Evaluation of radiotherapy efficacy and prognostic analysis for solid and cystic brain metastases

doi:10.21203/rs.3.rs-3903445/v1

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Evaluation of radiotherapy efficacy and prognostic analysis for solid and cystic brain metastases

https://doi.org/10.21203/rs.3.rs-3903445/v1

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Purpose

Brain metastases (BMs) are commonly categorized into cystic and solid. Despite advances in treatment modalities, the prognosis for patients with cystic and solid BMs following radiotherapy remains poorly understood. We use a retrospective design to elucidate the disparities in survival between these two patient groups undergoing radiotherapy and identify factors influencing overall survival (OS) of BMs in solid tumor.

Methods

This retrospective study encompasses 212 patients diagnosed with BMs. We meticulously analyzed the clinical characteristics, radiation therapy modalities, and risk factors influencing overall survival among these patients, categorized by BMs type, post-brain radiation therapy.

Results

A statistically significant difference in mOS was observed between the two cohorts (Solid vs. Cystic: 23.1 vs. 14.6 months). Subgroup analysis unveiled distinctions in mOS, particularly in patients with EGFR-mutant lung adenocarcinoma (Solid vs. Cystic: 23.1 vs. 6.43 months). The volume of BMs and the biological effective dose (BED) emerged as significantly prognostic factors for patients with cystic BMs. For patients with solid BMs, fraction dose, BED and the number of BMs were identified as independent prognostic factors for survival.

Conclusion

Brain radiotherapy shows superior survival benefits for lung cancer patients with solid BMs compared to those with cystic BMs, particularly in EGFR-mutant lung cancer. In particular, patients receiving BED ≥ 60Gy have a more favorable prognosis than those receiving BED < 60Gy, regardless of the type of BM (solid or cystic) in lung cancer.

cystic BMs

radiation therapy

combination therapy

lung cancer

risk factors

Brain metastases (BMs) are among the most common intracranial tumours in adults and are a significant contributor to mortality in patients with malignant tumours[1, 2]. Recent advances in medical technology have prolonged the survival of cancer patients and consequently increased the incidence of BMs. A small proportion of patients have BMs at initial diagnosis, and approximately 20–40% of patients develop BMs during the course of their disease[3]. Melanoma is the most common primary cause of BM, followed by lung, renal cell and breast cancer[4]. Unfortunately, the prognosis for patients with BM is poor, with a median survival of only 1 to 3 months without intervention[5].

Radiographically, BMs can be classified as either cystic or solid. Solid BMs are the predominant pattern and consist primarily of solid tumour cells or tissue. They typically present as solid masses or nodular lesions, occasionally interspersed with small cystic areas. Cystic BMs, on the other hand, manifest as metastatic brain lesions characterized by fluid-filled or cystic structures. These lesions typically result from the spread of cancer cells from the primary tumour to the brain via the bloodstream or lymphatic system, forming cystic sacs or cysts containing fluid or semisolid material. Cystic BMs are recognizable as lesions with cystic or low-density areas on imaging and often show both morphological and clinical differences from solid BMs. Some previous research studies have defined cystic BMs as lesions with a cystic component of more than 50% of the total volume, whereas those with a cystic component of less than 50% are classified as solid BMs[6, 7].

Treatment options for BMs include surgery, whole-brain radiation therapy (WBRT), WBRT with a simultaneous integrated boost, stereotactic radiosurgery/stereotactic body radiotherapy (SRS/SBRT), chemotherapy, targeted therapy and immunotherapy with immune checkpoint inhibitors (ICIs). These treatments have significantly prolonged the survival of patients with BMs[8, 9]. Local therapies, particularly radiotherapy (RT), play a pivotal role in the treatment of BMs. However, several retrospective clinical studies have reported varying prognosis of radiotherapy for solid and cystic BMs. One study showed that solid BMs in NSCLC had significantly better local control rates than cystic BMs after RT with no difference in mOS[9]. Brigell showed that SBRT results in a higher local control rate compared to WBRT in patients with solid BMs, but the radiotherapy models have a limited effect on the local control rate of cystic BMs[10]. Contrary to the aforementioned studies, Wang reported that there was no difference in prognosis and local control between patients with cystic and solid BMs treated with RT[6].

