Incidence of patients with bone metastases at diagnosis of solid tumors in adults: a large population-based study

Introduction

Bones are one of the most common sites of metastases for many types of solid cancers (1-4). Bone metastases have an increased risk of serious skeletal-related events (SREs), such as pathological fractures, pain, hypercalcemia, and spinal cord compressions, which can seriously impair patients’ quality of life (5-9). Bone metastases also lead to a significant increase in mortality and morbidity (10-12).

In the United States, around 350,000 people die each year from bone metastasis (13). Several patients with bone metastasis and SREs are affected by breast or prostate cancer, while lower rates are observed in patients with lung, kidney, thyroid, or other cancers (4,14). The incidence rate of bone metastases in the United States is still unknown, and estimates have varied from 21,000–400,000 per annum. Though bone metastases can impact the mortality and quality of life of patients with cancer, more extensive population-based studies researching the incidence and prognosis of patients with bone metastases are lacking. Previous studies have shown that the prevalence of bone metastases is more than 70% in patients with metastatic breast and prostate cancer, and approximately 30% in metastatic renal cell carcinoma (1,12,15-18). However, there are no studies which provide information on the incidence of bone metastasis in other common cancers or systemic malignancies. Also, earlier studies cannot reflect the recent incidence and survival trends of patients with bone metastases (19).

Our study was conducted to estimate the incidence and prognosis of patients with bone metastases using the Surveillance, Epidemiology, and End Results (SEER) database that includes information on cancer incidence, treatment, and survival for approximately 30% of the American population (20). Specifically, we estimated the incidence proportion of patients’ bone metastases among solid tumors, considering tumor histology at the time of initial diagnosis.

Methods

Data source and cohort population

For our study, the SEER database was used. Inclusion criteria were adult patients (age ≥18 years) with a diagnosis of an invasive solid tumor originating outside of the bone and joints between January 1, 2010, and December 31, 2016. Patients were excluded if information relating to the presence or absence of bone metastases was unavailable. Other exclusion criteria were patients with diagnosis of carcinoma in situ and patients with a diagnosis of a rare tumor such as thymus cancer, heart cancer, mediastinum cancer, pleura cancer, spleen cancer, reticuloendothelial cancer, skin cancer, connective and soft tissue cancer, adrenal gland cancer, parathyroid gland cancer, other endocrine gland cancer, mesothelioma, Kaposi sarcoma, and lymphoma. For the survival analysis, patients were excluded if they were diagnosed at the time of the autopsy or at the issuing of the death certificate, or if they had unknown survival time or survival status.

Statistical analysis

Total numbers and incidence proportions of patients who were diagnosed with bone metastases were computed and then stratified by cancer type. The patients with lung cancer were classified by tumor histology using the International Classification of Disease for Oncology, 3rd Edition (ICD-O-3). Metastatic stage was conducted following the 7th edition of the American Joint Committee on Cancer staging manual, and then we defined patients with metastatic cancer as a subset with metastatic disease. We defined patients with bone metastases as a subset with bone metastases. The incidence proportion was defined as the number of patients diagnosed with bone metastases and a specific primary cancer divided by the total number of individuals diagnosed with that primary cancer; we also defined a second incidence proportion in which the denominator was restricted to patients with metastatic disease. The metastatic status of the brain, lung, and liver was also available, and we used it to characterize the extent of systemic disease, and subsequently calculated the incidence and median survival of patients with bone metastases classified by the extent of systemic disease. For survival estimates, we used the Kaplan-Meier method, taking into account a P value ≤0.05 as significant. The statistical analysis was generated and visualized with SPSS software (version 18; IBM Corp., USA).

Results

First, we identified 9,316,084 patients aged ≥18 years who were diagnosed with an invasive solid malignancy originating outside of the bone and joints between January 1, 2010 and December 31, 2016. The SEER database includes information on cancer incidence, treatment, and survival for approximately 30% of the American population. Patients were excluded in the cohort if the carcinoma is was in situ. Patients with an unknown bone metastases stage were excluded, leaving 2,470,634 patients for analysis. We then selected most of the sites where cancer often occurred, leaving 2,207,796 patients for the final incidence analysis (Figure 1).

