Sage Journals: Discover world-class research

Abstract

Purpose:

Evidence on the incidence, prevalence, and outcomes of bone metastases among patients with systemic malignancy is limited. This study aimed to evaluate it using the Surveillance, Epidemiology, and End Results (SEER) database.

Methods:

We collected patients diagnosed with solid malignant tumors deriving outside of the bone, hematologic malignancies, Kaposi sarcoma, lymphoma, and myeloma from the SEER database (from 2010 to 2013). The incidence, prevalence, and outcomes of these systemic malignancies with bone metastases were then analyzed.

Results:

A total of 67,605 patients with bone metastases at cancer diagnosis were included. The highest rate of bone metastases was observed in patients with small-cell lung cancer at the time of alternative primary site cancer diagnosis. Among 226,816 cases with metastatic disease, cases with breast cancer (65.58%), and prostate cancer (89.60%) had a high incidence proportion (>10%) of identified bone metastases. Patients with additional bone metastases resulting from prostate cancer, breast cancer, and testis cancer presented the best survival time.

Conclusions:

Incidence and prognosis differ considerably among bone metastases with different primary malignancy sites. These results may encourage appropriate application of bone imaging.

Keywords

bone metastases incidence SEER survival

Introduction

Malignant tumors have become a major public health problem worldwide. Cancer accounted for nearly one-fourth of the deaths in the United States, the second largest cause of death after heart disease.¹ Additionally, as the leading cause of death, cancer seriously affects patient quality of life globally. Metastasis is a critically insidious biological feature of malignant tumors. Most patients with cancer do not die from primary cancer but from secondary metastatic disease.

The bone is the most common site of such secondary metastases, secondary to the lung and liver.² Bone metastasis is a malignant tumor of the extraosseous organ or tissue.³ These metastatic cells are transferred by the lymphatic blood system to the bone, which then continues to grow and form a tumor. According to the American Cancer Society, about 400,000 new cases of malignant bone metastasis are diagnosed in the United States each year.⁴ The incidence of advanced malignant tumors with bone metastasis is 30–75%, especially common in patients with advanced prostate cancer and breast cancer.^5
–7 Importantly, bone metastases often cause limb dysfunction, pathological fractures, spinal cord compression, and severe pain, seriously affecting the quality of life of patients with advanced cancer and poor prognoses.⁸

Despite the influence of bone metastases on cancer patients, large-scale research studies examining the incidence, prevalence, and outcomes of patients with bone metastases remain lacking. In this study based on the Surveillance, Epidemiology, and End Results (SEER) database, we calculated estimates for the incidence and prognosis of systemic malignancies with bone metastases according to tumor type, age, gender, income, and lymph node involvement among others.

Methods

Selection of the study cohort

The SEER publishes the largest publicly available cancer data set, representing approximately 28% of the US population.⁹ Worldwide, there was acquiescence for research works from the SEER database. Information related to bone metastases was available for patient registered between 2010 and 2013. Patients were excluded from the study if data relating to bone metastases, survival time (months), and presence of other distant metastases were incomplete. Finally, 1,356,371 patient records were included in the final cohort.

Statistical analysis

Patient data were stratified by both tumor and histology type. The absolute number and incidence of bone metastasis were calculated according to tumor type, age, sex, tumor stage, race, and lymph node stage.¹⁰ Race representation among our study cohort included those patients identified as Caucasian, Hispanic, African American, Asian American, unknown race, and other race. Tumor, as well as lymph nodes, was staged according to the guidelines outlined in the American Joint Committee on Cancer tumor–node–metastasis staging system (seventh edition).¹¹

We used the SEER database to collect cases between 2010 and 2013. A total of 1,356,371 patients, above the age of 18 and those diagnosed with solid malignant tumor deriving outside of the bone, hematologic malignancies, myeloma, lymphoma, and Kaposi Sarcoma, were included in this study.

Results

Study population and incidence

Data from 1,401,813 patients diagnosed with a malignancy between 2010 and 2013 and 226,816 patients with distant metastasis were included in the SEER database. A total of 67,605 patients, 29.81% of patients with distant metastasis, were finally found to have bone metastases and were included in this study (Figure 1).

Figure 1.

Incidence proportion of patients diagnosed with bone metastases. (a) Proportion within entire cohort, (b) proportion within subset with metastatic disease, and (c) median survival of patients with identified bone metastases, stratified by primary cancer site.

The proportion of patients who had bone metastases identified varied considerably according to the cancer type (Table 1 and Figure 1(a)). The three largest incidence proportions of bone metastases among this sample population were observed in patients with small-cell lung cancer, bronchioloalveolar carcinoma, and non–small-cell lung cancer (NSCLC) (adenocarcinoma), respectively (22.99%, 21.37%, and 19.16%, respectively). Contrastingly, brain cancer, penis cancer, and thyroid cancer had the lowest proportion of bone metastases (0.11%, 0.37%, and 0.69%, respectively). In ascending order, patients with renal pelvis (39.61%), breast (65.58%), as well as kidney and prostate (89.60%) cancers were observed to have the top three incidence proportion of bone metastases.