Currently, reports comparing the prognosis of patients with cystic and solid BMs after radiotherapy are limited and inconsistent. Due to the rarity of cystic BMs, there is still a lack of definitive evidence from large clinical research trials to support the optimal treatment of cystic BMs. Therefore, we aimed to analyze the differences in survival and response to radiotherapy in these two groups of patients and to investigate the factors associated with overall survival in BMs. We have tried to find more appropriate treatments for different types of BM.

Research manuscripts reporting large datasets that are deposited in a publicly available database should specify where the data have been deposited and provide the relevant accession numbers. If the accession numbers have not yet been obtained at the time of submission, please state that they will be provided during review. They must be provided prior to publication.

Interventionary studies involving animals or humans, and other studies that require ethical approval, must list the authority that provided approval and the corresponding ethical approval code.

Definition and Research Groups of BMs

Cystic BMs were defined as lesions with a low signal center with ring enhancement on contrast-enhanced T1-weighted MRI and high signal intensity on T2-weighted images, with cystic lesion volume exceeding 50% of the total volume. The diagnosis of cystic BMs required contrast-enhanced MRI. Cystic-solid BMs and solid BMs were categorized as solid BMs. In this study, a senior central nervous system radiologist distinguished between cystic lesions and solid lesions.

Patients

This study was approved by the institutional review and ethics committee. We conducted a retrospective review of all patients with BMs who underwent brain radiotherapy at Hubei Cancer Hospital from February 2018 to August 2019. The study included their basic information, clinical records, treatment regimens, imaging data, and survival outcomes. All patients were evaluated by radiologists, radiation oncologists, and physicists. Inclusion criteria were as follows: 1) a definite histopathological diagnosis of the primary lesion, including: lung cancer, breast cancer, gastrointestinal tumours, and et al; 2) newly diagnosed BMs; 3) patients received brain radiotherapy in our institution; 4) comprehensive clinical and imaging follow-up data available.

Clinical data were collected for all patients, including gender, age, smoking history, performance status (PS) score, presence of brain-related symptoms caused by BMs (seizure symptoms, neurological and psychiatric symptoms, intracranial hypertension symptoms), primary diseases (NSCLC, breast cancer, gastrointestinal tumors, melanoma, etc.), immunohistochemistry and genetic testing status of primary tumors, presence of metastases in other body sites (bone metastases, liver metastases, etc.), locations of intracranial metastases (brainstem, cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe, basal ganglia, thalamus), maximum diameter of BMs, extent of peritumoral edema (none, minimal, significant), volume changes of peritumoral edema after brain radiation therapy (no significant change, decrease, increase), radiation therapy modalities and doses, changes in BMs size on follow-up imaging (1 month after radiotherapy, 6 months after radiotherapy, 1 year after radiotherapy), treatments before and after radiotherapy, systemic treatment regimens, use of combination therapy and associated treatment efficacy.

Treatment Regimen and Follow-up Evaluation

Systemic treatments included chemotherapy (following international standards for regimens and doses), immunotherapy with ICIs before and after radiotherapy, TKI therapy, and anti-angiogenesis therapy (e.g.,bevacizumab, endostar). Brain radiotherapy regimens included WBRT, WBST + BOOST, and SBRT. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) was used to assess the treatment responses, which were classified as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The objective response rate (ORR) was the sum of CR and PR, while the disease control rate (DCR) was the sum of objective response rate (CR + PR + SD).

Statistical analysis

Progression-free survival (PFS) referred to the time from the initiation of intracranial radiotherapy to PD or death. Intracranial progression-free survival (iPFS) indicated the time from the commencement of radiotherapy for BMs to intracranial progression during treatment or death. OS was calculated from the star of radiotherapy for BMs until death or the last follow-up assessment. The last follow-up date was March 23, 2023.

Statistical analysis was performed using SPSS version 25.0. The Kaplan-Meier method was used for survival estimation, and Cox regression analysis was used for multivariate survival analysis of cystic and solid BMs and prognostic factors. A two-tailed test with P < 0.05 was considered statistically significant.