Figure 1 Selection of study patients.

Between 2010–2016, a total of 2,207,796 patients had a diagnosis of cancer from common solid organs, and 426,594 patients had metastatic disease. We found 113,317 patients with bone metastases, which accounted for 5.13% of all patients, and 26.56% of those patients had metastatic disease.

Next, we found that the rate of bone metastases varied widely by primary cancer type (Table 1; Figure 2). As shown in Table 1, the bone metastasis rate is the highest in lung cancer. More specifically, the rate of bone metastases is 23.19% for small-cell lung cancer (SCLC), 22.50% in non-small cell lung cancer not otherwise specified and others [NSCLC (NOS/others)], 20.28% for adenocarcinoma of the lung (ADC), 8.44% in squamous cell carcinoma of the lung (SCC), and 4.11% in bronchioloalveolar carcinoma [NSCLC (BAC)]. In analyzing the gastrointestinal tumors, the rate of bone metastases is 7.99% in the esophagus, 4.47% in the gastric system, 4.42% in the hepatobiliary system, 3.80% in the pancreas, 3.26% in other digestive organs, 1.24% in colorectum, and 1.00% in the anus. Among patients with renal cancer, prostate and breast cancer,16.08%, 5.69%, and 3.73% of patients were respectively found to have bone metastases.

Table 1 Incidence proportion and median survival of patients with identified bone metastases at diagnosis by primary cancer site
Full table

Figure 2 Incidence proportion of patients diagnosed with bone metastases within the entire cohort. SCLC, small-cell lung cancer; NSCLC, non-small cell lung cancer; BAC, bronchioloalveolar carcinoma; NOS, not otherwise specified; ADC, adenocarcinoma of the lung; SCC, squamous cell carcinoma of the lung; GI, gastrointestinal; GU, genitourinary; GYN, gynecologic.

Moreover, Table 1 and Figure 3 show the incidence proportion of patients with bone metastases among the metastatic subset (patients with stage IV disease at diagnosis). The incidence of bone metastases among the metastatic subset is 88.74% in prostate cancer, 53.71% in breast cancer, and 38.65% in renal cancer. In descending order, patients with other cancers of the genitourinary system (except renal, bladder, prostate, testicular) (37.91%), ADC (36.86%), other gynecologic cancers (except ovarian, endometrial, and endometrial cancer) (36.02%), SCLC (34.56%), NSCLC (NOS/others) (33.55%), and bladder cancer (31.08%), showed an incidence proportion of bone metastases of >30%.

Figure 3 Incidence proportion of patients diagnosed with bone metastases within subset with metastatic disease. SCLC, small-cell lung cancer; NSCLC, non-small cell lung cancer; BAC, bronchioloalveolar carcinoma; NOS, not otherwise specified; ADC, adenocarcinoma of the lung; SCC, squamous cell carcinoma of the lung; GI, gastrointestinal; GU, genitourinary; GYN, gynecologic.

Table 1 and Figure 4 show the median survival time of patients with bone metastases in different systemic malignancies. The median survival time among patients with breast cancer and bone metastases, prostate cancer, and bone metastases and thyroid cancer, and bone metastases are 27, 25, and 23 months, respectively. The survival time of the 3 cancers mentioned above is higher than the others. The median survival time of other tumors with bone metastases is less than 10 months. In general, survival is worse in patients with digestive system cancer and bone metastases compared with other types of primary cancer. The median survival time in patients with hepatobiliary, gastric, and anal tumors is 3 months. Among patients with pancreatic tumor and bone metastases, the median survival time is 2 months.

Figure 4 Median survival of patients with identified bone metastases. SCLC, small-cell lung cancer; NSCLC, non-small cell lung cancer; BAC, bronchioloalveolar carcinoma; NOS, not otherwise specified; ADC, adenocarcinoma of the lung; SCC, squamous cell carcinoma of the lung; GI, gastrointestinal; GU, genitourinary; GYN, gynecologic.

