Prevalence and prognosis of bone metastases in common solid cancers at initial diagnosis: a population-based study

Abstract

Objective

Bone is one of the most common target sites for advanced tumours. The objective was to survey the prevalence and prognosis of bone metastases in 12 common solid malignant tumours.

Design

A retrospective cohort study.

Methods

A total of 1 425 332 patients with a primary cancer between 2010 and 2015 were identified using the Surveillance, Epidemiology, and End Results database. We computed the prevalence and prognosis of bone metastases in each cancer and compared their survival in different stages. The Kaplan-Meier method and Cox logistic regression were used to analyse survival and quantify the effect of bone metastases.

Results

This study included 89 782 patients with bone metastases at diagnosis. Lung cancer had the highest prevalence (18.05%), followed by liver cancer (6.63%), nasopharyngeal carcinoma (6.33%) and renal cancer (5.45%). Breast cancer (32.1%), prostate cancer (25.9%), thyroid cancer (46.9%) and nasopharyngeal carcinoma (24.8%) with only bone metastases had a 5-year survival rate of over 20%. Compared with patients at the stage previous to metastasis, bone metastases significantly increased the risk of mortality and decreased survival, especially for those with prostate cancer (adjusted HR: 18.24). Other concomitant extraosseous metastases worsened patient survival. Bone was the most common site of metastasis for prostate cancer, while for colorectal cancer, multiorgan metastases were predominant.

Conclusions

This study provides the prevalence and prognosis of bone metastases at the initial diagnosis of common solid cancers. In addition, it demonstrates the impact of bone metastases on survival. These results can be used for early screening of metastases, clinical trial design and assessment of prognosis.

STRENGTHS AND LIMITATIONS OF THIS STUDY

• This study is a large-scale and population-based design based on the Surveillance, Epidemiology, and End Results database.

• The impact of bone metastasis on survival was statistically quantified.

• Information on the location, size and number of bone metastases was unavailable.

• Records of bone targeted treatment were unavailable, which may have led to some bias in survival rates.

Background

Bone is one of the most common target sites of metastases in advanced cancer, especially lung, breast and prostate cancer.^{1 2} With the development of medical technology, the survival of patients with different cancers has improved significantly. However, the number of patients with bone metastases has been increasing in recent decades.^{3 4} Tumours cause a loss of bone mass in several different ways leading to skeletal related events (SREs) defined as pathological fractures, severe bone pain, the need for radiotherapy, spinal cord compression and hypercalcaemia.^5–7 Bone pain is the most common symptom.⁸ Patients with bone metastases develop their first SRE shortly after diagnosis and most of them suffer from at least one SRE which results in increased costs, poor prognosis and decreased quality of life.^9–13

The earlier bone metastases are diagnosed and treated, the greater the benefits for patients. The treatment of bone metastases aims to relieve symptoms, preserve or reconstruct function and improve the quality of life, which requires a comprehensive understanding of the primary diseases.^{5 14 15} Most studies focus on bone metastases originating from a monotumour. It has been reported that patients with bone metastases in breast, prostate and thyroid cancer have superior prognoses than those with lung and gastrointestinal cancer.^16–18 Accordingly, survival is related to the characteristics of primary tumours.

The survival data of these cancers with bone metastases can help doctors develop preliminary treatment strategies including radiotherapy, surgery and targeted therapy, especially for patients with severe bone destruction or pathological fracture.^{8 19–21} According to the guidelines, the selection of therapy for metastatic lesions, particularly surgical treatment, requires the consideration of survival. However, there are few large-scale and multiple systemic studies on the prevalence and prognosis of bone metastases in common solid tumours.

In this study, the objective was to use the Surveillance, Epidemiology, and End Results (SEER) database to survey the prevalence and prognosis of bone metastases in 12 common solid malignant tumours at initial diagnosis. We also attempted to compare the prognosis of three stages of tumours, namely, stage before metastasis, bone metastases only and bone metastases with other synchronous metastases to investigate the impact of bone metastases on survival.

