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.

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

Keywords: Adjuvant radiation; Bone metastasis; Cancer; Lung cancer; Metastatic spinal tumors; Multidisciplinary team; Perioperative management; Personalization of medical services; Predictive factors; Predictive preventive personalized medicine (PPPM); Risk assessment; Surgery; Targeted prevention.

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

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

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

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

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

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

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