Incidence proportion and median survival time of patients with bone metastases, as organized based on the presence or absence of brain, liver, and lung metastases, are shown in Table 2. In summary, the incidence of bone metastasis was higher, and survival time was shorter among patients with more extensive metastases at diagnosis. The incidence of bone-only metastasis was 13.98% in NSCLC (NOS/others), 12.64% in SCLC, and 11.81% in ADC. In descending order, patients with bladder cancer (5.14%), SCC (4.90%), esophageal cancer (4.52%), gastric cancer (2.86%), hepatobiliary cancer (2.74%), renal cancer (2.65%), breast cancer (2.22%), and NSCLC (BAC) (2.02%) showed an incidence proportion of bone metastases of >2%. The median survival time among patients with bone-only metastases in thyroid cancer, breast cancer, prostate cancer, and anal cancer was 60, 35, 27, and 20 months, respectively.

Table 2 Incidence proportion and median survival of patients with bone metastases by extent of systemic disease
Full table

For patients with head and neck cancer, the incidence of comorbidity with liver metastases and bone metastasis was 42.47%. Among patients with was cancer, the incidence of comorbidity with liver metastasis and bone metastasis is higher in NSCLC (BAC) (54.17%), ADC (53.73%), and NSCLC (NOS/others) (44.10%) than in SCC (39.59%) and SCLC (37.15%). Furthermore, we found that the incidence of comorbidity of brain metastases and bone metastasis was higher than other sites among patients with digestive system cancer and gynecologic cancer.

Table S1 shows the incidence proportions of patients diagnosed with bone metastases, classified according to primary cancer, age, race, and gender. Median survival estimates, and those of age, race, gender, and cancer type, are displayed in Table S2.

Table S1 Incidence proportion of patients with identified bone metastases at diagnosis by primary cancer site as stratified by age, race, and gender
Full table

Table S2 Median survival of patients with bone metastases by age, race, and gender
Full table

Discussion

In our study, we showed the number and incidence proportion of patients with bone metastases and the prognosis of identified bone metastases among patients with cancer of the digestive system with the lowest median survival time. To our knowledge, this is the first epidemiologic study of bone metastases using the entire SEER database. Roodman et al. pointed out that the exact prevalence of bone metastasis remains unknown, and patients with bone metastases are usually incurable (21). Therefore, it is probable that our study may have widespread applications and could be useful in the formation of screening paradigms for bone metastases, clinical treatment and trial design, and counseling of different subsets of patients with cancer.

Incidence of bone metastasis

In 1997, Coleman et al. reported that the incidence of bone metastasis was 30–40% for patients with lung cancer, which is higher than our results (22). In 2013, Sathiakumar et al. reported that the incidence of bone metastasis among lung cancer patients was 19.8%, based on data from 1999 to 2006 (23). Al Husaini et al. pointed out that the incidence of skeletal metastasis in advanced-stage lung cancer was 30–40% (24).

In our study, we found that the incidence of bone metastases was 16.89% in patients with newly diagnosed lung cancer and 33.10% in patients with metastatic lung cancer. A comparison of our findings with those of other studies confirms that the rate of bone metastasis among lung cancer is gradually decreasing, which has contributed to the popularization of screening and the development of effective treatment strategies. Additionally, we found the incidence of bone metastases among patients with SCLC to be higher than that of patients with non-small cell lung cancer (NSCLC). Yerushalmi et al. found that the incidence of bone metastases among patients with breast cancer had decreased steadily over 3 time periods (25) (1989–1991: 7.5%, 1992–1997: 5.3%, 1998–2001: 3.5%). Jensen et al. noted that the incidence rate of bone metastases among patients with breast cancer was 3.6% in a population of 35,912 patients (19). In this study, the incidence was slightly lower than that reported by earlier studies. Pietropaoli et al. indicated that only approximately 1% of patients with stage IV carcinoma of the head and neck had concomitant bone metastases (26), which is similar to our results.

