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Abstract

Introduction

The rising number of cancer patients with metastatic bone disease (MBD) reflects advancements in treatment. The concept of oligometastatic disease, associated with improved prognosis, has emerged. This study evaluated prognostic factors, including oligometastases, in patients undergoing urgent orthopaedic surgery for MBD to inform preoperative decision-making and reduce morbidity and mortality from immobilization.

Materials and Methods

We retrospectively analysed records of patients who underwent surgery for MBD between 2005 and 2022. Data included medical history, tumour type, metastatic status, surgical method, lesion location, imaging, and survival outcomes. Multivariate survival analyses were conducted.

Results

The number of metastases and presence of visceral metastases significantly influenced survival. Patients with single metastases had a median survival of 65 months, oligometastases 25 months, and polymetastases 11 months. Visceral metastases were associated with a median survival of 9 months versus 27 months without. Tumour type also impacted prognosis, with thyroid cancer patients having the highest median survival and lung cancer patients the lowest. Pathological fractures reduced survival significantly (11 months vs 36 months without fractures).

Conclusion

Oligometastatic disease is a strong prognostic factor for MBD patients undergoing orthopaedic surgery, with better outcomes compared to polymetastatic disease. Other key factors include tumour type, visceral metastases, and pathological fractures. Improved staging, risk assessment, and early interdisciplinary collaboration could mitigate pathological fractures and improve outcomes.

Keywords

cancer metastases metastatic bone disease oligometastases pathological fracture prognosis

Introduction

The increasing number of patients with Metastatic Bone Disease (MBD) presents a growing challenge in orthopaedic oncology due to improved therapies extending survival. Up to 70% of those with advanced breast, prostate, or lung cancer develop bone metastases.^1–5 These metastases cause complications, known as skeletal-related events (SREs), that severely affect quality of life and life expectancy. SREs include bone pain, fractures, spinal cord compression, hypercalcaemia, and bone marrow suppression, leading to reduced mobility and increased hospitalisation.^1,6–9 In 2005, the healthcare cost in the USA alone was estimated at $13 billion.⁶

The most common cancers that develop bone metastases are breast, lung, prostate, renal, and thyroid. Life expectancy with bone metastases is influenced by several factors. Patients with fewer metastases often have a better prognosis than those with extensive spread.^2,5,8,10,11 The number, size, and location of bone lesions affect treatment options and survival.^2,12 Patients with up to five metastases (oligometastases) have a significantly better outlook and may need different treatment.^13,14 Prognostic models like PATHfx 3.0 and Optimodel exist, though none are clearly superior.¹⁵ In some cases, lab. parameters like albumin or C-reactive protein (CrP) are used to estimate prognosis.¹⁶

Treating metastasised bone disease requires a multidisciplinary approach involving systemic therapies, local treatments, and supportive care. Treatment goals must be set collaboratively, with curative approaches considered for singular or few metastases. Palliative care includes chemotherapy, targeted therapies, immunotherapy, radiotherapy, surgery, and medical measures aimed at symptom relief, disease control, and improving quality of life.^3,17

In orthopaedic oncology, preventive and reactive surgeries are distinguished in palliative care.¹ Preventive surgery aims to avoid fractures and pain, with tools like the Mirel’s score used to assess fracture risk.¹⁸ Prophylactic fixation is more effective and cost-efficient than treating fractures.¹⁹ Reactive surgery addresses existing fractures or neurological issues, with procedures varying by location.^8,20–22 Choosing the right surgery is challenging due to poor prognostic tools. Surgical options carry moderate to high complication rates, such as 3.7%–35% early complications in mega-endoprostheses and 2%–22% late complications in intramedullary nails, often due to implant failure.²² Accurate prognosis is key for selecting the right operation.

Studies show that visceral metastases, pathological fractures, and certain tumour types (especially lung cancer) are linked to poorer prognosis in MBD patients undergoing orthopaedic surgery.^7,19,23 However, the impact of oligometastasis (up to five metastases) has not been thoroughly analysed. The primary objective of our study is to assess whether prognosis differs between single, oligo-, and polymetastases in orthopaedic oncology patients. The other influencing factors mentioned above were included in the study as secondary objectives in order to incorporate them in the multivariate model. These additional patient-specific, disease-specific, and lesion-specific factors will also be examined for their impact on overall prognosis. Finally, the study will evaluate whether the scoring systems currently in use are being applied appropriately, specifically whether patients undergoing curative resection have better overall survival.

