Predictive factors, preventive implications, and personalized surgical strategies for bone metastasis from lung cancer: population-based approach with a comprehensive cancer center-based study

Abstract

Background

Bone metastasis (BM) and skeletal-related events (SREs) happen to advanced lung cancer (LC) patients without warning. LC-BM patients are often passive to BM diagnosis and surgical treatment. It is necessary to guide the diagnosis and treatment paradigm for LC-BM patients from reactive medicine toward predictive, preventive, and personalized medicine (PPPM) step by step.

Methods

Two independent study cohorts including LC-BM patients were analyzed, including the Surveillance, Epidemiology, and End Results (SEER) cohort (n = 203942) and the prospective Fudan University Shanghai Cancer Center (FUSCC) cohort (n = 59). The epidemiological trends of BM in LC patients were depicted. Risk factors for BM were identified using a multivariable logistic regression model. An individualized nomogram was developed for BM risk stratification. Personalized surgical strategies and perioperative care were described for FUSCC cohort.

Results

The BM incidence rate in LC patients grew (from 17.53% in 2010 to 19.05% in 2016). Liver metastasis was a significant risk factor for BM (OR = 4.53, 95% CI = 4.38–4.69) and poor prognosis (HR = 1.29, 95% CI = 1.25–1.32). The individualized nomogram exhibited good predictive performance for BM risk stratification (AUC = 0.784, 95%CI = 0.781–0.786). Younger patients, males, patients with high invasive LC, and patients with other distant site metastases should be prioritized for BM prevention. Spine is the most common site of BM, causing back pain (91.5%), pathological vertebral fracture (27.1%), and difficult walking (25.4%). Spinal surgery with personalized spinal reconstruction significantly relieved pain and improved daily activities. Perioperative inflammation, immune, and nutrition abnormities warrant personalized managements. Radiotherapy needs to be recommended for specific postoperative individuals.

Conclusions

The presence of liver metastasis is a strong predictor of LC-BM. It is recommended to take proactive measures to prevent BM and its SREs, particularly in young patients, males, high invasive LC, and LC with liver metastasis. BM surgery and perioperative management are personalized and required. In addition, adjuvant radiation following separation surgery must also be included in PPPM-guided management.

Graphical abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s13167-022-00270-9.

Introduction

Bone metastasis (BM) is a potential complication of advanced lung cancer (LC) patients. When BM occurs, patients are frequently vulnerable to skeletal-related events (SREs), which can seriously impair their daily activities and even result in death [1–3]. LC has the highest BM risk among cancers and is the most common primary source of BM [4, 5]. As a result, it is necessary to identify high-risk LC-BM patients, actively prevent BM and its SREs, and develop personalized treatment strategies for LC-BM based on predictive, preventive, and personalized medicine (PPPM or 3PM) principles [6]. Major risk factors identification, predictive tools development, and treatment outcome research are critical approaches to implementing PPPM/3PM in cancer [6].

The LC-BM is osteolytic and causes many intractable SREs by drug therapy. BM surgery is a direct and effective way to treat SREs [7]. Nonetheless, given the poor prognosis of advanced LC, many LC-BM patients are negative to BM surgery. Over the last few decades, due to great leaps in LC chemotherapy and targeted therapy, advanced LC patients have exhibited a prolonged overall survival [8, 9]. Hence, BM surgery is increasingly necessary for SREs treatment [10, 11]. BM surgery, especially spinal metastasis surgery, is a highly complex and individualized technique [12]. It includes various procedures, such as open BM resection and minimally invasive percutaneous vertebroplasty (PVP) [13, 14]. Our institution Fudan University Shanghai Cancer Center (FUSCC) is one of the largest national comprehensive cancer centers in China and has extensive experience in LC-BM treatment based on our multidisciplinary team (MDT). This study seeks to (1) develop an individualized risk stratification model for BM, (2) identify key populations for BM prevention, and (3) provide personalized BM surgical strategies and perioperative management key points. We attempted to take the first step toward shifting the diagnosis and treatment paradigms of LC-BM patients away from reactive medicine and toward PPPM/3PM [15, 16].

Methods

Study population

This study included LC-BM patients from the Surveillance, Epidemiology, and End Results (SEER) and FUSCC study cohorts. SEER cohort extracted data from the SEER-18 registries program (https://seer.cancer.gov/). LC patients were extracted using the site recode ICD-O-3/WHO 2008 of “Lung and bronchus.” The inclusion criteria were (1) LC as first primary cancer and (2) LC diagnosed with positive histology. A total of 233,308 LC patients were included from January 1, 2010, to December 31, 2017. LC patients less than 18 years old, patients reported by autopsy only, patients with survival less than 1 month, and patients with unknown BM status were excluded. Then 203,942 LC patients with and without BM were analyzed for BM risk factors. After excluding patients in 2017 and patients without BM, 33,093 LC-BM patients with at least 1-month follow-up were examined for survival (Fig. 1A).

Fig. 1.

Flowchart showing patient selection. A Retrospective SEER cohort between 2010 and 2017; B prospective Fudan University Shanghai Cancer Center (FUSCC) cohort between 2017 and 2020. Abbreviations: SEER, Surveillance, Epidemiology, and End Results

FUSCC cohort prospectively enrolled LC-BM patients who underwent BM surgery from May 1, 2017, to July 31, 2020 (Fig. 1B). The inclusion criteria were (1) patients diagnosed with LC; (2) clinical evidence supporting BM lesion from LC; (3) patients with an estimated survival of more than 3 months; and (4) patients with BM surgery indications. Patients who do not tolerate anesthesia, surgery, and those who lack medical information were excluded. We enrolled 59 representative patients, including 56 patients for spinal metastasis surgery, 2 patients for femoral metastasis surgery, and 1 patient for humeral metastasis surgery. Of 56 patients with spinal metastasis, 11 underwent minimally invasive PVP, 42 underwent separation surgery, and 3 underwent total en bloc spondylectomy (TES). Tomita’s score was used for surgery candidates with spinal metastasis, and those with a score > 8 were deemed unfit for surgery [17]. This study was approved by FUSCC review board and obtained informed consent.

Data collection

In SEER cohort, patients’ age, sex, LC site, laterality, histologic type, differentiation, and T and N stage were extracted. Specific distant metastasis sites were extracted, such as the bone, lung, brain, and liver metastasis. Surgery treatment information was obtained. Patients’ overall survival (OS) status and time were obtained.

In FUSCC cohort, patient’s age, gender, body mass index (BMI), smoking, and alcohol intake status were recorded. Patient’s symptoms and signs were questioned at hospital admissions, such as lower limbs pain and numbness status, difficultly walking, and paraplegia. Pain was scored by skilled nurses at hospital admission using the numerical rating scale (NRS) [18]. Walking ability on level ground and to climb stairs were assessed using the Barthel Index scale [19]. Briefly, walking ability on level ground was scored at 15 (complete independence), 10 (some assistance is required), 5 (much assistance is required), and 0 (full dependence). Ability to climb stairs was scored at 10 (complete independence), 5 (some assistance is required), and 0 (much assistance is required).