Materials and methods

We used data from the SEER database sponsored by the National Cancer Institute. This database collects and publishes cancer prevalence, treatment and survival data, which consists of 18 population-based registries of SEER data, covering approximately 28% of the US population. We identified eligible patients using SEER*Stat V.8.3.5 software (http://www.seer.cancer.gov/seerstat).²²

Data on the presence or absence of metastases at the time of diagnosis has been made available since 2010. We included patients diagnosed with microscopically confirmed primary malignancy between 2010 and 2015 that originated from the following sites: lung and bronchus, breast, prostate, liver, kidney, bladder, stomach, colon, rectum, thyroid, nasopharynx and cervix uteri. Patients were excluded if data relating to the presence or absence of metastases were unknown or not available. In total, 1 425 332 patients were eligible including 85 296 diagnosed with bone metastases. Then, we excluded patients with incomplete follow-up data and a survival time of zero, leaving 1 45 774 patients with stage before metastasis, bone metastases only and bone metastases with other synchronous metastases eligible for survival analyses.

Statistical analysis

Patients were stratified by primary cancer type. Absolute numbers and prevalence of patients with bone metastases were computed according to cancer type. The prevalence was defined as the percent of primary cancer patients with bone metastases among the total cohort of a specific cancer. We also calculated another prevalence, namely, the ratio of cases with bone metastases to total cases with distant metastases.

Cases were classified into the stage before metastasis, bone metastases only and bone with other sites of metastases including the lungs, brain and liver at the time of diagnosis according to the American Joint Committee on Cancer (AJCC) staging system (2010, seventh vision) in SEER software. Patients with follicular thyroid carcinoma or papillary thyroid carcinoma under 45 years of age with metastases were classified as stage II. We used the Kaplan-Meier method to calculate the 1-year, 3-year, 5-year and median survival rates. HRs and corresponding 95% CIs were obtained by using Cox logistic regression. Age was adjusted for survival.

SPSS statistical software V.21.0 (Chicago, USA) was used for all statistical analyses, and p<0.05 was considered statistically significant.

Patient and public involvement

Patients and the public were not involved in the design or planning of the study.

Results

There were significant differences in the number and proportion of patients with bone metastases at diagnosis depending on the primary tumour type (table 1). A total of 1 425 332 patients were newly diagnosed with a solid malignancy and 85 296 patients had bone metastases according to the SEER database between 2010 and 2015. Lung, breast and prostate cancer were prone to invade bone in numerous cases. Lung cancer had the highest prevalence (18.05%) of bone metastases at diagnosis among the entire cohort, followed by liver (6.63%), nasopharynx (6.33%) and renal cancer (5.45%) which were all over 5%. Prevalence was only 3.66% and 4.61% in breast and prostate cancer, respectively. However, the prevalence of bone metastases to all distant metastases was highest in breast cancer (64.20%), prostate cancer (59.89%), nasopharyngeal carcinoma (52.85%), lung cancer (35.82%), renal cancer (35.10%), liver cancer (33.99%) and thyroid cancer (31.48%) (figure 1).

Table 1.

Number of patients and prevalence in 12 common solid tumours

Primary sites of cancer	Total number of patients with cancer	Total number of patients with distant metastases at diagnosis	Number of patients with bone metastases at diagnosis	Prevalence of bone metastases among entire cohort (%)	Prevalence of bone metastases among patients with distant metastases (%)
Lung and bronchus	261 479	131 777	47 200	18.05	35.82
Breast	362 197	20 628	13 244	3.66	64.20
Prostate	285 483	21 967	13 157	4.61	59.89
Liver	18 613	3631	1234	6.63	33.99
Renal	76 416	11 856	4161	5.45	35.10
Bladder	103 265	7490	1412	1.37	18.85
Stomach	33 575	11 785	1595	4.75	13.53
Colon	144 471	30 316	1506	1.04	4.97
Rectum	44 232	7716	640	1.45	8.29
Thyroid	74 549	1706	537	0.72	31.48
Nasopharynx	3080	369	195	6.33	52.85
Cervix uteri	18 666	2662	448	2.40	16.83

Figure 1.

The prevalence of patients with bone metastases in common solid cancers. A, Prevalence of bone metastases among the entire cohort. B, Prevalence of bone metastases among patients with distant metastases.