We planned to use our centre’s tumour database to categorize patients with metastases into three groups: singular, oligo-, and polymetastasis. We would then track their survival through the cancer registry to validate the concept of oligometastasis as a useful distinction for estimating prognosis.

Material and methods

Study population

We retrospectively reviewed the records of patients surgically treated for metastatic bone disease, excluding the spine, between 01/2005 and 12/2022 at our institution, an orthopaedic oncology unit at a university hospital. Metastatic spinal lesions are assessed and treated neurosurgically at our centre, so no data were available for operated lesions. Patients with multiple myeloma were included, as this condition typically presents clinically and radiologically as osteolytic lesions and is considered a differential diagnoses of bone metastases. Although these cases are excluded by definition in relation to the primary objective of studying oligometastases, they are relevant for addressing the secondary research questions. A total of 315 patients were eligible for inclusion. However, 118 patients were excluded due to incomplete survival data, high-energy trauma unrelated to MBD, biopsy as operation, or inadequate preoperative imaging (see Table 1). Therefore, 197 patients were included in the final analysis. Ethical approval was granted by the local ethics committee.

Table 1.

Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
• Patient undergoing orthopaedic operation for MBD (including multiple myeloma)	• Incomplete data on survival status
• Operation between 2005 and 2022 at our institution	• Adequate high-energy trauma in the context of MBD
	• Inadequate preoperative imaging
	• Biopsy as operation

Data collection and statistical analysis

Patient characteristics, history, pathology, and imaging results were collected from patient records. Mirels’ evaluations of radiographs were independently performed by two experienced orthopaedic oncology specialists. The long bones were classified into proximal end segment, proximal diaphyseal segment, mid diaphyseal segment, distal diaphyseal segment, and distal end segment, according to the AO classification. The proximal end and proximal diaphyseal segments are referred to as “proximal” in the text. Metastatic disease was categorized as single, oligometastatic (2-5 bone metastases), or polymetastatic (>5 bone metastases). Metastatic status was not assessed for multiple myeloma. Survival status was calculated in months based on the date of the last confirmed tumour follow-up or patient death, as recorded by the State Cancer Registry.

Statistical analysis was performed using SPSS 27.0. All patients meeting the inclusion and without exclusion criteria were analysed. Categorical data were compared using the Chi² test. Since continuous data were not normally distributed, non-parametric tests were used to assess differences: the Mann-Whitney U test for two categories, and the Kruskal-Wallis test for more than two categories. The respective medians with interquartile ranges are provided. Median survival was estimated using Kaplan-Meier estimators, plotted as Kaplan-Meier curves, with statistical differences calculated using the log-rank test. These factors were further analysed using multivariate Cox regression. A p-value of <0.05 was considered statistically significant.

Results

Baseline characteristics

The patient cohort consisted of 102 women and 95 men. The age of the patients ranged from 35 to 91 years, with a median of 66 years (IQR 58–73 years). Sixty-five patients were under 60 years of age, 66 were between 61 and 70, and 66 were over 70 years old. There were no significant age differences between the gender groups (p = .94). The primary tumour diagnosis was made between 1995 and 2022. The median time from primary diagnosis to metastasis-related surgery was 20 months (IQR 1-69 months).

Bone metastasis was the first manifestation of cancer in 43 out of 197 patients (21.8%). Metastatic status was singular in 27 patients, oligometastatic in 21 patients, and polymetastatic in 106 patients. Visceral metastases were present in 78 of the 154 assessed patients. Multiple myeloma was the most common cancer, affecting 48 patients, followed by renal cancer (44 patients), breast cancer (42 patients), lung cancer (26 patients), prostate cancer (4 patients), thyroid cancer (3 patients), and other cancers (37 patients).

A total of 125 patients presented with a pathological fracture. The distribution among anatomical regions was as follows: 117 lower limb, 57 upper limb, 18 pelvis, and five chest wall cases. The affected bones were 110 femur, 48 humerus, 18 pelvis, seven tibia/fibula, three clavicle/scapula, and 11 other bones. Bone lesions were characterized as mixed in 39 cases and osteolytic in 158. According to the AO classification for long tubular bones, there was a predominance of proximal localization, with 79 cases in the proximal end segment, 33 in the proximal shaft segment, 33 in the mid-shaft segment, 19 in the distal shaft segment, and 10 in the distal end segment. Mirel’s score had a median of 9 (IQR: 8–10). Wide resection with megaendoprosthetic reconstruction was performed in 41 patients and intralesional surgery in 156 cases (124 osteosynthesis, 32 endoprosthesis).