Imaging examinations (X-ray, computed tomography (CT), and magnetic resonance imaging (MRI)) and blood and biochemical routine tests were performed before and after BM surgery. Inflammatory and immune indexes (leucocytes, neutrophils percentage, lymphocytes percentage, monocytes percentage, neutrophil to lymphocyte ratio), hemoglobin, platelets, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), hepatic function indexes (alanine transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL)), nutrition indexes (total protein, albumin, pre-albumin, and globulin), and serum Ca²⁺ level were all recorded.

Skilled anesthesiologists conducted the American Society of Anesthesiologists (ASA) grade before BM surgery [20]. Surgical approaches, duration, blood loss, and transfusion volume were recorded. Resected BM specimens were sent to pathological examination using hematoxylin–eosin (HE) and immunohistochemistry (IHC) staining. Radiation is an excellent adjuvant treatment option for LC-BM patients after separation surgery to kill spinal metastatic cancer cells, suppress osteoclasts, and promote osteolytic lesions calcification. Follow-up on survival was conducted via institutional outpatient records and telephone until November 22, 2021.

Statistical analysis

Continuous data were presented by mean ± standard deviation (SD) or median (interquartile range) and examined by Student’s t-test or Mann-Whiney U test, respectively. Categorical data were presented by number with percentage and examined by chi-square test. In SEER cohort, univariable and multivariable logistic regression analyses were conducted to identify BM risk factors. Age, sex, LC site, laterality, LC histology, LC differentiation, T and N stage, and lung, liver, and brain metastasis were entered into a multivariable logistic regression modeling in a method of stepwise forward LR. Odds ratio (OR) with 95% confidence interval (CI) was reported. An individualized nomogram for BM risk assessment was accordingly constructed based on logistic regression model using R software 4.1.2 (https://www.r-project.org/). Receiver operator characteristic (ROC) curve with calculated area under the curve (AUC) and calibration curve were employed to internally validate the nomogram predictive performance. Survival differences stratified by clinicopathologic characteristics were displayed using Kaplan–Meier curves and examined using log-rank test. Univariable and multivariable Cox proportional hazard regression analyses were conducted to examine independent prognostic factors for LC-BM patients. In FUSCC cohort, paired t-test and Wilcoxon matched-pairs signed-rank test was conducted for pre- and postoperative comparison of biochemical index, pain score, and activity ability score. Statistics and graphs were conducted using SPSS 24.0 and GraphPad Prism 7.0. A two-sided P < 0.05 was considered statistically significant.

Results

Baseline characteristics of LC-BM patients in SEER

Baseline demographic and clinical characteristics of SEER cohort were presented in Supplementary Table 1. LC-BM patients from 2010 to 2016 were selected for epidemiological features analysis. LC-BM patient’s number increased over the years. BM incidence in LC was significantly increased from 17.53% in 2010 to 19.05% in 2016. LC-BM patient’s 3-month survival rates increased from 59.1% in 2010 to 62.3% in 2016. LC-BM patients’ 6-month survival rates increased from 40.3% in 2010 to 45.2% in 2016. More details were presented in Supplementary Fig. 1.

Risk factors for BM and individualized nomogram

As shown in Table 1, BM incidence was obviously high in young patients, males, main bronchus LC, bilateral LC, LC adenocarcinoma/small cell carcinoma, poorly/undifferentiated LC, LC with higher T and N stages, and LC with lung, liver, and brain metastases. Powerful BM independent risk factors mainly included liver metastases (OR = 4.53, 95% CI = 4.38–4.69), followed by poorly/undifferentiated LC (OR = 2.74, 95% CI = 2.52–2.99), N3 stage (OR = 2.28, 95% CI = 2.18–2.39), and adenocarcinoma (OR = 2.07, 95% CI = 2.00–2.14).

Table 1.

Univariable and multivariable logistic regression analysis for BM risk factors (n = 203942)

Characteristics	Patient’s number (2010–2017)			Univariable logistic		Multivariable logistic
	BM	Total	Incidence (%)	OR (95% CI)	P	OR (95% CI)	P
Age (years)
< 60	10352	46612	22.21	1.00		1.00
60–69	12835	67306	19.07	0.83 (0.80–0.85)	< 0.001*	0.94 (0.91–0.97)	< 0.001*
70–79	10216	62132	16.44	0.69 (0.67–0.71)	< 0.001*	0.86 (0.83–0.89)	< 0.001*
≥ 80	4322	27892	15.50	0.64 (0.62–0.67)	< 0.001*	0.81 (0.78–0.85)	< 0.001*
Sex
Female	16429	98773	16.6	1.00		1.00
Male	21296	105169	20.2	1.27 (1.24–1.30)	< 0.001*	1.27 (1.24–1.30)	< 0.001*
LC site
Upper lobe	18674	109015	17.1	1.00		1.00
Lower lobe	9520	55388	17.2	1.00 (0.98–1.03)	0.768	1.08 (1.05–1.11)	< 0.001*
Middle lobe	1528	9362	16.3	0.94 (0.89–1.00)	0.05	1.02 (0.96–1.08)	0.540
Main bronchus	1913	8448	22.6	1.42 (1.34–1.49)	< 0.001*	1.06 (1.00–1.13)	0.053
Overlapping lesion	379	2215	17.1	1.00 (0.89–1.12)	0.981	0.88 (0.78–0.99)	0.041*
NOS	5711	19514	29.3	2.00 (1.93–2.07)	< 0.001*	1.15 (1.09–1.20)	< 0.001*
LC laterality
Left	15038	81832	18.4	1.00		1.00
Right	20312	115193	17.6	0.95 (0.93–0.97)	< 0.001*	0.92 (0.90–0.95)	< 0.001*
Bilateral	654	1840	35.5	2.45 (2.22–2.70)	< 0.001*	0.89 (0.80–1.00)	0.051
NOS	1721	5077	33.9	2.28 (2.14–2.42)	< 0.001*	0.96 (0.89–1.04)	0.299
LC histology
Squamous cell carcinoma	5231	48681	10.7	1.00		1.00
Adenocarcinoma	20444	99228	20.6	2.16 (2.09–2.23)	< 0.001*	2.07 (2.00–2.14)	< 0.001*
Small cell carcinoma	5943	24857	23.9	2.61 (2.51–2.72)	< 0.001*	1.04 (1.00–1.09)	0.074
Other	3430	20020	17.1	1.72 (1.64–1.80)	< 0.001*	1.35 (1.29–1.43)	< 0.001*
NSCLC, NOS	2677	11156	24.0	2.62 (2.49–2.76)	< 0.001*	1.71 (1.62–1.81)	< 0.001*
LC differentiation
Well	659	14155	4.7	1.00		1.00
Moderately	3519	40668	8.7	1.94 (1.78–2.11)	< 0.001*	1.77 (1.62–1.93)	< 0.001*
Poorly	9661	60680	15.9	3.88 (3.58–4.21)	< 0.001*	2.74 (2.52–2.99)	< 0.001*
Unknown	23886	88439	27.0	7.58 (7.00–8.21)	< 0.001*	4.36 (4.01–4.74)	< 0.001*
T stage
T1	2788	33091	8.4	1.00		1.00
T2	6390	43413	14.7	1.88 (1.79–1.97)	< 0.001*	1.38 (1.31–1.45)	< 0.001*
T3	6366	29963	21.2	2.93 (2.80–3.08)	< 0.001*	1.58 (1.49–1.66)	< 0.001*
T4	8720	33142	26.3	3.88 (3.71–4.06)	< 0.001*	1.69 (1.61–1.78)	< 0.001*
Unknown	13461	64333	20.9	2.88 (2.75–3.00)	< 0.001*	1.64 (1.54–1.74)	< 0.001*
N stage
N0	5209	62045	8.4	1.00		1.00
N1	2235	13449	16.6	2.18 (2.06–2.29)	< 0.001*	1.64 (1.54–1.73)	< 0.001*
N2	12831	52041	24.7	3.57 (3.45–3.70)	< 0.001*	2.05 (1.97–2.13)	< 0.001*
N3	6031	19663	30.7	4.83 (4.63–5.03)	< 0.001*	2.28 (2.18–2.39)	< 0.001*
Unknown	11419	56744	20.1	2.75 (2.65–2.85)	< 0.001*	1.59 (1.50–1.68)	< 0.001*
Lung metastases
No	26361	174887	15.1	1.00		1.00
Yes	9997	26569	37.6	3.40 (3.31–3.50)	< 0.001*	1.98 (1.92–2.05)	< 0.001*
Unknown	1367	2486	55.0	6.88 (6.35–7.46)	< 0.001*	2.60 (2.36–2.86)	< 0.001*
Liver metastases
No	25=818	181558	14.2	1.00		1.00
Yes	11019	21032	52.4	6.64 (6.44–6.84)	< 0.001*	4.53 (4.38–4.69)	< 0.001*
Unknown	888	1352	65.7	11.5 (10.3–12.9)	< 0.001*	3.78 (3.31–4.31)	< 0.001*
Brain metastases
No	27728	176150	15.7	1.00		1.00
Yes	9054	26513	34.1	2.78 (2.70–2.86)	< 0.001*	1.59 (1.54–1.64)	< 0.001*
Unknown	943	1279	73.7	15.0 (13.3–17.0)	< 0.001*	4.54 (3.92–5.25)	< 0.001*

