Ishibashi Y, Kobayashi H, Ando T, Okajima K, Oki T, Tsuda Y, Shinoda Y, Sawada R, Tanaka S. Prognostic factors in patients with bone metastasis of lung cancer after immune checkpoint inhibitors: A retrospective study. World J Orthop 2024; 15(12): 1155-1163 [PMID: 39744733 DOI: 10.5312/wjo.v15.i12.1155]
Corresponding Author of This Article
Hiroshi Kobayashi, PhD, Department of Orthopaedic Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 113-8655, Tokyo, Japan. hkobayashi-tky@umin.ac.jp
Research Domain of This Article
Orthopedics
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yuki Ishibashi, Hiroshi Kobayashi, Toshihiko Ando, Kouichi Okajima, Takahiro Oki, Yusuke Tsuda, Sakae Tanaka, Department of Orthopaedic Surgery, The University of Tokyo, Bunkyo-ku 113-8655, Tokyo, Japan
Yusuke Shinoda, Department of Rehabilitation, The Saitama Medical University, Morohongo 350-0495, Saitama, Japan
Ryoko Sawada, Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Hyogo, Japan
Author contributions: Ishibashi Y and Kobayashi H wrote the manuscript and reviewed the relevant literature; Okajima K, Oki T, Tsuda Y, Shinoda Y, Sawada R, and Tanaka S contributed to the conception and design of the study and critically revised the manuscript. All authors have read and approved the final manuscript.
Institutional review board statement: This study was approved by the University of Tokyo Hospital’s institutional review board (approval number: 11019). All study procedures followed the ethical standards of the 1975 Helsinki Declaration (as revised in 2000) and national law.
Informed consent statement: As we use a blanket consent system, no consent form was provided for this study.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: Data sharing is not applicable to this article as no new data were created or analyzed in this study.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hiroshi Kobayashi, PhD, Department of Orthopaedic Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 113-8655, Tokyo, Japan. hkobayashi-tky@umin.ac.jp
Received: August 21, 2024 Revised: October 14, 2024 Accepted: November 8, 2024 Published online: December 18, 2024 Processing time: 118 Days and 2.2 Hours
Abstract
BACKGROUND
Accurate data on the prognosis of bone metastases are necessary for appropriate treatment. Immune checkpoint inhibitors (ICIs) are widely used in the treatment of gene mutation-negative non-small cell lung cancer (GMN-NSCLC).
AIM
To investigate the prognostic factors in patients with bone metastases from GMN-NSCLC following ICI use.
METHODS
This retrospective cohort study included 45 patients with GMN-NSCLC who were treated for bone metastases from 2017 to 2022 and received chemotherapy after diagnosis. Using Kaplan–Meier curves and Cox proportional hazards models, we evaluated the association between overall survival (OS) and clinical parameters, including serum biochemical concentrations and blood cell count.
RESULTS
Univariate analysis showed that Eastern Cooperative Oncology Group performance status ≤ 1 and the use of ICIs and bone-modifying agents after bone metastasis diagnosis were significantly associated with a favorable OS. Multivariate analysis revealed that ICI use after bone metastasis diagnosis was significantly associated with a favorable OS.
CONCLUSION
ICI use after bone metastasis diagnosis may be a favorable prognostic factor in patients with bone metastases of GMN-NSCLC. Consideration of ICI treatment for bone metastasis and GMN-NSCLC is warranted to establish a more accurate predictive nomogram for patients with bone metastasis.
Core Tip: Use of Immune checkpoint inhibitors after bone metastasis diagnosis may be a favorable prognostic factor in patients with bone metastases from gene mutation-negative non-small cell lung cancer.
Citation: Ishibashi Y, Kobayashi H, Ando T, Okajima K, Oki T, Tsuda Y, Shinoda Y, Sawada R, Tanaka S. Prognostic factors in patients with bone metastasis of lung cancer after immune checkpoint inhibitors: A retrospective study. World J Orthop 2024; 15(12): 1155-1163
Accurate data on the survival prognoses of patients with bone metastases are essential to recommend appropriate treatments. Lung cancer is a common primary cancer with a high bone metastasis risk, affecting approximately 15%–40% of patients with lung cancer[1,2]. Non-small cell lung cancer (NSCLC) accounts for approximately 85%–90% of all lung cancer cases[3]. Previous reports have associated multiple bone metastases, the tumor histological type, the use of molecularly targeted drugs, Eastern Cooperative Oncology Group performance status (ECOG PS), and alkaline phosphatase and lactate dehydrogenase (LDH) levels with the prognosis of patients with bone metastasis of lung cancer[4,5]. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with prognosis in patients with stage IV NSCLC[6]. However, these analyses were conducted before 2017[4-6], and given significant advancements in lung cancer treatments, updated studies are warranted.
