Survival and prognostic factors in non-small cell lung cancer patients with brain metastases limited access to systemic therapy

doi:10.21203/rs.3.rs-2324452/v1

Background

Survival after diagnosis of brain metastases in non-small cell lung cancer (NSCLC) patients was dismal even after local therapy (surgery or brain irradiation), partly because of the systemic burden. Paucities of medical oncologists and molecular testing plus disparities in health care coverage resulted in limited access to systemic chemotherapy, let alone targeted drug or immunotherapy, for brain metastatic non-small cell lung cancer (BM-NSCLC) in Thailand. In this study, we aimed to explore prognostic factors affecting overall survival and evaluate survival outcome in BM-NSCLC limited access to systemic therapy.

Methods

We retrospectively collected 83 BM-NSCLC from a tertiary care hospital in Thailand. Data regarding clinical characteristics and treatment factors including age, sex, performance status, histology, neurologic symptom, extra-cranial metastasis (ECM), receiving whole brain radiotherapy (WBRT) and receiving systemic treatment were collected as independent factors. Associations between these variables and time to death were analyzed using the Cox proportional hazard regression.

Results

The patients' mean age was 63.1 year (SD 8.9). Most of the patients had adenocarcinoma (73%), presented with major neurological symptom (84%), and had brain metastases at their initial diagnosis of lung cancer (65%). Nearly 30% had ECM while 14% received systemic treatment. Three-quarters of patients received WBRT. Less than 15% were tested for actionable mutations. The median survival time was 2.7 months (95%CI: 2.2–4.1 months). One-month, three-month, six-month, and one-year survival probability was 78.3% (95%CI: 52.6–73.2%), 47.0% (95%CI: 36.0-57.2%), 26.5% (95%CI: 17.6–36.3%), and 9.6% (95%CI: 4.5–17.1%), respectively. Multivariable analysis showed that having extra-cranial disease was significantly associated with death (HR 4.22, 95%CI:1.27-14.0,p = 0.019 for first diagnosis lung with any ECM; HR 6.33, 95%CI:1.62–24.79, p = 0.008 for controlled lung & ECM; and HR 11.32, 95%CI:2.89–56.1, p = 0.003 for uncontrolled lung or ECM). Receiving systemic treatment was significantly associated with a reduced risk of death (HR0.39, 95%CI:0.18–0.80, p = 0.011). WBRT was insignificantly associated with prolonged survival (HR 0.79, 95%CI:0.43–1.44, p = 0.441).

Conclusion

Extracranial disease and lack of systemic treatment significantly shortened survival in BM-NSCLC.

brain metastases

non-small cell lung cancer

overall survival

prognostic factors

systemic therapy

Brain metastases (BM) are the most common brain tumor, ten times more frequent than primary malignant brain tumors⁽¹⁾. According to data from the National Health Security Office, Thailand, from 2005 to 2014, for all brain tumor patients, 19.9 percent were diagnosed with BM (18,623 of 477,864,852) and the prevalence doubled from 2.48 per 100,000 populations in 2005 to 5.21 per 100,000 populations in 2014⁽²⁾, consistent with Swedish study reporting that the annual age-adjusted incidence rate of hospitalization for BM doubled from 7 to 14 patients per 100,000 between 1987 and 2006⁽³⁾. Therapeutic resources were needed to support the growing demands.

The most common primary tumor to metastasize intracranially is non-small cell lung cancer (NSCLC). BM will develop in about 9 percent of the patients⁽⁴⁾. In Thailand, there were 313 and 275 new cases of NSCLC in 2010 and 2020, respectively^{(5, 6)}. The trend was comparable to data in the United States of America (USA), 56.1 and 43.2 per 100,000 populations in 2008 and 2018, consecutively⁽⁷⁾. However survival was still dismal, especially ones with BM⁽⁸⁾.In the past, treatment for BM was whole brain radiotherapy (WBRT) with or without surgery. Regarding advances in cancer therapy, stereotactic radiosurgery (SRS) or systemic pharmacotherapy was preferred over WBRT, recommended in EANO-ESMO 2021 guidelines⁽⁹⁾. For patients with NSCLC with asymptomatic BM, upfront immune checkpoint inhibitor with or without systemic chemotherapy should be administered in ones without actionable oncogenic driver alterations, while upfront systemic targeted therapy should be given in ones with actionable oncogenic driver alterations. But, for countries with limited resources, accessibility of advanced radiotherapy technologies or high-priced cancer drugs was impossible. Besides, two-thirds of patients with brain metastatic non-small cell lung cancer (BM-NSCLC) died of extracranial disease rather than intracranial progression⁽¹⁰⁾, emphasizing the importance of systemic agents for the patients.