^*Statistically significant

Abbreviations: LC lung cancer, BM bone metastases, NOS not otherwise specified. NSCLC non-small cell lung cancer, OR odds ratio, CI confidence interval

As shown in Fig. 2, an individualized nomogram was established for BM risk estimation and stratification. The nomogram incorporated a patient’ age, sex, LC site, laterality, histology, differentiation, T stage, N stage, lung metastasis, liver metastasis, and brain metastasis status. A patient with a BM probability more than 70% was considered as high-risk individual while that less than 70% was considered as low-risk individual. As shown in Fig. 3, internal validation by ROC and calibration curves demonstrated that the nomogram had a good predictive performance for BM risk estimation (AUC = 0.784, 95%CI = 0.781–0.786).

Fig. 2.

An individualized nomogram for predicting BM risk. A specific LC patient’s BM risk can be estimated by adding the points from each variable and vertically projecting the total points on the BM probability scale. A BM probability more than 70% is considered as high-risk while that less than 70% is considered low-risk. Abbreviations: LC, lung cancer; BM, bone metastasis

Fig. 3.

ROC curve with reported AUC and calibration curve to display the nomogram predictive performance for BM risk. Abbreviations: ROC, receiver operator characteristic curve; AUC, area under the curve

Survival and prognostic factors of LC-BM patients

Overall, the median OS time of LC-BM patients was 5.0 (4.91–5.09) months in SEER cohort. As shown in Supplementary Fig. 2, poor prognosis was more common in older patients, males, LC in overlapping lesions/main bronchus, bilateral LC, squamous and small cell carcinoma, poorly/undifferentiated LC, LC with higher T and N stages, LC with other organs metastases, patients without LC surgery, and patients without metastases surgery. OS did not differ between patients with BM with and without BM surgery.

Cox regression analyses revealed that powerfully independent prognostic factors included older age (HR = 1.66, 95% CI = 1.59–1.72) followed by poorly/undifferentiated LC (HR = 1.33, 95% CI = 1.22–1.46), liver metastases (HR = 1.29, 95% CI = 1.25–1.32), brain metastases (HR = 1.20, 95% CI = 1.16–1.23), and males (HR = 1.18, 95% CI = 1.15–1.21) (Table 2). To encourage the use of 3PM, an individualized nomogram was also accordingly constructed to predict a specific LC-BM patient’s survival rate (Supplementary Fig. 3).

Table 2.

Univariable and multivariable Cox regression analysis for LC-BM patient’s survival (n = 33093)