Oligometastases and prognosis

The number of metastases correlated with prognosis, allowing us to confirm our primary objective. For patients with a single operated bone metastasis, the median survival was 65 months. In cases of oligometastasis, the median survival was 25 months (CI: 11–39 months), while for patients with more than five metastases, it was only 9 months (CI: 3–15 months; p < .01; see Figure 1).

Figure 1.

Graph showing the relationship between cumulative survival and number of metastases.

Other patient-specific, disease-specific and lesions-specific factors

There was no significant effect of gender on prognosis, with women having a median survival of 20 months (CI: 15–25 months) and men 14 months (CI: 4–24 months; p = .59). Similarly, age did not significantly impact prognosis: patients under 60 years had a median survival of 18 months (CI: 0–41 months), those aged 61 to 70 years had 25 months (CI: 17–33 months), and patients over 70 years had 13 months (CI: 7–19 months; p = .08).

The presence of visceral metastases negatively impacted prognosis, with a median survival of 5 months (CI: 1–9 months) compared to 29 months (CI: 6–52 months; p < .01; see Figure 2). Thyroid cancer had the best survival rate with a median survival of 65 months, followed by breast cancer with 54 months (CI: 19–89 months), multiple myeloma with 36 months (CI: 7–65 months), renal cancer with 29 months (CI: 5–53 months), prostate cancer with 12 months (CI: 8–16 months), lung cancer with 12 months (CI: 0–27 months), and other cancers with 6 months (CI: 1–11 months; p = .02; see Figure 3). The diagnosis of a previously unknown malignancy did not significantly affect prognosis, with a median survival of 40 months compared to 17 months (CI: 10–24 months; p = .18).

Figure 2.

Graph showing the relationship between cumulative survival and visceral metastases.

Figure 3.

Graph showing the relationship between cumulative survival and the frequent tumour types (thyroid and prostate cancer were excluded due to very few and early censored cases).

Pathological fracture was significantly associated with worse median survival, at 10 months (CI: 3–17 months), compared to 36 months (CI: 13–59 months) in patients without a pathological fracture (p = .01). Neither anatomical region (p = .36), affected bone (p = .96), bone quality (p = .11), affected bone segment (p = .37), nor Mirel’s score (p = .16) showed a significant difference in survival after surgery.

Multivariate Cox regression analysis of prognostic factors

A multivariate Cox regression analysis was performed using the preoperative factors identified as significant in the univariate analysis to assess their impact on postoperative survival. The analysis revealed that metastatic load—categorized as singular, oligo-, and polymetastases—the presence of visceral metastases, and tumour type were significant influencing factors (see Table 2).

Table 2.

Cox regression analysis of significant factors influencing postoperative survival excluding laboratory parameters.

Factor	Significance	Hazard ratio	Confidence interval
Cox regression analysis including metastatic status thus excluding multiple myeloma n = 154
Tumour type	0.003	1.177	1.059 – 1.308
Metastatic load	0.037	1.569	1.027 – 2.397
Visceral metastases	0.020	1.724	1.092 – 2.724
Pathological fracture	0.140	1.388	0.898 – 2.145
Cox regression analysis excluding metastatic status thus including multiple myeloma n = 197
Tumour type	0.067	1.062	0.996 – 1.133
Pathological fracture	0.026	1.562	1.054 – 2.315

A limitation of this analysis is that patients with multiple myelomas were excluded, as these were considered systemic diseases, and their metastatic status was not categorized. When metastatic status was excluded from the Cox model (thus including the complete patient cohort), pathological fracture emerged as the only significant factor in the multivariate analysis (see Table 2).

Current adequacy of scoring

Patients undergoing curative surgery with wide resection and megaendoprosthetic reconstruction had significantly better survival rates (over 50% alive) than those who underwent intralesional surgery, which had a median survival of 12 months (CI: 6–18; p < .01). There was no difference in prognosis within the intralesional surgery group (p = .30).