Table 1.

Incidence proportion and median survival of patients with identified bone metastases at diagnosis by primary site.

Site	Subsite	Number of patients with cancer (any stage)	Number of patients with metastatic disease	Number of patients with bone metastases at diagnosis	Incidence proportion of bone metastases among entire cohort (%)	Incidence proportion of bone metastases among subset with metastatic disease (%)	Median survival in months (interquartile range) among patients with bone metastases
Head and neck	Brain	17,452	226	19	0.11	8.41	4.0 (2.0–24)
	Oral cavity and pharynx	39,301	1706	542	1.38	31.77	6.0 (2.0–11)
	Other head and neck	14,010	646	167	1.19	25.85	6.0 (2.0–12)
Thyroid	Thyroid	48,399	1022	333	0.69	32.58	8.0 (2.0–21)
Breast	Breast	2,39,916	13,484	8843	3.69	65.58	11.0 (3.0–23.0)
Lung	SCLC	20,332	13,762	4674	22.99	33.96	4.0 (1.0–8.0)
	NSCLC (squamous)	38,390	12,745	4060	10.58	31.86	3.0 (1.0–6.0)
	NSCLC (adeno)	79,595	39,022	15,250	19.16	39.08	4.0 (1.0–9.0)
	BAC	8124	5131	1736	21.37	33.83	2.0 (1.0–8.0)
	NSCLC (Other)	38,926	20,919	7320	18.80	34.99	2.0 (0.0–5.0)
Urinary	Kidney and renal Pelvis	54,317	7637	3025	5.57	39.61	4.0 (2.0–11)
	Ureter	1797	175	60	3.34	34.29	4.5 (2.0–9.0)
	Urinary bladder	69,514	2521	955	1.37	37.88	3.0 (1.0–8.0)
	Other urinary	932	156	58	6.22	37.18	1.5 (0–5)
GYN	Uterus	62,668	5512	694	1.11	12.59	5.0 (1.0–10)
	Ovary	20,867	5576	233	1.12	4.18	3.0 (0–8.5)
	Other GYN	7640	939	89	1.16	9.48	3.0 (1.0–9.0)
AND	Penis	1334	46	5	0.37	10.87	4.0 (2.5–15)
	Prostate	2,04,600	10,912	9777	4.78	89.60	12.0 (5.0–22)
	Testis	9165	1113	71	0.77	6.38	11.0 (4.0–25)
	Other AND	422	15	5	1.18	33.33	8.0 (3.0–36)
Melanoma	Melanoma	76,213	2794	627	0.82	22.44	4.0 (1.0–9.0)
All others		22,364	2832	713	3.19	25.18	5 (2–10)

SCLC: small-cell lung cancer; BAC: bronchioloalveolar carcinoma; NSCLC: non–small-cell lung cancer; GYN: Gynecologic; AND: Andrology.

Survival estimates

Median survival in patients with primary bone metastases is presented in Table 1. The three longest median survival times among patients were 12 months (prostate cancer), 11 months (breast cancer), and 11 months (testis cancer). Median survival was also stratified by age, race, and sex in patients with bone metastases from malignant tumors, as presented in Table 2.

Table 2.

Incidence proportion of patients with identified bone metastases at diagnosis by sex, race, and age, respectively.

Site	Sex		Race			Age (years)
Site	Female	Male	White	Black	Other/unknown	18–39	40–49	50–59	60–69	≥70
Brain	8	11	17	1	1	6	1	3	2	7
Oral cavity and pharynx	131	441	372	97	73	30	68	148	142	154
Eye and orbit, larynx, nose, nasal cavity and middle ear, trachea, mediastinum, and other respiratory organs	50	134	142	34	8	23	20	50	37	54
Thyroid	554	467	790	89	142	74	82	158	275	432
Breast	8740	103	6874	1342	627	525	1171	2164	2334	2649
Lung	14,118	18,922	26,912	3651	2477	226	1417	6086	10,321	14,990
Digestive organs	2378	5530	5723	937	721	175	548	1676	2261	2721
Urinary	1215	2883	3435	387	276	57	272	835	1200	1734
GYN	1016	0	747	177	92	59	120	227	290	320
AND	0	9858	7413	1765	680	52	205	1332	2738	5531
Melanoma	164	463	614	6	7	40	59	133	158	237

GYN: Gynecologic; AND: Andrology.

Discussion

The prognosis of malignant tumors with bone metastasis is demonstrably poor.^12,13 Devastating consequences of bone metastases include pain, hypercalcemia, pathological bone fractures, and nerve-compression syndromes.¹⁴ With the development of surgical, radiotherapeutic, and chemotherapeutical clinical applications in recent years, patient quality of life has improved and survival times have been prolonged.^15
–17 Unfortunately, most of these patients still die due to their bone metastasis.¹⁸ In fact, factors affecting the outcomes of patients with bone metastases are complex and include not only the treatment methods but also patient age, gender, ethnicity, and cancer type.¹⁹

Our study demonstrated the incidence, prevalence, and outcomes of bone metastases originating in patients with primary malignancies separate from the bone. This is the first epidemiological research of bone metastases using a population-based database. Our results may also lead to the reevaluation of the importance of early bone screening among patients with newly diagnosed cancers. Such an initiative has important clinical significance for clinical trial design as well as treatment options among cancer patients.