Characteristics	Patient’s number (2010–2016)			Median OS time (95% CI), months	Univariable Cox		Multivariable Cox
	Total	All-cause deaths	Death rate (%)		HR (95% CI)	P	HR (95% CI)	P
Age (years)
< 60	9217	8351	90.6	7 (6.78–7.22)	1.00		1.00	-
60–69	11206	10354	92.4	6 (5.82–6.18)	1.13 (1.10–1.16)	< 0.001*	1.14 (1.11–1.18)	< 0.001*
70–79	8899	8390	94.3	5 (4.84–5.16)	1.30 (1.26–1.34)	< 0.001*	1.33 (1.29–1.38)	< 0.001*
≥ 80	3771	3635	96.4	3 (2.83–3.17)	1.55 (1.49–1.61)	< 0.001*	1.65 (1.58–1.72)	< 0.001*
Sex
Female	14359	13087	91.1	6 (5.83–6.17)	1.00		1.00	-
Male	18734	17643	94.2	5 (4.89–5.11)	1.20 (1.17–1.23)	< 0.001*	1.18 (1.15–1.21)	< 0.001*
LC site
Upper lobe	16340	15107	92.5	6 (5.85–6.15)	1.00		1.00	-
Lower lobe	8343	7700	92.3	5 (4.80–5.20)	1.01 (0.98–1.04)	0.578	1.00 (0.98–1.03)	0.794
Middle lobe	1323	1215	91.8	6 (5.43–6.57)	0.96 (0.91–1.02)	0.179	0.96 (0.90–1.01)	0.129
Main bronchus	1679	1589	94.6	5 (4.57–5.43)	1.15 (1.09–1.21)	< 0.001*	1.09 (1.04–1.15)	0.001*
Overlapping lesion	331	315	95.2	5 (3.98–6.03)	1.18 (1.05–1.32)	< 0.001*	1.16 (1.04–1.30)	0.008*
NOS	5077	4804	94.6	4 (3.79–4.21)	1.17 (1.13–1.20)	< 0.001*	1.14 (1.09–1.18)	< 0.001*
LC laterality
Left	13149	12183	92.7	6 (5.85–6.15)	1.00		1.00	-
Right	17836	16558	92.8	5 (4.88–5.12)	1.03 (1.00–1.05)	0.040*	1.02 (1.00–1.05)	0.05
Bilateral	597	559	93.6	4 (3.46–4.54)	1.15 (1.06–1.25)	0.001*	1.01 (0.92–1.11)	0.819
NOS	1511	1430	94.6	4 (3.61–4.39)	1.15 (1.09–1.22)	0.001*	1.01 (0.94–1.07)	0.842
LC histology
Squamous cell carcinoma	4604	4410	95.8	4 (3.86–4.15)	1.00		1.00
Adenocarcinoma	17826	16111	90.4	6 (5.84–6.16)	0.68 (0.66–0.71)	< 0.001*	0.72 (0.69–0.74)	< 0.001*
Small cell carcinoma	5218	5074	97.2	7 (6.80–7.20)	0.84 (0.81–0.87)	< 0.001*	0.77 (0.74–0.81)	< 0.001*
Other	3031	2848	94.0	4 (3.77–4.23)	0.91 (0.87–0.95)	< 0.001*	0.89 (0.85–0.94)	< 0.001*
NSCLC, NOS	2414	2287	94.7	4 (3.76–4.24)	0.91 (0.86–0.95)	< 0.001*	0.91 (0.86–0.96)	< 0.001*
LC differentiation
Well	595	533	89.6	9 (7.71–10.3)	1.00		1.00	-
Moderately	3144	2849	90.6	7 (6.56–7.44)	1.09 (0.99–1.19)	0.081	1.07 (0.98–1.18)	0.134
Poorly	8634	8083	93.6	5 (4.85–5.15)	1.44 (1.32–1.57)	< 0.001*	1.34 (1.22–1.46)	< 0.001*
Unknown	20720	19265	93.0	5 (4.89–5.12)	1.34 (1.23–1.47)	< 0.001*	1.25 (1.15–1.37)	< 0.001*
T stage
T1	2788	2592	93.0	7 (6.57–7.43)	1.00		1.00	-
T2	6390	6069	95.0	6 (5.77–6.23)	1.15 (1.10–1.20)	< 0.001*	1.09 (1.04–1.14)	< 0.001*
T3	6366	6061	95.2	5 (4.80–5.20)	1.23 (1.18–1.29)	< 0.001*	1.14 (1.09–1.19)	< 0.001*
T4	8720	8365	95.9	5 (4.82–5.18)	1.27 (1.21–1.32)	< 0.001*	1.16 (1.11–1.21)	< 0.001*
Unknown	8829	7643	86.6	5 (4.83–5.18)	1.19 (1.14–1.24)	< 0.001*	1.12 (1.07–1.18)	< 0.001*
N stage
N0	5209	4848	93.1	6 (5.72–6.28)	1.00		1.00	-
N1	2235	2117	94.7	5 (4.61–5.39)	1.10 (1.04–1.15)	< 0.001*	1.08 (1.03–1.14)	0.003*
N2	12831	12311	95.9	5 (4.86–5.14)	1.20 (1.16–1.24)	< 0.001*	1.15 (1.11–1.19)	< 0.001*
N3	6031	5767	95.6	6 (5.76–6.24)	1.15 (1.11–1.19)	< 0.001*	1.10 (1.06–1.15)	< 0.001*
Unknown	6787	5687	83.8	5 (4.79–5.21)	1.10 (1.06–1.14)	< 0.001*	1.04 (0.99–1.09)	0.128
Lung metastases
No	23054	21329	92.5	6 (5.88–6.12)	1.00		1.00	-
Yes	8756	8179	93.4	5 (4.81–5.19)	1.08 (1.05–1.10)	< 0.001*	1.03 (1.00–1.06)	0.062
Unknown	1283	1222	95.2	5 (4.57–5.43)	1.10 (1.04–1.16)	0.002*	0.98 (0.92–1.05)	0.542
Liver metastases
No	22616	20683	91.5	6 (5.87–6.13)	1.00		1.00	-
Yes	9668	9266	95.8	4 (3.84–4.16)	1.33 (1.29–1.36)	< 0.001*	1.29 (1.26–1.32)	< 0.001*
Unknown	809	781	96.5	5 (4.47–5.53)	1.21 (1.12–1.29)	< 0.001*	1.13 (1.03–1.23)	0.007*
Brain metastases
No	24406	22626	92.7	6 (5.88–6.12)	1.00		1.00	-
Yes	7821	7279	93.1	5 (4.83–5.17)	1.09 (1.06–1.12)	< 0.001*	1.17 (1.14–1.20)	< 0.001*
Unknown	866	825	95.3	4 (3.55–4.45)	1.16 (1.08–1.24)	< 0.001*	1.09 (1.01–1.19)	0.032*
Surgery of LC
No	32448	30194	93.1	5 (4.91–5.09)	1.00	-	1.00	-
Yes	599	493	82.3	10 (8.49–11.5)	0.59 (0.54–0.64)	< 0.001*	0.66 (0.60–0.72)	< 0.001*
Unknown	46	43	93.5	3 (1.10–4.90)	1.23 (0.91–1.65)	0.184	1.07 (0.64–1.78)	0.795
Surgery of metastases
No	31349	29133	92.9	5 (4.91–5.09)	1.00		1.00
Yes	1699	1554	91.5	5 (4.57–5.43)	0.92 (0.88–0.97)	0.002*	0.98 (0.93–1.03)	0.450
Unknown	45	43	95.6	3 (1.03–4.97)	1.24 (0.92–1.67)	0.157	1.18 (0.71–1.96)	0.535

Abbreviations: OS overall survival, LC lung cancer, BM bone metastases, NOS not otherwise specified, HR hazard ratio, CI confidence interval

^*Statistically significant

LC-BM clinical and laboratory characteristics in FUSCC

Patient’s baseline characteristics in FUSCC cohort were presented in Table 3. Back pain (91.5%) was the most common symptom causing hospitalization, including lumbar back pain (40.7%), chest back pain (23.7%), and lumbar back pain with radiation to the lower limb (22.0%) and neck pain (5.1%). Other common symptoms and signs included lower limbs numbness (18.6%), vertebral body pathological fracture (27.1%), walking difficultly (25.4%), and lower limbs paraplegia (8.5%). Approximately 79.7% of BM was synchronously multiple lesions. The most common BM surgical location was the thoracic vertebra (52.5%), followed by the lumber (35.6%) and cervical vertebra (5.1%).

Table 3.