In 2015, nivolumab, a monoclonal antibody targeting programmed cell death 1, was introduced as an immune checkpoint inhibitor (ICI). In addition, pembrolizumab, widely used as an ICI, has been used in treating NSCLC in Japan since 2016. ICIs have been widely used in patients with gene mutation-negative NSCLC (GMN-NSCLC) and have remarkably improved survival prognosis[7,8]. These findings suggest that the survival of patients with GMN-NSCLC may have changed significantly recently. Therefore, this study aims to investigate the survival and prognostic factors in patients with bone metastases from GMN-NSCLC following ICI use.
MATERIALS AND METHODS
This single-center retrospective cohort study included 45 patients who were treated by orthopedic doctors for bone metastasis in GMN-NSCLC at the University of Tokyo Hospital from April 2017 to October 2022 and who received chemotherapy after diagnosis. All patients were identified from the University of Tokyo Hospital's bone metastasis database and received chemotherapy according to the lung cancer treatment guidelines of the Japan Lung Cancer Society. The diagnosis of bone metastasis was confirmed through positive results in multiple examinations, including computed tomography, magnetic resonance imaging, and positron emission tomography.
We evaluated the associations between overall survival (OS) and clinical parameters that could serve as potential prognostic factors, including age, sex, the tumor histological type, programmed cell death ligand-1 tumor proportion score (TPS), brain metastases, adrenal metastasis, ECOG PS, treatment and chemotherapy before bone metastasis diagnosis, ICI and bone-modifying agents use after bone metastasis diagnosis. OS was defined as the time from bone metastasis diagnosis (confirmed through imaging) to the last follow-up or death date. We defined treatment as a therapeutic intervention, such as surgery, radiation, or chemotherapy, for lung cancer. In addition, serum concentrations of biochemicals and blood cell counts, albumin, C-reactive protein (CRP), LDH, white blood cell count, NLR, and PLR were assessed within 1 month before or after bone metastasis diagnosis.
The following cut-off values were determined as per previous studies: Albumin, 3.5 g/dL, based on the Controlling Nutritional Status[9,10]; CRP, 0.4 mg/dL[11]; LDH, 225 U/L[4]; white blood cell count, 8500/μL, based on the Palliative Prognosis Score[12]; NLR 5; PLR, 185[6].
In addition, the ICI use group was divided into two subgroups according to the TPS value and compared with the ICI non-use group. Furthermore, we examined the correlation between the TPS and NLR, a known favorable prognostic factor when using ICIs[13]. We evaluated patients’ Katagiri scores and compared survival between the groups based on these scores[11].
Statistical analyses
Statistical analyses were performed using JMP Pro version 14 (SAS Institute Inc., Cary, NC, United States). OS was calculated using Kaplan–Meier survival curves, with data recorded at the end of March 2023. Differences in survival were compared using univariate analysis with the log-rank test. Independent prognostic factors were identified through multivariate analysis using the Cox proportional hazards model. Odds ratios (ORs) and 95%CIs were determined. The correlation between TPS and NLR was statistically analyzed using the Mann–Whitney U test for nonparametric variables. Statistical significance was set at P < 0.05.
RESULTS
Patients’ clinical characteristics are summarized in Table 1. This study included 29 men and 16 women, with a median age of 70 years (range: 42–87). The tumor histological type was adenocarcinoma in 37 cases, squamous cell carcinoma in three cases, and indistinguishable or other in five cases. All 45 patients had multiple bone metastases. In total, 28 patients used ICIs after bone metastasis diagnosis. TPS was evaluated in 35 patients, which was ≥ 50% in 15 patients. Details of the ICI used are summarized in Table 2, with only 15 patients receiving pembrolizumab.
Table 2 Types of immune checkpoint inhibitors used in patients (n = 28).
Type of immune checkpoint inhibitors
Number
Pembrolizumab
15
Nivolumab
2
Atezolizumab
3
Durvalumab
3
Ipilimumab
0
Pembrolizumab + atezolizumab
2
Pembrolizumab + durvalumab
1
Nivolumab + durvalumab
1
Nivolumab + ipilimumab
1
The median follow-up duration was 12 months (range: 1–65). The median OS was 16 months (95%CI: 10–33 months), and the 1-year survival rate was 60% (Figure 1).
Figure 1 Overall survival of 45 patients with non-small cell lung cancer after bone metastasis diagnosis.