The survival rates in three different stages (stage before metastasis, bone metastases only and bone with other sites of metastases) at diagnosis varied with the primary cancer type (table 2). One-year survival for patients with bone metastases only ranged from 82.0% for breast cancer to 15.7% for stomach cancer. Three-year survival was highest in patients with thyroid cancer (66.0%) and lowest in those with stomach cancer (2.5%). Breast cancer (32.1%), prostate cancer (25.9%), thyroid cancer (46.9%) and nasopharyngeal carcinoma (24.8%) patients with only bone metastases had a 5-year survival rate of over 20%. Patients with liver cancer with bone metastases experienced the shortest median survival (4 months). The survival curves of the three states are presented in figure 2. We also used a univariate Cox proportional hazards model to analyse the effects of metastases on survival (table 2). Compared with patients at the stage before metastasis, bone metastases significantly increased the risk of mortality and reduced survival especially for patients with prostate cancer (adjusted HR: 18.24, 95% CI 17.02 to 19.54). Interestingly, in thyroid cancer, patients with bone metastases had a longer survival than those with stage IVB without any distant metastases (median survival 60 months vs 32 months). In prostate cancer, the number of patients with simple bone metastases was much greater than those with concomitant other site metastases. Conversely, in patients with colorectal cancer, multiple organ metastases were dominant. In cases with other concomitant extraosseous metastases, survival worsened and the risk of death was further aggravated, but in gastric cancer and liver cancer, this trend had a smaller effect on survival.

Table 2.

Survivals and HRs in three groups by primary cancer

Primary sites of cancer		Number	1-year survival (%)	3-year survival (%)	5-year survival (%)	Median survival (months, 95% CI)	Log-rank P value	Adjusted*HR (95% CI)
Lung and bronchus	Stage before metastasis (IIIB)	14 368	50.8	19.8	12.9	13 (12.68 to 13.32)	<0.001	1.00
	Bone metastases only	16 117	27.6	7.0	3.5	6 (5.84 to 6.16)		1.79 (1.74 to 1.84)
	Bone+other metastasis sites	20 995	20.1	3.7	1.4	5 (4.89 to 5.12)		2.26 (2.21 to 2.32)
Breast	Stage before metastasis (IIIC)	8706	93.5	74.5	61.0	NA	<0.001	1.00
	Bone metastases only	6777	82.0	51.8	32.1	38 (36.67 to 39.33)		2.28 (2.15 to 2.41)
	Bone+other metastasis sites	4619	64.2	32.6	16.3	21 (19.86 to 22.14)		4.21 (3.98 to 4.47)
Prostate	Stage before metastasis (III)	24 896	99.0	96.2	92.3	NA	<0.001	1.00
	Bone metastases only	10 427	79.4	43.3	25.9	30 (29.06 to 30.94)		18.24 (17.02 to 19.54)
	Bone+other metastasis sites	1166	58.1	27.7	18.5	16 (14.07 to 17.93)		32.13 (29.14 to 35.44)
Liver	Stage before metastasis (IVA)	648	30.2	10.1	6.4	6 (5.27 to 6.73)	<0.001	1.00
	Bone metastases only	661	19.1	2.6	1.0	4 (3.52 to 4.48)		1.34 (1.19 to 1.51)
	Bone+other metastasis sites	251	12.5	1.2	NR	3 (2.58 to 3.42)		1.76 (1.51 to 2.06)
Renal	Stage before metastasis (III)	11 385	89.6	73.7	63.3	NA	<0.001	1.00
	Bone metastases only	1561	50.7	24.3	14.1	13 (11.85 to 14.15)		5.04 (4.69 to 5.42)
	Bone+other metastasis sites	1955	28.2	7.7	3.8	6 (5.57 to 6.43)		9.72 (9.11 to 10.38)
Bladder	Stage before metastasis (III)	3886	66.8	40.5	31.4	24 (22.26 to 25.74)	<0.001	1.00
	Bone metastases only	702	26.0	5.4	1.1	6 (5.25 to 6.78)		3.51 (3.19 to 3.85)
	Bone+other metastasis sites	446	14.0	1.8	NR	4 (3.32 to 4.68)		5.11 (4.57 to 5.71)
Stomach	Stage before metastasis (IIIC)	1621	56.8	20.0	12.2	14 (13.16 to 14.84)	<0.001	1.00
	Bone metastases only	631	15.7	2.5	1.8	5 (4.39 to 5.62)		2.84 (2.56 to 3.16)
	Bone+other metastasis sites	553	18.7	4.2	2.1	5 (4.43 to 5.57)		2.70 (2.42 to 3.02)
Colon	Stage before metastasis (IIIC)	7884	77.3	50.5	38.2	37 (35.06 to 38.94)	<0.001	1.00
	Bone metastases only	80	39.0	20.3	NR	7 (2.57 to 11.43)		2.90 (2.22 to 3.79)
	Bone+other metastasis sites	944	30.0	4.5	2.3	6 (5.20 to 6.80)		4.84 (4.47 to 5.25)
Rectum	Stage before metastasis (IIIC)	1711	85.1	57.1	42.2	45 (39.99 to 50.01)	<0.001	1.00
	Bone metastases only	61	59.8	16.0	NR	17 (12.78 to 21.22)		2.99 (2.16 to 4.14)
	Bone+other metastasis sites	386	41.7	10.9	NR	10 (8.37 to 11.63)		4.84 (4.19 to 5.60)
Thyroid	Stage before metastasis (IVB)	640	61.0	48.3	41.3	32 (19.44 to 44.56)	<0.001	1.00
	Bone metastases only	236	79.4	66.0	46.9	60 (52.50 to 67.50)		0.62 (0.48 to 0.80)
	Bone+other metastasis sites	208	40.8	20.4	6.7	8 (4.98 to 11.03)		1.93 (1.57 to 2.37)
Nasopharynx	Stage before metastasis (IVB)	351	84.0	62.7	49.2	57(NA-NA)	<0.001	1.00
	Bone metastases only	75	65.8	29.7	24.8	17 (10.08 to 23.92)		2.39 (1.66 to 3.45)
	Bone+other metastasis sites	97	56.2	11.6	NR	15 (10.68 to 19.32)		3.56 (2.06 to 4.87)
Cervix uteri	Stage before metastasis (IVA)	350	59.7	30.1	26.1	16 (13.26 to 18.75)	<0.001	1.00
	Bone metastases only	184	47.2	16.6	12.1	12 (9.48 to 14.52)		1.50 (1.20 to 1.88)
	Bone+other metastasis sites	196	24.6	7.3	4.6	6 (4.90 to 7.10)		2.58 (2.09 to 3.20)