Clinical and laboratory characteristics of patients undergoing BM surgery in FUSCC (n = 59)

Characteristics	Value
Age (years), mean ± SD	61.1 ± 9.2
≤ 49	6 (10.2)
50–59	20 (33.9)
60–69	21 (35.6)
≥ 70	12 (20.3)
Gender
Female	28 (47.5)
Male	31 (52.5)
BMI (Kg/m2), mean ± SD	23.2 ± 3.3
Smoking	12 (20.3)
excessive drinking	8 (13.6)
Symptoms and signs at admission
Back pain	54 (91.5)
Location of the pain
Lumbar back pain	24 (40.7)
Lumbar back pain with radiation to lower limb	13 (22.0)
Chest back pain	14 (23.7)
Neck pain	3 (5.1)
Numbness of the lower limbs	11 (18.6)
Pathological fracture of vertebral body	16 (27.1)
Difficultly walking	15 (25.4)
Lower limb paraplegia	5 (8.5)
Number of BM lesions
Single	12 (20.3)
Multiple	47 (79.7)
Surgical location of BM lesions
Cervical vertebra	3 (5.1)
Thoracic vertebra	31 (52.5)
Lumber vertebra	21 (35.6)
Sacral vertebra	1 (1.7)
Femur	2 (3.4)
Humerus	1 (1.7)
Histology of LC
Adenocarcinoma	38 (64.4)
Squamous cell carcinoma	7 (11.9)
Small cell carcinoma	3 (5.1)
Not otherwise specified	11 (18.6)
Liver metastasis	4 (6.8)
Brain metastasis	9 (15.3)
Previous treatments
Surgery of LC	15 (25.4)
Chemo-radiotherapy	20 (32.2)
Targeted therapy (EGFR-TKIs)	16 (25.4)
Blood routine tests on admission, mean ± SD
Leucocytes (× 109/L; normal range 3.5 ~ 9.5)	7.4 ± 3.6
Increased	11 (18.6)
Neutrophils percentage (%; normal range 40 ~ 75)	70.1 ± 10.6
Increased	16 (27.1)
Lymphocytes percentage (%; normal range 20 ~ 50)	21.2 ± 8.9
Decreased	26 (44.1)
Monocytes percentage (%; normal range 3 ~ 10)	6.3 ± 2.1
Increased	1 (1.7)
Decreased	4 (6.8)
Platelets (× 109/L; normal range 125 ~ 350)	232.2 ± 74.1
Increased	5 (8.5)
Decreased	4 (6.8)
Neutrophil to lymphocyte ratio	5.2 ± 6.7
Hemoglobin (g/L; normal range 130.0–175.0)	126.7 ± 16.4
Anemia	12 (20.3)
Biochemical tests on admission, mean ± SD
ALP (U/L; normal range 45–125)	127.1 ± 84.8
Increased	19 (32.2)
Decreased	1 (1.7)
LDH (U/L; normal range 120–250)	232.3 ± 147.6
Increased	14 (23.7)
Decreased	3 (5.1)
ALT (U/L; normal range 9–50)	31.1 ± 35.5
Increased	9 (15.3)
Decreased	5 (8.5)
AST (U/L; normal range 15–40)	27.8 ± 29.1
Increased	6 (10.2)
Decreased	12 (20.3)
TBIL (umol/L; normal range 3.4–17.1)	10.2 ± 5.0
Increased	4 (6.8)
Total protein (g/L; normal range 65–85)	68.7 ± 4.5
Decreased	12 (20.3)
Albumin (g/L; normal range 40–55)	40.8 ± 4.8
Decreased	28 (47.5)
Prealbumin (mg/L; normal range 250–400)	253.6 ± 60.8
Decreased	25 (42.4)
Globulin (g/L; normal range 20–40)	28.4 ± 3.3
Ca2+ (mmol/L; normal range 2.11–2.52)	2.23 ± 0.11
Decreased	8 (13.6)

Abbreviations: BM bone metastases, LC lung cancer, BMI body mass index, EGFR-TKIs epidermal growth factor receptor-tyrosine kinase inhibitors, ALP alkaline phosphatase, LDH lactate dehydrogenase, ALT alanine transaminase, AST aspartate aminotransferase, TBIL total bilirubin, SD standard deviation

Adenocarcinoma was the main LC type (71.9%). Approximately 25.4% of patients underwent LC surgery, 32.2% underwent chemo-radiotherapy, and 25.4% underwent targeted therapy (EGFR-TKIs). Before BM surgery, 27.1% of patients had elevated neutrophil levels, 44.1% had decreased lymphocyte levels, and 20.3% had anemia. Low nutrition status was common in LC-BM patients, with 20.3% having decreased total protein, 47.5% having low albumin in, and 42.4% having reduced pre-albumin. ALP levels were elevated in 32.2% of patients. No hypercalcemia was found in the patients.

LC-BM limb surgery

A representative LC-BM limb surgery was presented in Fig. 4A–I. A female patient aged 62 had a pulmonary nodule (Fig. 4A) and presented left medial thigh pain for 1 week. An X-ray revealed a low-density mass in the middle of the left femur (Fig. 4B). After anesthesia, the incision (5 cm) was made above the tip of the left femur greater trochanter, passing through the lateral side of the thigh and the patella to the upper tibia (Fig. 4C). Then, the skin and subcutaneous tissues were incised to expose the proximal femur and hip joint. The separation was performed toward the gluteus medius fibers direction. Vastus lateralis muscle at the great trochanter basolateral margin was separated (Fig. 4D). The femoral neck and anterior articular capsule were sufficiently exposed, and the femoral head was removed using a head extractor. The right knee capsule was cut open, the cruciate ligament was cut off, and the meniscus was removed. Next, the vastus intermediates muscle and the whole femur involving the metastasis were removed (Fig. 4E). Then, the knee, femoral head, and femoral shaft prosthesis were installed (Fig. 4F). The strength line and flexion and extension function were confirmed to be satisfactory. The surgical lower extremity was as long as the contralateral normal lower extremity. Finally, the wound was washed and sutured layer by layer, with drainage tubes places (Fig. 4G). Postoperative X-ray showed a satisfactory prosthesis implantation surgery effect (Fig. 4H and I).

Fig. 4.

Personalized LC-BM limb surgery procedure. A X-ray shows that the primary pulmonary nodule (23 mm) is located in the right lower lung lobe (arrow indicated), with spicules of margin and pleural indentation; B X-ray shows a low-density mass in the medullary cavity of the middle left femur, with damage of cortical bone and rough thickening of local periosteum; C preoperative body surface marking; D exposure of femur lesions and soft tissues that need to be removed; E measurement of the resected specimen of femur tumor; F installation of knee joint prosthesis, femoral head prosthesis, and femoral shaft prosthesis; G drainage tubes with negative pressure are placed, and the wound is sutured layer by layer; H and I postoperative X-ray shows a satisfactory prosthesis implantation

PVP for LC spinal metastasis

The clinical characteristics of patients undergoing PVP were presented in Table 4. PVP was recommended for (1) patients experiencing severe pain due to vertebral body deformation; (2) patients with no nerve root compression; and (3) patients with poor body conditions who cannot tolerate open surgery. A representative PVP in FUSCC was presented in Fig. 5. A 67-year-old female patient was diagnosed with multiple LC metastatic spinal tumors. Preoperative MRI and CT scans showed L2, L4, and L5 metastases (Fig. 5A–E). After anesthesia, the bilateral vertebral pedicle body surface projection points of L2 and L4 were located and punctured (Fig. 5F). Puncture needles were located in L2 and L4 vertebral bodies under C-arm fluoroscopy (Fig. 5G and H). A working channel was placed through the guide needle. Then, bone cement (4–5 mL) was pushed into the vertebral body (Fig. 5I and J). C-arm fluoroscopy revealed adequate bone cement diffusion. Finally, the puncture needles were pulled out after the bone cement had hardened. A similar PVP operation performed for L5 (Fig. 5K-O). Postoperative X-rays revealed a good surgical effect of bone cement dispersion in L2, L4, and L5 (Fig. 5P and Q).