Univariate analysis revealed that the following factors were significantly associated with a favorable OS: ECOG PS ≤ 1 (P = 0.0079), ICI use after bone metastasis diagnosis (P = 0.031) (Figure 2A), and the use of bone-modifying agents after bone metastasis diagnosis (P = 0.027) (Table 3). Denosumab was the bone-modifying agent used. The multivariate analysis revealed that ICI use after bone metastasis diagnosis (hazard ratio, 0.35; 95%CI: 0.14–0.86, P = 0.023) was significantly associated with a favorable OS (Table 4).
Figure 2 The Kaplan–Meier curves for overall survival of patients.
A: The Kaplan–Meier curves for overall survival of patients classified according to immune checkpoint inhibitor use; B: The Kaplan–Meier curves for overall survival of patients classified according to tumor proportion score and immune checkpoint inhibitor use. TPS: Tumor proportion score; ICI: Immune checkpoint inhibitor.
Table 3 Univariate analysis of overall survival in patients with bone metastasis of gene mutation-negative non-small cell lung cancer.
Characteristic
n
Median OS
95%CI
P value
Age
0.51
≥ 70
23
14
7-not censored
< 70
22
19
10–54
Sex
0.72
Male
29
15
8–33
Female
16
16
8-not censored
Histological type
0.47
Adenocarcinoma
37
16
10–54
Others
8
14
1-not censored
Brain metastases
0.35
Yes
8
33
3–33
No
37
14
8–19
Adrenal metastasis
0.85
Yes
4
Not censored
4-not censored
No
41
16
8–33
ECOG PS
0.0079
≥ 2
16
8
3–33
≤ 1
29
19
13-not censored
Treatment before bone metastasis diagnosis
0.39
Yes
19
16
8-not censored
No
26
14
8–54
Chemotherapy before bone metastasis diagnosis
0.89
Yes
21
14
8–54
No
24
16
7–33
ICI use after bone metastasis diagnosis
0.031
Yes
28
22
8-not censored
No
17
13
5–16
Use of bone-modifying agent after bone metastasis diagnosis
0.027
Yes
36
16
12–54
No
9
5
2–33
Albumin
0.63
> 3.5
25
16
10-not censored
≤ 3.5
20
16
5–54
C-reactive protein
0.72
≥ 0.4
33
16
7–33
< 0.4
12
15
8-not censored
Lactate dehydrogenase
0.83
≥ 225
25
16
5–33
< 225
20
15
8–54
White blood cells
0.22
> 8500
20
14
5–22
≤ 8500
25
16
10–54
Neutrophil-to-lymphocyte ratio
0.47
≥ 5.0
21
16
8–33
< 5.0
24
15
8-not censored
Platelet-to-lymphocyte ratio
0.93
≥ 185
35
16
10–33
< 185
10
15
3–54
Table 4 Multivariate analysis of overall survival in patients with bone metastasis of gene mutation-negative non-small cell lung cancer.
Characteristic
HR
95%CI
P value
Use of ICIs after bone metastasis diagnosis
Yes
0.35
0.14–0.86
0.023
Use of bone-modifying agent after bone metastasis diagnosis
Yes
0.43
0.16–1.2
0.12
ECOG PS
≤ 1
0.5
0.20–1.3
0.14
We categorized our patients into three groups based on TPS and ICI and performed univariate analysis for OS. The first group comprised patients with TPS ≥ 50% and ICI use, the second group comprised patients with TPS < 50% or those not tested for TPS who also used ICIs, and the third group comprised patients without ICI use (Table 5 and Figure 2B). The first group tended to have a better OS (P = 0.079), but the difference was not statistically significant. To determine whether peripheral blood markers could predict TPS, we analyzed the relationship between TPS and the NLR, an indicator of inflammation. No statistical difference was observed; however, patients with TPS ≥ 50% tended toward a higher NLR (P = 0.099).
Table 5 Univariate analysis following the division of patients into three groups based on tumor proportion score and immune checkpoint inhibitors use.
n
Median OS
95%CI
P value
TPS ≥ 50% and ICI use
12
54
3-not censored
0.079
TPS ≤ 49% or not tested and ICI use
16
19
8-not censored
No use of ICI
17
13
5–16
The patients’ Katagiri scores were as follows: Four patients scored 4 points, 21 scored 5 points, 18 scored 6 points, and two scored 7 points. However, no statistical significance difference was observed between OS and Katagiri scores (P = 0.92). We categorized the patients into two groups: A group comprising patients with 4 or 5 points and the other comprising patients with a score of 6 or 7 points. Nevertheless, no significant difference in OS was observed between the two groups (P = 0.78).