Regarding Thailand's health care schemes, there are three government schemes. Firstly, the Civil Servant Medical Benefit Scheme (CSMBS) provides health care benefits to government officials and their family members. Secondly, the Social Security Scheme (SSS) covers private employees. And lastly, the Universal Coverage Scheme (UC) which is available to all Thai nationals. Most of our population (72 percent) is covered under the UC scheme. Since the delivery of expensive cancer therapy needs to achieve a balance between accessibility of cancer care and the economic status of the country, this resulted in limited systemic treatment options for NSCLC patients owing to the differences in health care coverage. For instance, the standard double-platinum based chemotherapy is available for all health care schemes but the use of a central nervous system active agent, such as alectinib, is limited to patients covered under the CSMBS scheme. None of patients with the UC and SSS schemes can get reimbursed for the CNS active agents, they have to pay out-of-pocket. Moreover, healthcare professionals, particularly medical oncologists, and molecular testing were inadequate in the country. All of this leads to limited access to systemic anti-cancer therapy for NSCLC patients in Thailand.

Prognostic factors for survival in patients with BM receiving WBRT were investigated in numerous studies. A review by Gilbride, et al in 2018 demonstrated a prognostic nomogram for any primary cancers generated by analyzing over 1000 patients⁽¹¹⁾. While Nieder, et al reported prognostic scores in patients with primary NSCLC. Prognostic factors used in published studies included performance status, age, gender, status of primary cancer, extra-cranial disease, number of brain metastases, histology, volume of brain metastatic lesion, neurologic symptom, use of steroid, status of brain metastasis and molecular markers including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase gene (ALK)⁽¹²⁾. Nevertheless, the study conducted in place with restricted provision of systemic treatment was required in order to properly determine treatment for patients with BM-NSCLC limited access to systemic anti-cancer therapy. The aims of the present study were to explore prognostic factors affecting overall survival (OS) and evaluate survival outcome in the patients.

We conducted a retrospective cohort study which collected patients treated at Sawanpracharak hospital, a university-affiliated tertiary care center in Thailand between January 2019 and December 2019. Eligible criteria were adults (> 18 years) who had histologically proven primary NSCLC with computed tomography or magnetic resonance imaging confirmed brain metastases. We excluded patients who had other concomitant malignancy. This study was approved by the institutional review board. The primary outcome was overall survival, calculated from the diagnosis of brain metastasis to the date of death from any cause or to the last follow-up. The final statuses of the patients were determined as at November 30, 2020, using local death registry data and hospital records. Patients who survived until this date were censored for the computation of overall survival. Clinical and treatment characteristics including age, sex, Karnofsky performance status (KPS), histology, neurological symptoms, extra-cranial disease, receiving further systemic treatment, and receiving WBRT were collected as potential predictors. Scales and definitions were chosen based on previous literature and clinical experiences (Table 1). The survival curve was demonstrated using Kaplan Meier analysis. Cox proportional hazard regression was used for survival analyses. Proportional hazard assumptions were tested using Schoenfeld residuals. The one-month, three-month, six-month, and one-year survival rate and median survival time were also calculated. Hazard ratios (HRs) and 95% confidence interval (95% CI) were estimated for each candidate prognostic factor in univariable and multivariable analyses. We defined P-value < 0.05 as statistically significant. The estimated survival functions after multivariable Cox regression were plotted for significant prognostic factors at specific covariate values. Analyses were conducted with Stata/SE, release 17 (StataCorp LP, College Station, TX, USA).

Table 1

Prognostic studies in Brain metastases
Prognostic scores / nomograms	RPA^13,14	DS- GPA³⁹	BSBM¹⁶	SIR¹⁵	Rades¹⁷	Rotterdam¹⁸	Bamholtz-Sloan¹⁹	Chao²⁰	Golden²¹	Lung- molGPA⁴⁰	TATA²²
Disease	All primary cancer							NSCLC
Performance status	/	/	/	/	/	/	/	/		/	/
Age	/	/		/	/		/		/	/	/
Gender											/
Extra-cranial status	/	/	/	/	/	/	/	/	/	/	/
Primary NSCLC status	/		/			/	/
Number of lesions		/		/	/		/		/	/	/
Histology										/
Volume of largest lesion				/
Neurologic symptom											/
Steroid use						/
Brain metastases type											/
EGFR/ALK status										/	/

We collected 83 patients with BM-NSCLC. There were 81 patients died by the time of analysis. Clinical characteristics were shown in Table 2. The mean age was 63.1 (SD 8.9) years. Most of the patients had adenocarcinoma and presented with major neurological symptom. Half of the cohort had recursive partitioning analysis (RPA) class II. Majority of them had brain metastases at their initial diagnosis of lung cancer (65%). Nearly 30 percent had extracranial metastasis (ECM) while 14 percent received systemic treatment. Three-quarters of the cohort received WBRT. Less than 15 percent got genetic mutation tested.