Table 4.

Perioperative characteristics and surgical effects of patients receiving PVP and separation surgery/TES in FUSCC (n = 56)

Characteristics	Minimally invasive PVP	Separation surgery/TES
Age	54.5 ± 11.1	62.8 ± 8.3
Male	4 (36.4)	25 (55.6)
BMI (kg/m2)	25.1 ± 4.0	22.9 ± 3.0
Tomita score	6.1 ± 0.7	5.8 ± 0.7
ASA grade
I	7 (63.6)	13 (28.9)
П/Ш	4 (36.4)	32 (71.1)
Duration of surgery (min)	69 (60–118)	157.5 (115.8–188.3)
Volume of blood loss (mL)	10 (10–10)	1000 (650–1550)
Blood transfusion	0 (0)	31 (68.9)
Length of hospital stay (days)	4 (2–7)	11 (7–15.5)
Surgical cost (¥)	6871.0 ± 1658.0	11,686.0 ± 2324.0
Pain (NRS scale)
Preoperative	5.0 ± 0.9	4.8 ± 1.3
Postoperative or follow-up	0.5 ± 0.8	1.2 ± 1.0
P	0.001*	< 0.001*
Walk on level ground (Barthel scale)
Preoperative	14.1 ± 2.0	8.9 ± 5.0
Postoperative or follow-up	14.6 ± 1.5	13.7 ± 3.1
P	> 0.999	< 0.001*
Climb stairs (Barthel scale)
Preoperative	9.1 ± 2.0	5.1 ± 3.9
Postoperative or follow-up	9.5 ± 1.5	8.3 ± 3.0
P	> 0.999	< 0.001*

Abbreviations: PVP percutaneous vertebroplasty, TES total en bloc spondylectomy, BMI body mass index, ASA American Society of Anesthesiologists, NRS numerical rating scale

^*Statistically significant

Walk on level ground measured by Barthel scale: 15, full independence; 10, need of some help; 5, need of much help; 0, full dependence

Climb stairs measured by Barthel scale: 10, full independence; 5, need of some help; 0, need of much help

Fig. 5.

Personalized percutaneous vertebroplasty (PVP) procedure. A and B Preoperative sagittal MRI and CT scans show L4 and L5 involvement (low signal on T1WI and slightly high signal on T2WI); C–E preoperative transverse CT scans show L2, L4, and L5 involvements; F preoperative body surface location of L2, L4, and L5; G and H C-arm fluoroscopy shows that puncture needles are located in L2 and L4 vertebrae; I and J bone cement is injected into the vertebral bodies of L2 and L4; K and L C-arm fluoroscopy shows that puncture needles are located in L5 vertebra; M and N bone cement is injected into L5; O C-arm fluoroscopy shows good dispersion of bone cement in L2, L4, and L5; P and Q postoperative X-ray shows a good dispersion of bone cement in L2, L4, and L5

The median PVP time was 69 (60–118) min, with a median blood loss of 10 mL. No bone cement leakage-related symptoms were recorded. The pain was significantly relieved after PVP [NRS score: (0.5 ± 0.80) vs. (5.0 ± 0.9), P < 0.05]. The PVP preoperative and postoperative activities in the group (walk on level ground and climb stairs) were both nearly in full independence (Table 4).

Separation surgery and TES for LC metastatic spinal tumors

The clinical characteristics of patients receiving separation surgery/TES were presented in Table 4. A representative separation surgery in FUSCC was presented in Fig. 6A–I. A male patient aged 63 was admitted to hospital due to lumbar back pain for 1 month. His pain aggravated when he bent down, accompanied by right lower limb pain and numbness. He had a lung adenocarcinoma resection history 2 years ago. Preoperative MRI and CT scan suggested L4 metastasis with a compression fracture, with T12, L1, and L2 metastasis (Fig. 6A–E). After anesthesia, a posterior median longitudinal incision was performed from T12 to the 1st sacrum. The spinous process, bilateral lamina, facet joint, and transverse process from T12 to the 1st sacrum were well exposed. Five bone-cemented-pedicle screws were placed on L2 and L5 bilateral pedicles and L3 right pedicle (Fig. 6F). Bone cement was similarly injected into T12 and L1. Then the spinous process, bilateral lamina, and L3-4left facet joint were resected to expose the dural sac at the L3–4 level. The left connecting rod was installed with a temporary pull open (Fig. 6G). Next, with careful bilateral lumbar nerve roots protection, the metastatic LC and its eroded bone and soft tissues were piecemeal completely resected under a magnifying glass. The space between the dura and the tumor was sufficiently large to favor postoperative radiotherapy. The L4 body residual lumen was tamped with bone cement. The right connecting rod and the cross-connection were installed. Postoperative X-ray showed a good surgical effect of the internal fixation and bone cement dispersion (Fig. 6H and I).

Fig. 6.

Personalized separation surgery and TES procedures. A and B Preoperative sagittal MRI and CT scans show L4 metastasis with compression fracture, with T12, L1, and L2 involvements (high signal on T2WI and low signal on T1WI); C–E preoperative transverse CT scans show that the right appendage and vertebral body of L4 are eroded by tumor tissues. Bone destruction and multiple osteolytic lesions are visible; F installation of bone cement injection system; G the dural sac at the L3–4 level is well exposed to piecemeal resect the metastasis and its eroded bone and soft tissues; H and I postoperative X-ray shows a good internal fixation and bone cement dispersion in T12, L1, L2, and L4. J and K preoperative sagittal MRI and CT scans show T8 metastasis with pathological fracture. BM protruded into the spinal canal and compacted the dural sac; L preoperative PET-CT shows an increased SUVmax of the T8 vetebra; M preoperative transverse CT shows the right appendage and vertebral body of T8 involvement; N pedicle screws are placed bilaterally at T6–7 and T9–10; O the right intervertebral discs (T7–8 and T8–9) are dissected, and the right connecting rod is installed, so are the left intervertebral discs; P measurement of the resected T8 metastasis; Q and R postoperative X-ray shows a good surgical effect of the internal fixation and the artificial vertebral body. Abbreviation: TES, total en bloc spondylectomy; PET-CT, positron emission tomography-computed tomography; SUVmax, maximum standard uptake value

A representative TES in FUSCC was presented in Fig. 6J–R. A female patient aged 55 was admitted to hospital due to chest back pain for 3 months. Preoperative MRI, CT, and PET-CT scans showed T8 vertebral body pathological fracture, with an increased SUVmax (Fig. 6J–M) and no other vertebra metastasis. After anesthesia, a posterior median longitudinal incision was performed using T8 as the midpoint. The spinous process, bilateral lamina, and zygapophyses of T6–10 were well exposed. Pedicle screws were placed bilaterally at T6–7 and T9–10 (Fig. 6N), and then the ribs were exposed to both sides along the T8 transverse process (about 3 cm). The spinous process, bilateral lamina, and ligamentum flavum of T7 were removed to expose the dural sac and intervertebral foramen at T7–8 level. The T8 adnexa structure was resected to expose the dural sac at T7–9 level. After the upper and lower T8 intervertebral discs were determined, the annulus fibrosus and the posterior longitudinal ligament were cut. The right intervertebral discs (T7–8 and T8–9) were dissected, and the right connecting rod was installed, as well as the left intervertebral discs (Fig. 6O). T8 was completely removed under careful protection of spinal cord and nerve roots (Fig. 6P). An artificial vertebral body was installed between T7 and T9. Finally, the bilateral connecting rods with cross-connection were installed. Postoperative X-ray showed a good surgical effect of the internal fixation and the artificial vertebral body (Fig. 6Q and R).