3.1.1.Characteristics of the Patients

Patient characteristics are shown in Table 1. Among them, 25% patients (42/168) had cystic BM. Lung cancer (77.8%) remained the most common primary site, followed by breast cancer (14.6%) and other tumour types (7.5%), including malignant melanoma, gastrointestinal tumours and et al. Lung cancer was more common in solid BMs (82% vs 63%), with a relatively low proportion of breast cancer (12.3% vs 28.5%), than in cystic BMs (p = 0.0143). Considering all patients, the median age of patients with BMs was 52.2 years, with a male/female ratio of 1:1. The mean volume of solid BMs was 4.3 mm3 (0.8–21.6 mm3) and the mean number at detection was 3.3 (1–12). For cystic BMs, the mean volume and number were 6.6 mm3 (0.8–31.9 mm3) and 3.8 (1–13 mm3), respectively. Patients received a median BED of 58.1Gy, with 57.2Gy (29 to 79.2Gy) in solid BMs and 60.8Gy (39 to 92.4Gy) in cystic BMs. Approximately half of the patients with cystic and solid brain metastases received SBRT or WBRT with a simultaneous integrated boost. Of these, 63 BMs patients received combination therapy with brain radiotherapy, with targeted therapy being the predominant type of combination therapy.

Table 1

Characteristics and comparison in patients with cystic or solid BMs
Characteristics	No. of patients with cystic lesions	No. of patients with solid lesions
Age (years)			0.0841
< 65	34	84
≥ 65	8	42
Sex			0.5929
Male	24	64
Female	18	62
Primary tumor			0.0058
Lung	24	95
Breast	12	15
Other	6	6
Pathological types			0.8781
adenocarcinoma	32	87
squamous cell carcinoma	4	11
Other or unknown	6	18
No. of BMs			0.3932
1	11	50
2	7	24
3	6	13
≥ 4 lesions	17	39
Neurologic symptoms			0.1549
Yes	14	49
No	28	53
Epliepsy
Yes	4	4
No	38	112
status of intracranial hypertension			0.5161
Yes	24	51
No	18	61
The volume of BMs (cm3 )			0.3621
≤ 4	22	67
> 4	20	43
Distribution of BMSS			0.3457
Frontal	29	56
Parietal	26	44
Tempora	16	25
Occipita	17	29
Cerebellum	13	48
Other	8	20
Smoking history			0.7080
Yes	12	47
No	30	79
Treatment			0.7301
WBRT	22	66
SBRT or WBRT + boost	20	62
Combination therapy
Yes	21	42	0.0648
No	21	86

3.1.2.Prognosis of cystic and solid BMs after radiotherapy

The median follow-up time was 53.7 months. As shown in Fig. 1A, patients with solid BMs had a superior mOS compared to patients with cystic BMs (23.1 vs. 14.6 months, P = 0.04). The prognosis of patients with cystic and solid BMs from primary breast cancer (Fig. 1B) and other types of cancer (Fig. 1C) did not show significant differences. However, in lung cancer patients, there appeared to be a prolonged mOS in those with solid BMs compared to those with cystic BMs (Fig. 1D, 23.1 vs. 12.5 months, P = 0.05). Notably, no discernible differences in intracranial control rates were observed between different tumors (Fig. 1E, F).

3.1.3.Prognosis of cystic and solid BMs derived from lung cancer after radiotherapy

Considering that the incidence of different between cystic BMs and solid BMs may be more likely to occur in lung cancer patients. We then performed the survival analysis in these lung cancer patients. There were no significant statistical differences in gender, age, pathological types, volume, number, RT model and combination therapy, as shown in Table 2. Excluding patients who did not undergo gene detection, 47% (9/19) of patients harbored an EGFR mutation (EGFR+), while 53% (10/19) of patients tested negative for the EGFR mutation, in cystic BMs. 32/65 of patients with solid BMs were found to have an EGFR mutation. Notably, 34 (82%) of patients with an EGFR mutation were treated with an EGFR TKIs, 78% in cystic BMs and 84% in solid BMs. The mOS of both groups did not show significant differences in NSCLC (P = 0.18, Fig. 2A), LUAD (Fig. 2B, P = 0.0626) and SCLC (Fig. 2C, P = 0.33). Notably, patients with LUAD and EGFR(+) had a significant difference in mOS between the solid and cystic groups (Fig. 2D, 23.1 months vs 6.43 months, P = 0.01). However, there was no significant difference in iPFS between patients with solid and cystic BMs derived from EGFR(-) and EGFR(+) lung cancers (Fig. 2E,F).