Table 2: Clinical characteristics

Characteristics	n = 83
Age (mean ± SD)	63.1 ± 8.9
Age < 65	46 (55%)
Female	36 (43.0%)
KPS ≥ 70%	44 (53.0%)
Histology • Adenocarcinoma • Non-adenocarcinoma	61(73.0%) 22 (27.0%)
EGFR/ALK mutation • Positive • Negative • Unknown	5 (6.0%) 7 (8.0%) 71 (86.0%)
Neurological symptoms • None • Mild • Major	3 (4.0%) 10 (12.0%) 70 (84.0%)
Extra-cranial disease - Controlled lung and no ECM - Controlled lung & ECM - Uncontrolled lung or ECM - First diagnosis lung with any ECM	5 ( 6%) 15 (19%) 7 ( 9%) 51 (65%)
Further systemic treatment	12 (14%)
WBRT	62 (75%)
RPA -Class I (7.1m) -Class II (4.2m) -Class III (2.3m)	3 ( 4%) 42 (52%) 36 (44%)

Abbreviations: ALK, anaplastic lymphoma kinase gene; ECM, extracranial metastasis; EGFR, epidermal growth factor receptor; KPS, Karnofsky performance status; WBRT, whole brain radiotherapy

The median survival time was 2.7 months (95%CI: 2.2-4.1 months). Survival probabilities were demonstrated in Figure 1. One-month, three-month, six-month, and one-year survival probability was 78.3% (95%CI: 52.6-73.2%), 47.0% (95%CI: 36.0-57.2%), 26.5% (95%CI: 17.6-36.3%), and 9.6% (95%CI: 4.5-17.1%), respectively.

Univariable and multivariable analyses for overall survival were done. The proportional hazard assumption was satisfied. In univariable analysis, being elderly (>65 years old), receiving systemic treatment and receiving WBRT were significantly associated with a reduced risk of death while having extra-cranial disease was significantly associated with death. In multivariable analysis, receiving systemic treatment remained a significant favorable prognostic factor for OS (HR 0.39, 95%CI:0.18-0.80, p=0.011). The unfavorable prognostic factor was having extra-cranial disease (HR 4.22, 95%CI:1.27-14.0,p=0.019 for having first diagnosis of lung cancer with any ECM; HR 6.33, 95%CI:1.62-24.79, p=0.008 for having controlled primary lung cancer and ECM; and HR 11.32, 95%CI:2.89-56.1, p=0.003 for having uncontrolled primary lung or ECM). It is worth noting that receiving WBRT became insignificantly associated with prolonged survival (HR=0.79, 95%CI:0.43-1.44, p=0.441) (Table 3). We plotted the estimated survivor function for key prognostic factors in Figure 2 and Figure 3.

Table 3: Multivariable analysis of Predictors for Overall survival

Characteristics	mHR (95% CI)	P value
Age>65	0.68 (0.41-1.13)	0.139
Female	1.47 (0.87-2.48)	0.148
KPS score > 70%	0.82 (0.47-1.42)	0.469
Histology Adenocarcinoma Non-adenocarcinoma	1 0.63 (0.34-1.16)	– 0.140
Neurological symptoms • None • Mild • Major	1 3.78 (0.59-24.2) 2.25 (0.44-11.5)	– 0.161 0.330
Extra-cranial disease - Controlled lung and no ECM - Controlled lung & ECM - Uncontrolled lung or ECM - First diagnosis lung with any ECM	1 6.33 (1.62-24.79) 11.32 (2.89-56.1) 4.22 (1.27-14.0)	– 0.008 0.003 0.019
Further systemic treatment	0.39 (0.18-0.80)	0.011
WBRT	0.79 (0.43-1.44)	0.441

Abbreviations: CI, confidence interval; ECM, extra-cranial metastasis; mHR, multivariable hazard ratios; KPS, Karnofsky performance status; WBRT, whole brain radiotherapy