The resected T8 vertebra was sent for pathological examination. HE staining showed wide adenocarcinoma tissues around the bone tissues. IHC staining [TTF-1 ( +), Napsin A ( +), CK7 ( +), CK AE1/AE3 ( +), p53 ( −), WT-1 ( −), CK20 ( −), CDX2 ( −), GATA3 ( −), HNF1β ( ±), and PAX8 ( −)] verified the lung adenocarcinoma origin (Fig. 7A–L).

Fig. 7.

Pathological immunophenotype of the resected BM (T8 vertebra). A HE Staining showing the adenocarcinoma tissues (red arrow) and the bone tissues (black arrow); B-D the positive expressions of TTF-1, Napsin A, and CK7 are currently the best combination indicating an origin of lung adenocarcinoma (TTF-1 and Napsin A are generally positive in 80% of lung adenocarcinoma, and CK7 is nearly positive in all lung adenocarcinoma); E positive CK (AE1/AE3) expression indicated carcinoma instead of sarcoma; F negative p53 expression indicated an unlikely squamous carcinoma; G negative WT-1 expression indicated an unlikely origin of mesothelioma; H and I negative CK20 and CDX2 expression indicated an unlikely origin of colorectal cancer; J negative GATA-3 expression indicated an unlikely origin of breast cancer; K and L negative HNF-1β and PAX8 expression indicated an unlikely origin of ovary and thyroid

The median separation surgery/TES time in FUSCC was 223 (176–265) min. A median blood loss was 1000 mL, and 68.9% of the patients received intraoperative blood transfusion. Patients undergoing open surgery obtained ambulation improvement at hospital discharge, which generally takes 11 days. LC-specific mortality instead of SREs was the main causes of death, such as dyspnea, chest fluid, hemoptysis, and multiple organ failure. The median survival time of FUSCC cohort was 11 (6–14) months. During the survival, pain was significantly relieved [(1.2 ± 1.0) vs. (4.8 ± 1.3), P < 0.05], and walking ability on the level ground was significantly improved [(13.7 ± 3.1) vs. (8.9 ± 5.0), P < 0.05]. Ability to climb stairs was also significantly improved [(8.3 ± 3.0) vs. (5.1 ± 3.9), P < 0.05] (Table 4).

Comparisons between BM open surgery and minimally invasive PVP on inflammation, immune, and nutrition status were presented in Supplementary Fig. 4. For patients undergoing PVP, inflammatory markers such as leucocytes, neutrophils, and NLR were significantly increased after PVP. Lymphocytes percentage significantly decreased after PVP. Hemoglobin and total protein were not significantly changed. For patients undergoing separation surgery/TES, inflammatory markers such as leucocytes, neutrophils, and NLR were significantly increased after surgery. Lymphocytes percentage was significantly decreased after surgery, as well as the hemoglobin and total protein.

Discussion

PPPM from cancer systematic biology to imageology

PPPM can be applied to many cancer care fields, such as prostate cancer [21], colorectal cancer [22], and breast cancer [23]. For instance, Kucera and colleagues [21] suggested that PPPM-based liquid biopsy tests and multi-omics phenotyping and genotyping are instrumental for prostate cancer diagnosis and prevention. Colorectal cancer is characterized by various genetic alterations, such as KRAS and BRAF mutations. An integrative PPPM viewpoint by Hagan et al. considered that those molecular mutations found in colorectal cancer can guide targeted treatments such as anti-EGFR therapy and estimate the patient’s prognosis in the future [22]. Therefore, it is interesting to characterize LC-BM using PPPM-based principles. Cheng T and Zhan X [24] considered that PPPM could explain cancer pathophysiological processes from systematic biology to radiomics and metabolomics. In the case of cancer cells, the bone is a convenient metastasis destination. LC-BM is a multi-step process that includes the following steps: First, circulating LC cells settle in the bone microenvironment and become dormant to avoid being attacked by the body’s immune system; second, dormant LC cells re-activate and initiate proliferation, resulting in large metastatic lesions; Lastly, LC cells disrupt the dynamic balance between osteoblasts and osteoclasts, causing bone resorption and osteolytic lesions [25–27]. Besides the classical “seed and soil” theory, “pre-metastatic niches” should be noted in cancer metastasis [23], especially in BM. In our study, the LC-BM X-ray revealed a worm-eaten type of bony defect with an obscure and irregular boundary. CT and MRI images revealed BM size, range, and adjacent tissues which are crucial to preoperative assessment. PET-CT has high sensitivity and specificity (both > 90%) for LC-BM diagnosis [28]. In our study case, metastatic LC at T8 vertebrae highly took in fluorodeoxyglucose (FDG). The T8 malignant BM was easily identified as hyper-metabolic on PET-CT.

Predictive factors and target population for prevention

The timing of diagnosis impacts LC-BM treatment and prognosis. The most common clinical examinations for BM diagnosis, according to standard guidelines, are X-ray, radionuclide bone scanning (ECT), CT, and MRI. Regardless, BM is frequently discovered when bone-related symptoms and signs (SREs) are severe. In most cases, LC-BM patients have advanced metastasis, with multiple BM lesions. It is important to predict BM risk and thus early diagnosis of BM in LC patients. In this study, we identified that liver metastasis is a strong BM predictor in LC patients. This might be because liver metastasis is a key indicator of cancer cells entering veins, which are the primary pathways for LC cells to reach the bones. Additionally, we discovered that liver metastasis is linked to a poor prognosis. Young male patients, those with more invasive LC, and distant site metastases should be considered key populations for BM prevention. Few previous SEER studies included metastasis surgery in the survival analysis [29, 30]. Our study discovered that BM surgery did not improve LC-BM patients’ survival in SEER cohort. This might be due to the high malignant biological behavior of LC when compared to breast and prostate cancers. PPPM plays an important role in cancer patients’ targeted prevention. The time interval of medical examinations should be narrowed in those patients to detect BM at early stage and prevent extensive metastasis.

