it was concluded that there was a consistent volumetric reduction in BM of patients submitted to SRS in a follow-up period of 6 months. Another study by Mohammadi et al.(30) involving 896 patients with 3,034 BM from cancers of different histological types with maximum diameter < 2 cm, associated better results of local progression in BM with size < 1cm. Baschnagel et al. (31) recorded local control in 1 year in 97% with BM < 2 cm diameter compared to 75% of local control in BM > = 2 cm. In our study, there was no correlation between initial volume of BM and treatment failure 1 year after SRS (p = 0.835). AUC ROC did not show a BM cutoff volume related to the best response to SRS.

Given the implications that intracranial BM may cause in the central nervous system, it is essential to discuss the location of BM in the context of its dimensional variation after treatment by SRS. Previous studies have addressed the distribution of BM in the therapeutic evaluation. Sawaya et al. (32) presented a division of tumors into degrees: grade I for tumors in non-eloquent areas, grade II for tumors located near eloquent areas and grade III for tumors located in eloquent areas. This distribution was adopted in the present study. In our study, evaluating the period of up to 12 months after SRS, there was no statistically significant correlation between local recurrence and location of BM(p = 0.459). In this study, regarding the location of BM in its different degrees relative to the eloquent area, there was no statistically significant correlation (p = 0.395).

The evaluation of the relationship between response to SRS and the location of posterior fossa BM was registered by Koyfman et al. (33) who obtained local control after SSR of 85% in 1 year of follow-up of patients. In work of Hatiboglu et al. (34) who evaluated the therapeutic response in patients with posterior fossa BM after SRS local control was 76%. The lower survival of patients was related to BM > = 4 ml. Another study conducted by Voong et al. (35) in a group of patients with different histological types of BM in posterior fossa, presented local control in 94% of the patients, with BM > = 2 cm presenting poorer results in local control and survival. Muhsen et al. (36) evaluated the outcomes of BM volume and peritumoral edema in 49 patients with 51 BM in the posterior fossa. Local control occurred in the first 2 months after SRS in 98.1%, with reduction of BM volume in 58.66% of cases and 78.1% of reduction of peritumor edema. BM had a median volume of 4.96 cm3 and a median diameter of 2.6 cm. In our study, there was no statistical significancy considering BM topography (p = 0.459). There was no statistically significant correlation between failure within 1 year and the location of BM being in supratentorial or infratentorial location (p = 0.744). The PFS was 262.5 days (+- 12.9) for patients with supratentorial BM and 259.4 days (+- 27.3) for patients with infratentorial BM.

According to Balagamwala et al. (21), RN is the main late effect of SRS and occurs in a median period of 1–2 years after treatment, is irreversible and may spoil tumor recurrence. A study conducted by Kohutek et al. (37) showed RN in 25.8% of patients treated for BM of cancers of different types of histological diseases by SRS, with a literature review showing rates of up to 30% of RN after SRS. Feng et al. (38) proposed a study of radiological correlation and histopathological evidence of RN. Our study showed a statistically significant correlation between the laterality of BM and local recurrence within 12 months after SRS, in which BM on the left side presented lower association with local recurrence (p = 0.039). PFS for left sided BM presented a mean value of 285.6 days (+- 15.4) and 234.7 (+-17.7) days for right sided BM.

After SRS, dose, volume and irradiated region seem to predict the occurrence of RN. Radiation therapy oncology group (RTOG) defined doses from different target dimensions: for lesions < 20 mm, maximum dose of 24 Gy; 21–30 mm: 18 Gy; 31–40 mm: 15 Gy. In addition, brain volume receiving dose > = 12 Gy and localization (occipital and temporal) were shown to be correlated with the development of RN in the treatment of vascular and non-vascular lesions of the brain (39–40). A study conducted by Romano et al. (41) evaluated 134 patients with 374 BM from cancers of different histological types. The local control rate was 88.7%. The multivariate analysis showed a better response with increased dose of SRS and reduction of local control in NSCLC histology.

At this present study, dose of SRS did not present statistically significant correlation in the evaluation of PFS within 12 months after SRS (p = 0.549).

Considering therapeutics in patients presenting BM, the correlation between initial volume and failure within 12 months after SRS had no statistical significance, and BM located on the right side of the brain showed local recurrence within 12 months after SRS. Longer time of observation may be useful to confirm such results. Further studies are important to confirm the correlation between topography of BM and failure after SRS.

AUC Area Under the Curve

BM brain metastases

cm centimeter

Gy Gray

mm millimeter

MRI magnetic resonance imaging

NSCLC non small cell lung cancer

PFS progression free survival

RANO-BM response asessment in neuro-oncology brain-metastasis

RN radiation necrosis

ROC receiver operating characteristic

SRS stereotactic radiosurgery

WBRT whole brain radiation therapy

Ethics approval: This research was approved by Ethic Committee at University of São Paulo in its ethical opinion number 2.579.524 (April 4^th, 2018). A waiver of informed consent is granted as it is a restrospective study.

Full Board Name: University of São Paulo- CEP (Comitê de Ética em Pesquisa/ (Research Ethics Committee)

Patient identifiers (names, medical record numbers, surgery accession numbers, dates of: birth, treatment, diagnoses, imaging, tests, follow-up and death) may be collected. Data from several sources need to be merged and checked making use of Protected Health Information (PHI) necessary.

Except for potential breach of confidentiality, there are no anticipated risks to patients. Complete confidentiality was maintened.

All methods applicable to this study were performed in accordance with the relevant guidelines and regulation, including Declaration of Helsinki.

Consent of Publication

Not Applicable

Availability of supporting data

Competing interests and contribution

The authors declare that they have no financial or non-financial competing interests.

Author’s Contribution

All authors contributed equally to this work. Eliseu Becco Neto, Eberval Gadelha Figueiredo and Sujit S. Prabhu conceived the study, designed and implemented the survey, and prepared the manuscript; Francisco de Assis de Souza Filho and Rodrigo Becco de Souza contributed to the design and implementation of the survey, and the preparation of the manuscript; Dhiego Bastos contributed to the design and implamentation of the survey; Eliseu Becco Neto collected and analyzed data.

All authors read and approved the final manuscript.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This study was supported by Universidade de São paulo and Conselho nacional de Desenvolvimento Científico e Tecnológico (CNPq). We thank all personnel involved in scientific institutions related to this research.

Data Availability

The data used to support the findings of this study are included within the article.

Funding

This research received no specific granting from any funding agency in the public, commercial or not-for-profit sectors.

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No competing interests reported.

Correlation between dimensions of brain metastases and therapeutic results after stereotactic radiosurgery.

Status:

Version 2

Abstract

Figures

Introduction

Methods

STATISTICAL ANALYSIS

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 2