As previously highlighted, the life quality of patients with bone metastases is poor. Early diagnosis of bone metastases may reduce mortality and treatment-related toxicity.¹⁵ For example, with NSCLC diagnosis screening for bone metastases is not routinely performed, therefore, bone metastases are usually discovered only due to severe pain or fracture. However, our data show that 17.19% of patients with NSCLC have bone metastases. These relatively high rates of bone metastases this cancer population may warrant the use of density testing of the bone at diagnosis. Conversely, screening has become standard practice for the treatment of brain cancer patients who have a relatively low risk of bone involvement where our data suggest an incidence at diagnosis of 0.11%.

Clinical trial design requires accurate estimates of disease incidence and prognosis. If bone metastasis is a standard exclusion criterion, the data from such studies may help researchers determine the number of patients to be eliminated.

We note that there are many variables independently related to bone metastasis. Patients lacking health insurance, unmarried individuals, and those with poor social status have been shown to have higher risk of bone metastasis. Notably, Hispanic and Asian patients are more likely to suffer bone metastases than Caucasians. Further study needs to be done to explore whether environmental or biological factors are also related to bone metastasis.

There are some limitations that can be identified in our study. Firstly, we could only identify incidences of bone metastases at the primary diagnosis due to a lack of clinical records of disease recurrence. Secondly, we did not have access to information about the number or size of each bone metastases. Thirdly, screening was not employed across all types of malignancies. To better understand the pattern of bone metastases, future research is needed in larger samples with more detailed information.

Footnotes

Author contributions

Wenli Jiang and Youlutuziayi Rixiati contributed equally to this work.

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

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Siegel

Miller

Jemal

. Cancer statistics, 2015. CA Cancer J Clin 2015; 65(1): 5–29.

Zeng

Fan

, et al. Clinical features and prognostic factors in patients with bone metastases from hepatocellular carcinoma after liver transplantation. BMC Cancer 2011; 11: 492.

Macedo

Ladeira

Pinho

, et al. Bone metastases: an overview. Oncol Rev 2017; 11(1): 321.

Siegel

Miller

Jemal

. Cancer statistics, 2017. CA Cancer J Clin 2017; 67(1): 7–30.

Cosphiadi

Atmakusumah

Siregar

, et al. Bone metastasis in advanced breast cancer: analysis of gene expression microarray. Clin Breast Cancer 2018; 18(5): e1117–e1122.

Logothetis

Morris

Den

, et al. Current perspectives on bone metastases in castrate-resistant prostate cancer. Cancer Metastasis Rev 2018; 37(1): 189–196.

Bienz

Saad

. Management of bone metastases in prostate cancer: a review. Curr Opin Support Palliat Care 2015; 9(3): 261–267.

Jehn

Diel

Overkamp

, et al. Management of metastatic bone disease algorithms for diagnostics and treatment. Anticancer Res 2016; 36(6): 2631–2637.

Hayat

Howlader

Reichman

, et al. Cancer statistics, trends, and multiple primary cancer analyses from the surveillance, epidemiology, and end results (SEER) program. Oncologist 2007; 12(1): 20–37.

10.

Aizer

Chen

McCarthy

, et al. Marital status and survival in patients with cancer. J Clin Oncol 2013; 31(31): 3869–3876.

11.

American Joint Committee on Cancer staging manual, 7th edition, http://www.cancerstaging.org (accessed July 2018).

12.

Graham

Qian

. Mesenchymal stromal cells: emerging roles in bone metastasis. Int J Mol Sci 2018; 19(4): pii: E1121.

13.

Coleman

. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006; 12(20 Pt 2): 6243s–6249s.

14.

Clines

Guise

. Mechanisms and treatment for bone metastases. Clin Adv Hematol Oncol 2004; 2(5): 295–302.

15.

Domchek

Younger

Finkelstein

, et al. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 2000; 89(2): 363–368.

16.

Yang

Liu

Wang

, et al. Diagnosis of bone metastases: a meta-analysis comparing ¹⁸FDG PET, CT, MRI and bone scintigraphy. Eur Radiol 2011; 21(12): 2604–2617.

17.

Fonager

Zacho

Langkilde

, et al. (18)F-fluoride positron emission tomography/computed tomography and bone scintigraphy for diagnosis of bone metastases in newly diagnosed, high-risk prostate cancer patients: study protocol for a multicentre, diagnostic test accuracy study. BMC Cancer 2016; 16: 10.

18.

Harries

Taylor

Holmberg

, et al. Incidence of bone metastases and survival after a diagnosis of bone metastases in breast cancer patients. Cancer Epidemiol 2014; 38(4): 427–434.

19.

Lin

Hsueh

Chao

. Long-term follow-up of the therapeutic outcomes for papillary thyroid carcinoma with distant metastasis. Medicine (Baltimore) 2015; 94(26): e1063.

Incidence,prevalence,and outcomes of systemic malignancy with bone metastases