Introduction
Bone metastases can occur in virtually any type of primary malignancy. Advances in cancer therapy have led to prolonged survival in patients with cancer, resulting in a rising incidence of metastatic spinal tumors in recent years 1 ) . A major issue in managing spinal metastases is the occurrence of skeletal-related events (SREs), such as pathological fractures or neurological compromise due to epidural spinal cord compression (ESCC). The incidence of SREs among patients with spinal metastasis is reported to be around 2.5%-5.0% 2 , 3 ) . While SREs often occur in patients with an established cancer diagnosis, in 8%-34% of cases an SRE (e.g. spinal cord compression or pathological fracture) is the first manifestation of an underlying malignancy 4 , 5 ) . The onset of an SRE can lead to severe pain and paralysis, resulting in diminished quality of life and even reduced survival 6 ) . Historically, metastatic spinal tumors were not considered to significantly affect overall prognosis, and as a result, treatment for spinal metastases was often deferred until serious complications such as intractable pain, pathological vertebral fracture, or spinal cord compression had occurred 7 ) . In recent years, however, the importance of a proactive multidisciplinary approach to bone metastasis has been recognized 7 , 8 ) . Many institutions have established dedicated “cancer boards” that bring together tumor specialists, radiologists, orthopedic/spine surgeons, and other experts to collaborate on the management of patients with bone metastases 8 ) . Kimura et al. 7 ) described holding a cancer board every 2-4 weeks to coordinate multidisciplinary treatment for patients with bone metastasis. In such conferences, cases (selected by the primary oncology team) are reviewed for confirmation of metastatic diagnosis, pain control strategies, prognosis estimation, indications for radiotherapy or surgery, and other aspects of care―an approach reported to improve outcomes in bone metastasis management 8 ) . A limitation of this model is that some spinal metastasis cases may still go unaddressed if they are not brought forth by the primary physician in charge of the patient. At our hospital, we implemented a multidisciplinary “liaison treatment” system in which spine surgeons are directly involved in the care of all patients with metastatic spinal tumors within the institution 9 ) . In this system, whenever a radiologist identifies a suspected metastatic spinal lesion on imaging studies (e.g. computed tomography, magnetic resonance imaging [MRI], bone scintigraphy), all such cases are reported to the spine surgery service. The spine surgeons then review the images and assess spinal stability using the spinal instability neoplastic score (SINS) 10 ) . We consider a SINS of ≥7 as indicative of potential spinal instability. Any case meeting this criterion is flagged, and the primary oncologist is contacted. We subsequently hold a monthly liaison conference―with a spine surgeon serving as the navigator―involving all relevant specialists to formulate a comprehensive treatment plan. We initiated this liaison treatment approach in December 2013, and now, a decade later, we have observed that despite intervening in every identified metastatic spinal tumor case, some patients still developed SREs. The aim of this study was to analyze in detail those cases in which SRE occurred despite the liaison system, and to identify factors that could help prevent SREs, especially in patients referred from outside institutions.
Methods
We retrospectively reviewed all cases of SRE among patients with metastatic spinal tumors at our hospital over a 10-year period (December 2013-December 2023). An SRE was defined as a SRE due to spinal metastasis, such as a pathological vertebral fracture or metastatic spinal cord compression requiring intervention. We collected data on the following variables for each case: age, sex, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 11 ) at initial presentation and at final follow-up, SINS 10 ) at presentation, primary tumor site, spinal level of the metastatic lesion that caused the SRE (cervical, thoracic, or lumbar spine), histological type of bone metastasis (osteolytic, osteoblastic/sclerotic, mixed, or intertrabecular type), grade of ESCC at the time of SRE 12 ) , timing of spine specialist intervention relative to SRE occurrence, and the clinical circumstances leading to the SRE. Initial PS and final PS were compared using the Wilcoxon signed-rank test, with a significance threshold of p<0.05. The data was analyzed with R software (R Core Team, 2023).