Discussion

In this retrospective study, we confirmed that categorizing metastatic disease into singular-, oligo-, and polymetastatic forms significantly correlates with prognosis and is useful for making relevant prognostic statements about patients (n = 154). Additionally, we validated the known prognostic risk factors, including visceral metastases and tumour type (n = 154), as well as pathological fracture (in a larger cohort including multiple myeloma; n = 197) in patients undergoing orthopaedic surgery for metastastic bone disease.

This is the first study specifically examining patients undergoing orthopaedic surgery for their disease, categorizing them into these distinct metastatic groups. This concept is currently being refined to enhance prediction accuracy.¹³ Some retrospective studies have shown a better prognosis for patients with oligometastases of specific carcinomas and have demonstrated the impact of aggressive surgical therapy.^14,24 Given that resection can be associated with significant morbidity and mortality in certain locations,²⁵ this underscores the need for even more individualized treatment approaches and multidisciplinary treatment planning. Additionally, the increasing survival rates mean that the durability requirements for reconstruction and osteosynthesis procedures are rising.²² This will further impact everyday clinical practice, increasing the demands and expertise needed to treat patients with bone metastases. Given the high incidence, such care must be made widely available across the medical system.

As previously shown. the presence of visceral metastases negatively impacted patient prognosis.^2,23 We observed a clear correlation between tumour type and prognosis among patients with solid cancer metastases, consistent with the findings of Ratasvuori et al., Raschka et al., and Salim et al.^2,23,26 Among the most common solid tumours, lung cancer patients had a significantly worse prognosis compared to those with other tumour types. This was also the strongest negative predictor in the study by Wänman et al.²⁷

In the Cox regression analysis of the total cohort, pathological fracture significantly impacted overall survival with a hazard ratio of 1.483. Blank et al. (2016) highlighted the higher costs and longer hospital stays associated with fractures but did not discuss their effect on prognosis.¹⁹ Mavrogenis et al. reached a similar conclusion in their retrospective analysis of patients with femoral metastases, finding that those with pathological fractures had a worse prognosis.²⁸ Raschka et al. reported similar results in a retrospective cohort comparable to this study.²³

Patients who underwent wide resection had better overall survival compared to those treated intralesionally. This difference is not necessarily due to the superiority of the surgery itself but rather to the appropriate use of wide resection for patients with a better overall prognosis. Nonetheless, this finding underscores that wide resection, as part of curative metastatic surgery, can lead to improved outcomes in the right patient cohort.

In contrast to the results of Wänman et al., we did not find a statistically significant correlation between age and gender and patients' prognosis.²⁷ This discrepancy may be attributed to our smaller patient cohort and the fact that their study included only patients with pathological fractures (reactive surgery), whereas our cohort also included patients undergoing preventive surgery.

Strength and limitations

A strength of this study is the long follow-up period and the fact that patients were treated at a single unit by the same team using consistent standards. However, limitations include the variability in cancer types and treatment strategies presented, as well as the retrospective design of the study.

Conclusion

Metastatic bone disease presents a growing challenge for our healthcare system in terms of both treatment and associated costs. Our study highlights that a one-size-fits-all approach to surgical treatment for bone metastases is inadequate, as prognosis can vary significantly. Key criteria for estimating prognosis before surgery include the number of metastases including the concept of oligometastases, the presence of visceral metastases, and tumour type. Additionally, there is a clear correlation between pathological fractures requiring surgery and prognosis. Therefore, better staging and improved multidisciplinary collaboration, including early prophylactic surgery, are crucial for preventing such fractures and enhancing patient outcomes.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

We acknowledge support by the German Research Foundation Projekt-Nr. 512648189 and the Open Access Publication Fund of the Thueringer Universitaets- und Landesbibliothek Jena.

Ethical statement

ORCID iD

Wolfram Weschenfelder

Appendix

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Prognostic impact of oligometastases in orthopaedic surgery for metastatic bone disease

Abstract

Introduction

Materials and Methods

Results

Conclusion

Keywords

Introduction

Material and methods

Study population

Data collection and statistical analysis

Results

Baseline characteristics

Oligometastases and prognosis

Other patient-specific, disease-specific and lesions-specific factors

Multivariate Cox regression analysis of prognostic factors

Current adequacy of scoring

Discussion

Strength and limitations

Conclusion

Footnotes

Declaration of conflicting interests

Funding

Ethical statement

ORCID iD

Appendix

References