DISCUSSION
Our study investigated the survival and prognostic factors in patients with bone metastases of GMN-NSCLC following ICI use. This study revealed that ICI use after bone metastasis diagnosis prolonged the OS in patients with bone metastases from GMN-NSCLC. Of these, patients with TPS ≥ 50% had a better OS. This study provides valuable insights to guide clinical decision-making regarding treating patients with bone metastasis from GMN-NSCLC.
Our primary finding was that ICI use prolonged the OS of patients with bone metastases from GMN-NSCLC. Notably, the Katagiri score, an established predictive nomogram, does not include ICI use as a predictive factor[11]. Several studies have shown that the use of ICIs in advanced NSCLC improves prognosis[14-16]. Considering our results, when treating patients with bone metastases of GMN-NSCLC, it is desirable to confirm the potential for future ICI utilization, estimate the OS, and treat the patient accordingly. Furthermore, an ECOG PS ≤ 1 and the use of bone-modifying agents after bone metastasis diagnosis were found to be other favorable prognostic factors in the univariate analysis. However, these factors were not statistically significant in the multivariate analysis. In contrast to our findings, several previous reports have consistently identified ECOG PS as a significant prognostic factor in patients with bone metastasis[4,5]. The observed discrepancy may be attributed to the smaller sample size in our study, and our findings may change following analysis with a more significant number of cases. Interestingly, bone-modifying agents tend to be associated with a favorable OS[17]. This indicates that patients not treated with bone-modifying agents may have a shorter survival. However, bone-modifying agents are known to reduce skeletal-related events (SRE) across various cancer types[18-20], and preventing SRE could prolong OS[20-22]. Therefore, the use of bone-modifying agents could be associated with better OS. Recently, scientists have attempted to conjugate BP to antineoplastic drugs and ICIs (antibodies) to treat bone metastases[23].
Regarding the efficacy of ICIs for NSCLC, the presence of bone metastasis has been reported by previous studies as an unfavorable prognostic factor in the treatment of advanced NSCLC with ICIs[24]. A previous study on breast cancer patients reported that the efficacy of ICIs was disappointing in patients with bone metastases, the bone microenvironment contributed unique signals, and traditional cancer therapies had limited effectiveness owing to off-target effects and poor distribution in the bones[25]. However, in our study, ICIs prolonged the OS in patients with GMN-NSCLC with bone metastasis. Therefore, ICI administration is a viable option for patients with GMN-NSCLC, even in cases of bone metastasis. In addition, our study revealed that patients treated with ICI and TPS ≥ 50% exhibited a more favorable prognosis. This finding corroborated established evidence that TPS is a significant predictive factor for ICI use in patients with advanced NSCLC[24]. In addition to high TPS as a predictive factor for ICIs, Banna et al[26] reported that a low NLR and high TPS were favorable predictive factors for ICIs in NSCLC[26]. In agreement with this report, a low NLR (< 2.1) has been reported to be a favorable prognostic factor in patients with bone metastasis of NSCLC treated with ICIs[17]. Herein, NLR did not influence OS significantly, and patients with a high TPS tended to have a high NLR, which conflicts with previous reports. This discrepancy may be attributed to our study’s relatively small sample size because a high TPS could reflect the sensitivity of ICIs. Therefore, further studies using a more significant number of cases to analyze the relationship between TPS and NLR may be needed.
Our study has several limitations. First, with only 45 patients included, the statistical power of the results is reduced, which may limit the robustness of the findings and the use of certain statistical methods. Second, treatment selection bias might have been present because although patients were treated following lung cancer treatment guidelines, the attending physician selected the most suitable treatment based on the general condition of individual patients, which may have influenced the use of ICIs. ICIs were used in 17 of 22 patients aged < 70 years and 11 of 23 patients aged ≥ 70 years, indicating a tendency for younger patients to be administered ICIs more frequently. Third, the timing at which bone metastases were diagnosed varied among patients. Various cases exist, encompassing patients who first visited the hospital with symptoms of bone metastasis and patients who were asymptomatic, but the metastasis was detected through routine imaging tests. These factors may affect the OS after bone metastasis diagnosis.
CONCLUSION
ICI use after bone metastasis diagnosis may be a favorable prognostic factor for the treatment of bone metastases from GMN-NSCLC. The present predictive nomogram does not include ICIs, which should be considered for use in patients with bone metastasis. Moreover, ICI use could be considered for GMN-NSCLC to establish an improved predictive nomogram for patients with bone metastasis from NSCLC.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Orthopedics
Country of origin: Japan
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade A
P-Reviewer: Xing Y S-Editor: Liu H L-Editor: A P-Editor: Zhao YQ
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