Results
Over the 10-year study period, a total of 1,479 patients with metastatic spinal tumors were identified and managed at our institution. Among these, 72 patients (4.8%) experienced an SRE related to their spinal metastasis. The median age of the SRE patients was 71 years (interquartile range 64-76), and 69% were male (50 males, 22 females). The mean ECOG performance status was 3.1 at the initial presentation, which improved to 2.4 at the final observation point; this improvement in PS was statistically significant (p=0.0002). The mean SINS was 8.9±2.4. Based on SINS categories, 18.3% of lesions were classified as stable (score 0-6), 72.4% as potentially unstable (score 7-12), and 9.1% as unstable (score 13-18). The most common primary tumor types among the SRE cases were prostate cancer (25%), lung cancer (18%), and breast cancer (15%). These three cancers together accounted for over half of the SRE cases ( Fig. 1 ). SREs occurred at all levels of the spine, but the thoracic spine was the most frequently involved region (59.7% of cases, Fig. 2 ). Among SRE involving the thoracic spine, the most common primary malignancy was prostate cancer (14/46; 30%), followed by breast cancer (5/46; 10.8%). Regarding the nature of the bone lesions, osteolytic metastases were the most prevalent (65% of cases), followed by mixed lytic-sclerotic lesions (15%), osteoblastic (sclerotic) lesions (11%), and intertrabecular type lesions (9%) ( Fig. 3 ). Among cases with osteolytic metastases, the most common primary malignancy was breast cancer (8/47; 17.0%), followed by prostate cancer (7/47; 14.8%). In terms of spinal cord compression severity, 62.5% of patients had high-grade ESCC (defined as ESCC grade II or higher) at the time of the SRE ( Fig. 4 ) 12 ) . Among cases classified as high-grade, the most common primary malignancy was prostate cancer (15/45; 33.3%). Among low-grade cases, multiple myeloma was the most frequent (3/27; 11.1%). Importantly, we examined the timing of spine specialist involvement for each case. In 54.2% of the SRE cases (39/72), the patients were first evaluated by our spinal surgery team after an SRE had already occurred (i.e. they were referred to us only after sustaining an SRE). Among these post-SRE referral cases, 77% (30/39) had experienced the SRE at an outside hospital before being referred to our institution, whereas 23% (9/39) had their SRE while already hospitalized or under care at our institution ( Fig. 5 ). Among SRE occurring at other facilities, prostate cancer was the most common primary malignancy (8/30; 26.6%). The remaining 33 patients (45.8% of cases) had our spine team's intervention before the occurrence of the SRE; however, an SRE developed despite ongoing management. Further details of the SRE cases are summarized in Fig. 6 . Notably, 69.5% (50/72) of the patients who experienced SRE had no prior history of cancer―in other words, the metastatic spinal tumor (and resultant SRE) was the first indication of an underlying malignancy in these patients. The other 30.5% (22/72) of SRE patients did have an existing cancer diagnosis prior to the SRE. Among those 22 patients with known malignancy, 72.7% (16/22) were receiving their primary cancer treatment at our hospital, while 27.3% (6/22) were being treated at other hospitals. Even among the 16 patients under our hospital's care; however, 37.5% (6/16) experienced an SRE as the initial presentation of their spinal metastases. The circumstances behind these six in-hospital cases were examined: in two patients (33.3%), the patients had interrupted or discontinued their cancer treatment on their own; in another two cases, the patients' primary cancers were refractory with no effective treatment options available at the time; and in the remaining two cases, the patients had been in remission from their primary cancer but subsequently developed a recurrence that presented as an SRE. Among the six patients who were under the care of other hospitals, half (3/6) had their spinal metastases detected through imaging (before an SRE occurred) and were then referred to us, whereas the other half (3/6) suffered an SRE as the first manifestation of metastasis and were referred after the acute event.
Discussion
The spine is known to be the most common site of bone metastasis in the body 13 ) . One contributing factor is the presence of Batson's paravertebral venous plexus, which is a valveless network of veins allowing retrograde flow of tumor cells to the vertebrae 14 ) . In terms of distribution, the thoracic spine accounts for approximately 60%-70% of metastatic spinal tumors, the lumbosacral spine 20%-25%, and the cervical spine about 10%-15% 15 ) . Thoracic vertebrae are particularly susceptible to metastases, in part because they retain a larger volume of red marrow into adulthood, resulting in slower blood flow and a favorable microenvironment for circulating tumor cells to implant 16 , 17 ) . Additionally, tumors located near the mediastinum (such as lung cancer and breast cancer) can directly invade adjacent thoracic vertebrae, further contributing to the high incidence of thoracic spine metastasis 18 ) . Consistent with these patterns, in our cohort, 59.7% of the SREs occurred at the thoracic spine level, far more than at other spinal levels. Approximately 10% of patients with metastatic spinal tumors will develop SRE over the course of their disease 19 ) . Certain cancers are particularly prone to cause SREs; for example, one systematic review reported SRE occurrence rates of about 20% in metastatic prostate cancer, 17.7% in lung cancer, and 11% in breast cancer 19 ) . In our series, prostate, lung, and breast cancers were, likewise, the three most common primary tumors among SRE cases (together comprising over half of all SRE patients), in line with those known trends (though our observed proportions varied slightly from the literature