Table 2

Patients’ characteristics and comparison between cystic and solid BMs derived from lung cancer
Characteristics	No. of patients with cystic lesions	No. of patients with solid lesions
Age (years)			0.1511
< 65	19	59
≥ 65	5	36
Sex			0.8190
Male	14	58
Female	10	37
Pathological types			0.5624
adenocarcinoma	17	69
squamous cell carcinoma	1	9
Other or unknown	6	17
No. of BMs			0.3894
1	7	36
2	2	17
3	2	10
≥ 4 lesions	12	32
The volume of BMs (mm3 )			0.8965
≤ 4	15	58
> 4	9	37
Treatment			0.1038
WBRT	9	19
SBRT or WBRT + boost	15	76
EGFR status			0.5805
Mutation	9(2)	32(5)
Wide type	10	33
Unknown	5	30
Combination therapy			0.4880
Yes	8	41
No	16	54

3.1.4.Factors affecting prognosis in patients with lung cancer BMs

To investigate the prognostic factors affecting lung cancer BMs after RT, we constructed risk models using multivariate Cox regression analysis. As shown in Fig. 3. the potential independent predictors and included in the multivariate Cox analysis in solid BMs from lung cancer (Fig. 3B). BED were independent prognostic factors for survival of both solid and cystic lung cancer BMs. The volume of metastases in cystic lung cancer BMs were independent prognostic factors. In addition, total dose and fraction were also independently associated with OS in solid lung cancer BMs.

Compared with solid BMs, cystic BMs are relatively rare in patients with solid cancers. Cystic BMs tend to have a worse prognosis and are often more malignant than solid BMs. Traditionally, surgery has been accepted as a reliable treatment for large, single BMs[11]. However, in recent years, stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) have emerged as safe and effective treatments for BMs[12]. Hongwei Wang and his team found that the mOS for patients with cystic BMs treated with stereotactic cyst aspiration combined with SRS was 19.5 months[13]. However, most reports on the treatment of cystic BMs have been individual case reports or retrospective reviews with small samples. There are not many clinical cohort studies directly comparing the prognosis of solid and cystic BMs after brain radiotherapy.

Previous reports have shown that cystic brain metastases predominantly originate from the lung and breast cancer[9]. This was confirmed in our sample. 85% of cystic brain metastases in our study originated from lung or breast cancer. However, compared with solid BMs, there were some differences within subgroups. The proportion of breast cancers is higher in cystic BMs than in solid BMs (28% vs 13%), while it is relatively lower in lung cancers (57% vs 82%) (P = 0.0058). In our study, we have shown that the survival benefit of radiotherapy for patients with solid BMs differed from those with cystic BMs. The presence of cystic BMs is associated with a worse mOS after RT (14.6 vs. 23.1 months, P = 0.04). Although our study did not find significant differences in prognosis between solid and cystic BMs in breast cancer and other cancers, it did indicate a potential advantage in lung cancer patients with solid BMs (P = 0.05). Importantly, patients with EGFR-positive (EGFR+) solid BMs from lung cancer appeared to be the ultimate beneficiaries.

These findings provide some insight into the therapeutic options. Previous data suggest that the OS of cystic BMs is relatively better than that of solid BMs after systematic treatment, especially in patients undergoing EGFR TKI treatment[9]. Some evidence suggests that the development of cystic BMs may be related to the breakdown of the blood-brain barrier[14], allowing greater access to TKIs. Similarly, RT to the brain promotes neuroinflammation and disrupts the blood-brain barrier[15]. Thus, our study suggests that radiotherapy is critical for solid BMs, particularly in patients with EGFR mutations receiving targeted therapy. However, radiotherapy alone may not be sufficient to treat cystic BMs, and the efficacy and safety of combination therapy needs to be further exploration.