*Adjusted by age.

NA, not applicable; NR, not reached.

Figure 2.

Cumulative survival and median survival of three groups, stage before metastasis, bone metastases only and bone with other sites of metastases. BM: bone metastases.

Discussion

Bone metastases frequently occur in solid tumours that are related to SREs leading to poor prognosis and an impaired quality of life. Accurate and generalisable estimates of incidence and prognosis are essential to selecting therapy options. There are few studies of bone metastases based on various systems and large-scale populations. Using data in the Danish National Patient Registry, researchers revealed the incidence and survival in the 10 most common primary types of cancer involved in 17 251 patients with bone metastases between 1994 and 2010.¹⁸ Another extensive population-based study in the USA including 382 733 patients with different solid tumours focused on the cumulative incidence of bone metastases in the first 5 years.² Consequently, we conducted this research differently to evaluate the impact of bone metastases from a new perspective.

This study provides a large-scale epidemiological analysis of bone metastases in the SEER programme, encompassing 28% of the USA. Similar to some previous studies, our research indicated that bone metastases from lung, breast and prostate cancers are the most common and account for the majority of all metastatic bone diseases.^{1 2} With the wide use of PET and CT, Michael et al found a higher incidence of bone metastases in lung cancer, ranging between 20% and 40% compared with 7% and 20% before the 20th century and 40% to 80% of these cases were detected in the initial period, which means that early metastasis could be treated in a timely manner.^{23 24} The incidence of bone metastases in lung cancer reported by Gustavo et al and Katrin et al was mainly dependent on the histological subtype.^{25 26}A population study in Denmark showed that the incidence of bone metastases in prostate cancer was only 3% at initial prostate cancer diagnosis based on the Danish National Patient Registry²⁷; similarly, the prevalence was 4.39% at initial diagnosis in our study. For bone metastases, malignant tumours have various risk factors. For breast cancer, it has been revealed in a series of studies that the proportion of bone metastases is low, mostly less than 5%. Age, hormone receptor status, human epidermal growth factor receptor 2 and tumour size play important roles in the process of bone metastases.^28–30 Ruatta et al reviewed and analysed patients with renal cancer in their clinics and found that approximately 4% of patients presented bone metastases at the time of initial diagnosis.³¹ Compared with other primary tumours in urinary cancer, bladder cancer had a lower prevalence of bone metastases in our research. Despite the low prevalence, bone is the most common metastatic site.³² Several studies have demonstrated that the incidence of bone metastases in gastrointestinal tumours ranges from 3% to 7% during the disease course.³³ Many retrospective studies have reported that the incidence of bone metastases varies widely. Those studies did not describe the time when bone metastases were recorded. In addition, the proportion of patients with bone metastases may be underestimated in the public registered database because of the proportion of asymptomatic metastatic patients. The results in our research provide a theoretical basis for early screening of bone metastases so that patients can receive prompt and systematic treatment to improve survival and quality of life.