For patients with BM-NSCLC limited access for anti-cancer therapy, receiving further systemic treatment and having extracranial disease was a significant favorable and unfavorable prognostic factor for OS, respectively. These emphasized the importance of extracranial disease control in patients with BM-NSCLC, commonly managed with systemic agents. The RPA classification, introduced in 1997 and validated in 2000, was proposed by Gaspar and colleagues, to predict survival in patients with BM, using prognostic factors including performance status, age, primary tumor status and extracranial metastases, classified into three classes^(13,14). After that, many scoring systems were conducted. Age, performance status, extracranial disease status, number of brain lesions and largest brain lesion volume were identified as reliable prognostic factors in the Score Index for Radiosurgery in Brain Metastases (SIR), based on a population of 65⁽¹⁵⁾. In a study with a larger population (110 patients), performance status, primary tumor control, and presence of extracranial metastases were evaluated to calculate the basic score for brain metastases (BS-BM). Using a backward elimination model, Lorezoni, et al reported that SIR and BS-BM were significantly associated with survival, but not RPA⁽¹⁶⁾. To analyze a prognostic score index, Rades, et al investigated potential prognostic factors and found that age, performance status, extracerebral metastases, interval tumor diagnosis to radiotherapy, and number of brain metastases were significantly associated with OS⁽¹⁷⁾. Lagerwaard, et al reported that performance status, systemic disease status, response to steroid and site of primary tumor were significant prognostic factors⁽¹⁸⁾. Primary site and histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions were included in the model for nomogram estimating survival created by Barnholtz- Sloan and colleagues⁽¹⁹⁾. For BM-NSCLC patients, Chao, et al revealed that only performance status and extracranial status were significant factors predicting survival⁽²⁰⁾, while Golden, et al presented that age < 65 years without extracerebral disease and at most 3 brain metastases were favorable prognostic factors^(21). To determine patients who may not benefit from WBRT, Agarwal, et al from Tata Memorial Hospital identified gender, performance status and epidermal growth factor receptor (EGFR) mutation status as significant factors influencing overall survival⁽²²⁾. Programmed death ligand 1 (PD-L1) expression was newly specified as a prognostic factor in the latest NSCLC graded prognostic assessment (GPA) published in 2022 by Sperduto, et al⁽²³⁾, whereas EGFR and ALK status, performance status, age, number of brain metastases and ECM were reaffirmed in this study. However, due to limited accessibility of systemic anti-cancer therapy, particularly targeted agents and immunotherapy in the present study, molecular markers were tested in only 14% of the patients and no PD-L1 expression was examined.

To the authors' knowledge, extracerebral status was included in all scoring systems proposed, underlining strong association between this factor and survival of BM patients, which was comparable to the present study’s results, HR of 6.33 (1.62-24.79), 11.32 (2.89-56.1) and 4.22 (1.27-14.0) for controlled lung lesion & ECM, uncontrolled lung lesion or ECM and first diagnosis lung cancer with any ECM, respectively were noted in the multivariable analysis. The severity was more prominent in uncontrolled extracranial disease, compared to controlled and treatment-naive ones. In spite of the limitation of accessibility of systemic agents, uncontrolled extracranial disease tends to have treatment resistance, particularly radiation and restriction to receive other interventions, such as surgery or ablation therapy, in terms of number, size or location of the tumor. Therefore, this disease stage is likely to have a poorer prognosis. Whereas the treatment-naive disease has a tendency of being sensitive to radiation and characteristics feasible for other local treatments. Hence, the stage has better survival than the controlled disease. However, the nature of these disease stages needs to be further studied in order to understand the mechanism thoroughly, leading to better treatment assignment for each stage.

Role of WBRT in patients with BM-NSCLC, who were unsuitable for surgery and SRS, have been questioned since results of the QUARTZ trial were published. Comparing dexamethasone alone to additional WBRT, both quality-adjusted life-years (QALYs) and OS were not improved in the irradiated group⁽²⁴⁾. With similar patient characteristics, the present study supported the findings, cranial radiation had no benefit increasing OS.