These preliminary findings prompted us to further investigate the role of radiotherapy and provide a basis for the choice of RT model in different types of lung BMs. Multivariate analysis showed that BED was an independent prognostic factor for both cystic and solid BMs. In addition, after adjustment for confounders, BED, total dose and fraction were independent risk factors for OS of solid BMs. The Radiation Therapy Oncology Group (RTOG) recommends the standard practice of using SRS (stereotactic radiosurgery, 18-24Gy) for solitary BMs, typically delivering a high dose in a single session[16]. For multiple BMs, the standard approach is whole brain radiotherapy (WBRT) combined with or without SRS. WBRT is typically delivered in fractionated treatments, with daily doses of 1.8-2.0Gy and a total dose typically in the range of 30-40Gy[17]. The results of this study suggest that a biologically effective dose (BED) of ≥ 60Gy provides a survival benefit for patients with solid BMs after brain radiotherapy. Thus, SBRT and WBRT plus stereotactic boost may also improve survival in patients with BMs due to high BED. We recommend concurrent EGFR TKI with SBRT or WBRT plus stereotactic boost as a treatment for EGFR-mutant NSCLC patients with solid BMs. However, this conclusion needs to be further confirmed by prospective studies. The choice of fractionation scheme for BMs of different locations, volumes and sizes has a certain guiding importance for radiation oncologists.

In addition, in the cystic BMs group, smaller BM size (P = 0.035) was associated with a worse prognosis in patients with cystic BMs. This finding contradicts common expectations where smaller tumor volume is typically associated with a better prognosis. However, our analysis showed that patients with smaller BMs had a higher incidence of extracranial lesions, whereas patients with larger BMs had fewer extracranial lesions (Table S1). Therefore, the poorer prognosis in patients with smaller BMs may be due to inadequate control of extracranial lesions and a higher distribution of systemic metastases to other organs, leading to a decrease in overall survival.

Due to its retrospective nature, our study inevitably has the following limitations. Firstly, the number of patients is limited, especially for diseases other than lung cancer. Secondly, some patients did not have sufficient follow-up imaging data, which prevented evaluation of the local control rate in this study and may have affected the results of iPFS.

Despite the limitation, our study draws several important conclusions. The prognosis of brain radiotherapy for patients with EGFR-mutated lung cancer with cystic BMs is significantly worse than that of patients with solid BMs. The addition of RT to the brain may enhance the efficacy of EGFR-mutant lung cancer with BMs undergoing target therapy. SBRT or WBRT plus a stereotactic boost are preferred RT approaches. Patients with lung cancer receiving BED ≥ 60Gy have a more favorable prognosis than those receiving BED < 60Gy, regardless of the type of BM (solid or cystic). However, for patients with cystic BMs, the treatment intensity of targeted combined with brain radiotherapy seems insufficient. New combination therapy models for cystic BMs need to be further explored.

BMs: brain metastases; OS: overall survival; BED: biological effective dose; RT: radiotherapy; WBRT: whole-brain radiation therapy; SRS/SBRT: stereotactic radiosurgery/stereotactic body radiotherapy; ICIs: immune checkpoint inhibitors

Informed Consent Statement: Not applicable.

Conflicts of Interest:

The authors declare no conflicts of interest.

Funding:

Please add: This research was funded by Chinese Society of Clinical Oncology (CSCO) Cancer Research Fund Project (Y-Young2022-0325), PARP Inhibitor Oncology Research Funding of China Anti-Cancer Association (CACA) (CETSDHRCORP252-4-004) and Cancer Precision Radiotherapy Spark Program of China International Medical Foundation (No. 2019-N-11-02).

Author Contribution

Conceptualization, Zilong Yuan, Desheng Hu and Guang Han; Data curation, Lu Sun and Shouyu Lin; Funding acquisition, Guang Han; Investigation, Wei Wei; Methodology, Yi Peng; Software, Lu Sun, Jianping Bi, Zilong Yuan, Ying Li and Yi Peng; Supervision, Desheng Hu and Guang Han; Validation, Wei Wei; Writing – original draft, Lu Sun and Shouyu Lin; Writing – review & editing, Jianping Bi and Ying Li.

Data Availability Statement:

Data are available on request.

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No competing interests reported.

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Evaluation of radiotherapy efficacy and prognostic analysis for solid and cystic brain metastases

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials and Methods

3. Results

3.1.1.Characteristics of the Patients

3.1.2.Prognosis of cystic and solid BMs after radiotherapy

3.1.3.Prognosis of cystic and solid BMs derived from lung cancer after radiotherapy

3.1.4.Factors affecting prognosis in patients with lung cancer BMs

4. Discussion

Abbreviations

Declarations

Conflicts of Interest:

Funding:

Author Contribution

Data Availability Statement:

References

Additional Declarations

Supplementary Files

Status:

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