Metastases are one of the main causes of mortality, especially metastases to vital organs. A study in Norway revealed that for all solid tumours, 66.7% of cancer deaths are caused by metastases.³⁴ Bone, as a supporting structure, plays a critical role in movement and is also the main site of hematopoiesis. Therefore, we aimed to determine the impact of bone metastases on survival. To reduce interference, we selected the stage closest to metastases and compared it with bone metastases only. It has been demonstrated that median survival was only 2–3 years after bone metastases were diagnosed compared with the overall 5-year survival rate of 85% in breast cancer.³⁵ In our research, bone metastasis decreased the 5-year survival from 61% at stage IIIC to 32.1% with bone metastases only and from 12.9% to 3.5% in lung cancer. Bone metastases tend to reduce survival, which depends on the type of primary tumour and the presence of other visceral metastases. Patients with bone metastases from breast and prostate cancer have relatively better survival than those with metastases from lung cancer.^{23 36 37} However, we showed that bone damage had the worse effect on survival in prostate cancer, followed by breast and lung cancers, based on the data of HR, although cases with bone metastases in breast and prostate cancers had a longer median survival. Patients with bone metastases exhibited better survival than those with single extraosseous metastases in breast and prostate cancer. Conversely, in other tumours, such as lung and colorectal cancer, patients have poor survival.^{38 39} Bone metastases involving a metastatic site reduce the 2-year overall survival from 35.5% to 15.8% in urothelial carcinoma.⁴⁰ The authors believe that patients with bone metastases are less likely to receive systematic therapy than those with other metastases due to their lower performance status score which may be one of the reasons for their worse survival. This situation also exists in patients with other tumours. According to table 2, patients with only bone metastases had the longest survival time in thyroid carcinoma. In other words, patients with thyroid cancer with only bone metastases had a better prognosis than patients with local aggression whose tumour invaded the prevertebral fascia or encased the carotid artery or mediastinal vessels (stage T4b). We believe there are multiple causes, such as tumour stage and treatment. The AJCC staging system of thyroid carcinoma is complicated and related not only to the extent of tumour invasion but also to age and pathological type. Through comprehensive treatment, the 5-year survival rate could reach 69%, which is higher than that of patients treated with I131 alone.⁴¹ As a result, we cannot assess the prognosis of thyroid carcinoma by AJCC stage alone. Similar to other tumours, the prognosis of thyroid carcinoma worsened when there were concomitant extraosseous metastases.

This study has several limitations. First, bone metastases in this study were identified at initial diagnosis. The SEER database does not provide information on the process of cancer so the prevalence of bone metastases will be underestimated as some patients do not present any osseous symptoms. Second, information was unavailable about the location, size and number of bone metastases which would have an impact on survival. Third, data on bone target treatment are unknown, which may have led to some bias in survival.

Conclusion

This study presents the prevalence and prognosis of patients with bone metastases at the initial diagnosis of common solid cancers based on a population-based analysis of SEER data. In addition, we quantified the effect of bone metastases on survival in different tumours. Using these results, we can better assess the patient’s survival status and choose the appropriate treatment to obtain the maximum benefit. In addition, these data could be used to guide the early screening of bone metastases and to reduce the occurrence of bone-related events.

Data availability statement

Data are available in a public, open access repository. Data used in this study are available from the Surveillance, Epidemiology, and End Results (SEER) database (https://seer.cancer.gov).

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

Data are derived from a public database (the Surveillance, Epidemiology, and End Results, SEER). This study was performed in accordance with the ethical standards in the 1964 Declaration of Helsinki.