Median survival time of 2.7 months (1-year survival rate of 9.6%) in the present cohort was comparable to ones reported in the QUARTZ trial⁽²⁴⁾ which were 9.2 weeks for the group with WBRT and 8.5 weeks for the group without WBRT. With half of patients had KPS at least 70% and 94% had active extracranial diseases but only 14% received further systemic treatment in the present study, while in the QUARTZ trial about two-third had KPS ≥ 70% with ECM of 55% and systemic anti-cancer treatment was allowed including after WBRT, suggesting that the present study’s survival outcome was fair even with poorer prognostic factors. In contrast, Kim and colleagues reported that BM-NSCLC patients receiving chemotherapy after WBRT had the median OS of 7 months (range, 0.9-25.3 months) with survival rate of 23% at 1 year⁽²⁵⁾. Whereas, compared to a recent update of NSCLC GPA⁽²²⁾, the least median survival was 6 months for an adenocarcinoma cohort with GPA of 0.0-1.0 which was analyzed in populations in three developed countries, provided with abundant treatment resources. Systemic chemotherapy had been the standard treatment for advanced NSCLC in the past. Regarding 16 randomized controlled trials (RCTs), chemotherapy improved survival of 9% at 12 months, increasing survival from 20% to 29% or an absolute increase in median survival of 1.5 months, compared to best supportive care (BSC) alone, demonstrated in Cochrane reviews in 2010⁽²⁶⁾. Although 35-40% of patients with BM-NSCLC responded to a combination of chemotherapy^(27-30), no strong evidence suggested the survival benefit of chemotherapy in the patients, which can be explained by inability of cytotoxic chemotherapy to cross the blood brain barrier. Nowadays, immunotherapy with or without chemotherapy was recommended in patients without actionable driver alterations, depending on PD-L1 expression, while targeted therapy was recommended in patients with actionable driver mutation^(32-33). Aforementioned statement included patients with brain metastases^(9,34). Despite no phase III RCT demonstrated systemic anti-cancer treatment can improve survival in BM-NSCLC patients, there are studies showing possible CNS efficacy of specific agents, for instance, improved median CNS progression-free survival (PFS) in patients with untreated EGFR-mutated advanced NSCLC administered with osimertinib, compared to ones with gefitinib or erlotinib, was reported in preplanned, exploratory analysis of the FLAURA study⁽³⁵⁾. According to the ALEX study, patients with stage III-IV ALK-positive NSCLC were randomized to receive alectinib or crizotinib. Surprisingly, for patients with CNS metastases at baseline, OS was significantly better in the alectinib arm⁽³⁶⁾. In addition, most patients with BM had extracranial diseases. According to German data, extracranial metastatic sites were observed in 60% of 5,074 patients with BM, with 50% of patients having lung cancer⁽³⁷⁾. While 32%, 55% and 62% of patients were reported with active extracranial disease in JLGK0901 (76% lung cancer)⁽³⁸⁾, QUARTZ (100% NSCLC)⁽²⁴⁾ and NRG CC001 (60% lung cancer)⁽³¹⁾ trials. Less than ten percent of the patients in the present cohort had controlled extracerebral disease, representing that most patients received delayed treatment or scarce treatment resources, especially systemic therapy in this setting. In accordance with the previous explanation, the role of systemic treatment was markedly considered in patients receiving intracranial radiation with active extracranial tumor to control the disease outside the brain, or even improve survival.

In conclusion, for patients with BM-NSCLC, presence of extracranial disease with absence of systemic treatment significantly diminished OS.

ALK: Anaplastic lymphoma kinase gene

BM: Brain metastases

BM-NSCLC: Brain metastatic non-small cell lung cancer

BSC: Best supportive care

BS-BM: Basic score for brain metastases

CI: Confidence interval

CSMBS: Civil servant medical benefit scheme

ECM: Extra-cranial metastasis

EGFR: Epidermal growth factor receptor

GPA: Graded prognostic assessment

HR: Hazard ratio

KPS: Karnofsky performance status

NSCLC: Non-small cell lung cancer

OS: Overall survival

PD-L1: Programmed death ligand 1

PFS: Progression-free survival

QALYs: Quality-adjusted life-years

RCT: Randomized controlled trial

RPA: Recursive partitioning analysis

SIR: Score index for radiosurgery

SRS: Stereotactic radiosurgery

SSS: Social Security Scheme

UC: Universal coverage scheme

USA: United states of America

WBRT: whole brain radiotherapy

- Ethics approval and consent to participate

This study was approved by the institutional review board of Sawanpracharak hospital (Approval number: 66/2563). The study was performed in accordance with the Declaration of Helsinki. All data management and analyses were conducted according to current legislation and regulation of privacy, without any possibilities for individual identification. The requirement for informed consent was waived by the institutional review board of Sawanpracharak hospital.

- Consent for publication Not applicable

- Availability of data and materials

The data underlying this article were provided by Sawanpracharak hospital by permission. Data will be shared on request to the corresponding author with permission of Sawanpracharak hospital.

- Competing interests Not applicable

- Funding Not applicable

- Authors' contributions

KT: Conceptualization; Data curation; Formal analysis; Roles/Writing - original draft; Writing - review & editing

AB: Roles/Writing - original draft; Writing - review & editing

SN: Writing - review & editing

- Acknowledgements Not applicable

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No competing interests reported.

Survival and prognostic factors in non-small cell lung cancer patients with brain metastases limited access to systemic therapy

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials And Methods

3. Results

4. DISCUSSION

abbreviations

Declarations

References

Additional Declarations

Status:

Version 1