PPPM in personalized surgery

PPPM has its unique meaning in surgery, such as preoperative planning, intraoperative execution, and postoperative management [31]. Prediction is reflected in the preoperative planning, such as PVP or open surgery/TES options. Prevention is reflected in intraoperative execution, such as preventing complications (e.g., bone cement leakage). In our study, the spine was the most common BM site causing SREs, owing to the abundance of venous plexuses surrounding the vertebrae [32]. Spinal structure is complex and variable once tumor involvement. It motivates us to develop patient-specific surgical plan and use personalized internal fixation. Those SREs significantly impact patients’ quality of life and can only be effectively treated surgically [33, 34]. The Tomita score is a simple and effective tool for predicting the prognosis of metastatic spinal tumors [35]. Spinal metastasis surgery requires an expected survival longer than 3 and even 6 months [36–38]. Our study discovered that the 3- and 6-month LC-BM survival rates improved significantly over time, indicating that an increasing number of LC-BM patients are candidates for BM surgery.

We demonstrated that the personalized PVP significantly reduced patients’ pain, with less blood loss, hospital stay length, and cost. The possible reasons for pain reduction after PVP include as follows: The injected bone cement stabilizes the fracture; bone cement and its thermogenesis destroy sensory nerve endings; and bone cement’s anti-tumor effects [39–41]. Bone cement leakage is a severe complication after PVP [42–45]. As demonstrated in our procedures, personalized strategies to prevent bone cement leakage included precisely controlled viscosity of bone cement and close monitoring of its distribution under X-ray.

In our study, besides pain relief, personalized separation surgery/TES significantly improved movement ability. Separation surgery mainly applies to patients with spinal cord or nerve roots compression and spinal instability and fracture [46]. It enlarges the space between BM and the spinal dural mater via a 360°-circular spinal cord decompression [47, 48]. In our study, individualized artificial vertebral body was used to match with bone defect as closely as possible. It should be noted that radiation is necessary after separation surgery to prevent a local recurrence [49, 50].

PPPM in personalized perioperative critical care

In our study, LC-BM patients had increased inflammation and decreased immune, nutritional, and hemoglobin levels before surgery. Since our institution is a specialized cancer center, many of the advanced patients have received comprehensive therapy before surgery. It is well known that malignancy itself and its associated systemic therapies significantly impact inflammation, immunity, anemia, and nutrition [51, 52]. We showed that the increased inflammation and decreased immune, nutrition, and hemoglobin levels aggravated after BM surgery strike. Therefore, personalized perioperative managements such as anti-inflammation and blood transfusion must be prepared to prevent vital organs injury.

Limitations and prospects

There are inevitably some limitations in our study. This study takes the first step to incorporate 3PM into LC-BM’s interdisciplinary problem. We recognize that, at present, there remains a long way to go before fully elucidating and managing LC-BM via PPPM. Nonetheless, we are confident that our current work contributes to the progression of 3PM and can guide LC-BM diagnosis and treatment paradigm to 3PM in a step-by-step fashion. Secondly, external validation is required for our existing nomogram. Inclusion of LC-BM patients from various centers is required to test and improve the nomogram’s predictive performance. Furthermore, an online nomogram is suggested for ease of use. Thirdly, radiation as a key adjuvant therapy after separation surgery, it also needs to be characterized via PPPM-based approaches. In the future, it is critical to conduct an independent study to understand PPPM-oriented radiation use in LC-BM patients.

Conclusions and recommendations

LC patients have a longer survival time due to rapid advancements in systemic therapy, but they are also exposed to more BM risk. The PPPM concept should be actively incorporated into BM-LC management including diagnosis, prevention, treatment, and prognosis. The term “cancer prevention” refers to a broad concept that encompasses three dimensions: primary prevention entails avoiding carcinogenic factors and lowering cancer incidence; secondary prevention involves early detection, diagnosis, and treatment of cancer to reduce cancer mortality; and tertiary prevention entails reducing and treating cancer recurrence and metastasis, as well as preventing complications and sequelae. The current LC-BM study is primarily concerned with secondary and tertiary prevention. The present study can help us predict a LC individual’s BM risk, identify a more targeted population for BM prevention, and provide a more personalized BM surgery experience (Fig. 8). From passive to active, PPPM shifts cancer diagnostic and therapeutic patterns [53]. With the help of PPPM, LC patients can prevent from BM and its associated SREs, predict BM risks and prognosis, and receive a personalized surgical treatment. PPPM principles should be sufficiently developed and applied throughout the LC-BM process from screening to surgical therapy. Moreover, PPPM also apply to investigate cancer molecular biology and immunology. In the future, PPPM-based strategies are expected to further manage LC-BM targeted therapy (EGFR-TKIs) and immune checkpoint therapy.

Fig. 8.

A schematic diagram showing 3PM-oriented LC-BM care pattern. BM predictors, key population for BM prevention, and personalized surgery experience and effects are well depicted. 3PM-based radiation use is the next focus. Abbreviations: LC, lung cancer; BM, bone metastasis; 3PM, predictive, preventative, and personalized medicine

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

BM

Bone metastasis

LC

Lung cancer

SREs

Skeletal-related events

SEER

Surveillance, Epidemiology, and End Results

FUSCC

Fudan University Shanghai Cancer Center

MDT

Multidisciplinary team

PVP

Percutaneous vertebroplasty

TES

Total en bloc spondylectomy

NOS

Not otherwise specified

NSCLC

Non-small cell lung cancer

OS

Overall survival

BMI

Body mass index

NRS

Numerical rating scale

CT

Computed tomography

MRI

Magnetic resonance imaging

ECT

Radionuclide bone scanning

PET-CT

Positron emission tomography-computed tomography

SUVmax

Maximum standard uptake value

ALP

Alkaline phosphatase

LDH

Lactate dehydrogenase

ALT

Alanine transaminase

AST

Aspartate aminotransferase

TBIL

Total bilirubin

ASA

American Society of Anesthesiologists

FDG

Fluorodeoxyglucose

HE staining

Hematoxylin–eosin staining

IHC

Immunohistochemistry

OR

Odds ratio

HR

Hazards ratio

CI

Confidence interval

ROC

Receiver operator characteristic curve

AUC

Area under the curve

Author contribution

Wangjun Yan and Yangbai Sun contributed to the study conception and design. Xianglin Hu, Wending Huang, Zhengwang Sun, Hui Ye, Kwong Man, and Qifeng Wang retrieved, analyzed, and interpreted the data. Xianglin Hu drafted the manuscript. Wangjun Yan and Yangbai Sun revised the manuscript. All authors read and approved the submission.

Funding

This work was supported by the National Natural Science Foundation of China (Number: 81872179; Recipients: Wangjun Yan).

Data availability

Data for the SEER cohort were extracted from the Surveillance, Epidemiology, and End Results Program (https://seer.cancer.gov/). Data for the FUSCC cohort were available from the corresponding authors upon appropriate request.

Code availability

Not applicable

Declarations

Ethics approval

This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center, Shanghai, 200032, China. All procedures performed in the study involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participate

Informed consent for participation in the FUSCC cohort was obtained in this study.

Consent for publication

All authors read and approved the submission.

Conflict of interest

The authors declare no competing interests.