values). The optimal management of bone metastasis requires a comprehensive, multidisciplinary approach that considers the status of the primary cancer, the patient's prognosis, and the individual's functional and social circumstances. To achieve this, many have advocated forming dedicated bone metastasis teams that include experts in oncology, palliative care, radiology, spine/orthopedic surgery, rehabilitation, and other relevant fields 7 ) . Ibrahim et al. 8 ) reported the benefits of such an approach by establishing an “osteo-oncology center” with a staff of 19 specialists; over 3 years, their center evaluated 425 patients with bone metastases and achieved a 98% patient satisfaction rate. Traditional cancer care pathways often involve lengthy waiting periods to obtain consultation from different specialties, which can add to patients' psychological stress. A coordinated multidisciplinary service (such as a tumor board or specialized metastasis team) allows more timely referrals and joint decision-making, thereby shortening wait times and alleviating some of the patients' anxiety 8 ) . A key finding of our study was that among patients who were referred to our department after experiencing an SRE, the vast majority (77%) had suffered from the SRE at an outside hospital before being referred. In other words, a large proportion of SRE cases occurred in patients who were not initially managed by a spine specialist or multidisciplinary team. This underscores the critical need for improved early detection and intervention for spinal metastases in the broader community setting, before catastrophic events like SREs occur. Research has shown that patients with spinal metastases often experience new-onset back pain for several weeks leading up to the development of neurological deficits 20 ) . Therefore, any patient with cancer who develops new, unexplained back pain (especially if accompanied by radicular pain or other neurological signs) should be promptly evaluated for possible spinal metastasis. We concur with the guidance of the United Kingdom National Institute for Health and Care Excellence, which recommends that new back pain or neurological symptoms in a patient with cancer should prompt an urgent whole-spine MRI and referral to a specialist metastatic spinal cord compression service 21 ) . Implementation of such protocols has been reported to significantly reduce the incidence of severe paralysis from spinal metastases 21 ) . It is crucial to raise awareness of these “red flag” symptoms among physicians in community hospitals and clinics so that patients with potential spinal metastases can be identified and referred before an SRE event rather than after the fact. Our analysis also revealed that 69.5% of the SRE patients had no prior history of cancer―their malignancy was essentially discovered due to the SRE. This finding highlights the importance of public education and routine health screening in the early detection of cancers. Improving participation in cancer screening programs or health check-ups might help diagnose primary cancers at an earlier stage, potentially before bone metastases develop or at least before they progress to cause SREs. To further improve the quality of care for patients with metastatic spinal tumors in our region, it will be necessary to not only educate healthcare providers and the public but also to strengthen the collaboration between specialized centers and local medical institutions. One practical way to enhance such collaboration is through the use of remote multidisciplinary case conferences (virtual tumor boards). Davis et al. 22 ) reported that switching to a virtual tumor board format during the coronavirus disease 2019 pandemic led to a 46% increase in specialist attendance compared to traditional in-person meetings. In addition to improved attendance, virtual multidisciplinary management has been associated with better patient outcomes, including prolonged survival in cancer patients 23 ) . At our institution, the liaison treatment system has proven effective in minimizing SRE occurrences among patients under our direct care 9 ) . Going forward, by adopting similar remote collaborative strategies and fostering tighter partnerships with surrounding hospitals and clinics, we aim to extend these benefits regionally and prevent SREs in patients who might otherwise present at outside facilities.
A limitation of this study is that the status within 1 year was unknown for 121 patients (8.1%) out of 1,479 cases. Patients who had likely passed away were considered untraceable if their status could not be reliably confirmed by telephone or newspaper records.
Conclusion
In this study, we reviewed the detailed clinical profiles of patients who experienced SREs from metastatic spinal tumors at our hospital under a liaison treatment system. We found that the majority of SRE cases were in patients who had been referred from other hospitals after an SRE had already occurred. This suggests that while our in-hospital liaison approach has been effective in reducing SREs among patients under our care, further efforts are needed to prevent SREs in the wider community. Strengthening collaboration with regional healthcare providers and improving early identification of spinal metastases (for instance, by recognizing back pain in patients with cancer as a warning sign) will be crucial to achieving this goal and reducing the incidence of catastrophic SREs.
Author Contributions: S.W., K.N. and Y.S., designed the study; K.U., H.I. and S.M. supervised the experiments; S.W. wrote the manuscript.
Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.
Ethical Approval: Approved by our Institutional Review Board (Kawasaki Medical School, approval number 3675).
Informed Consent: Informed consent for publication was obtained by all participants in this study.
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