Previous studies have reported that the incidence rate of bone metastases in patients with hepatocellular carcinoma ranges from 3% to 20% (27,28). These findings are consistent with our results. However, the studies just mentioned above only discussed the incidence rate of bone metastases in single cancers. There is no study which systematically analyzes the incidence of bone metastases in different cancers types. Our study shows that lung cancer is most likely to present with bone metastasis, which may support recent screening guidelines. Previous studies have shown that the incidence rate of bone metastases in metastatic prostate cancer is over 80%, while bone metastases occur in 65–80% of patients with metastatic breast cancer (29-34). Our study also indicates that the incidence proportion of bone metastases is high in patients with breast or prostate cancer. Previous studies have shown that bone metastases occur in approximately 30% of patients with invasive bladder cancer and renal cancer (35-38). In our study, the incidence rate of bone metastases was 16.08% and 1.48% in renal cancer and bladder cancer, respectively. Furthermore, bone metastases accounted for 38.65% and 31.08% of metastatic renal and bladder cancers, respectively. Though the rate of bone metastases is not high in bladder cancer, bone cancer accounts for a relatively large portion of the metastatic sites among patients with metastatic bladder cancer. Therefore, we must pay attention to the screening of bone metastases in this setting.

Survival

Our results show that cancer presented at diagnosis with bone metastases with the longest median survival time is breast cancer (27 months), followed by prostate cancer (25 months), and thyroid cancer (23 months). Previous studies had shown that the median survival time is 30 and 28 months among breast cancer patients with bone metastases and prostate cancer patients with bone metastases (39,40). These results are similar to ours. Bhatia reported that the prognosis of hepatocellular carcinoma with bone metastasis is extremely poor, with a median survival of only 1–2 months (41). We also found that the median survival time is the shortest in cancers of the digestive system. Silvestris et al. indicated that the median survival was 6 months in gastric cancer patients after bone metastasis diagnosis (42). Our results showed the median survival is 3 months among gastric cancer patients with bone metastases, which was a little shorter than the earlier study.

Clinical implications

Bone metastases are associated with an increased risk of mortality for patients with cancer and may lead to a poor quality of life (17,43,44). The early detection of bone metastases may minimize morbidity and mortality and lead to a better quality of life (45-47), while also being a fundamental step in anticancer treatment (48-50). The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology also recommended routine screening bone metastases in patients with SCLC, prostatic cancer, and high-metastasis-risk renal cancer (51-54). Our results support the current guidelines as these cancers are all at high risk of the development of bone metastases, although the routine use of bone screening is not recommended in NSCLC. Our data showed that the incidence of bone metastases at diagnosis in NSLCLC is relatively high. Therefore, in patients with a diagnosis of stage IV NSCLC, special focus should be dedicated to the screening of the bones.

Furthermore, screening of bone metastases is not routinely performed for patients with esophagus cancer (55). However, our data revealed a 7.99% and 20.74% incidence proportion of bone metastases in patients with esophagus cancer and metastatic esophagus cancer, respectively. Therefore, routine screening of bone metastases is necessary for patients with these cancers.

As screening was not routinely performed in these patients, bone metastases are always discovered only as a result of SREs, which may be a more advanced disease that shortens survival (56) and often requires surgical intervention or a more complex treatment plan. However, surgery for pathological fracture and loss of motor function and mobility might also increase mortality (5). Our data show a relatively high rate of bone metastasis in these populations—one which may be underestimated. Therefore, our findings may support the need to routinely screen for bone metastases at diagnosis for these patients.

As for patients with head and neck cancers, the incidence of comorbidity for liver metastasis and bone metastases is high. Patients with breast and bladder cancer have a high incidence of comorbidity with bone metastasis and brain, liver, or lung metastasis. Therefore, a diagnosis of bone metastases may be a strong signal that other sites of metastases may exist in patients. For lung cancer, we should pay attention to the comorbidity of bone metastases and liver metastases, while for digestive system cancer and gynecologic cancer, we may be more concerned about the comorbidity of bone metastases and brain metastases.

Previous studies have shown that patients with bone-only metastases have a better prognosis (57-59). For instance, previous investigators pointed out that the median survival time of patients with breast cancer and bone-only metastasis was about 20–50 months, which is much longer than multiple sites metastasis (60-63). This result is consistent with our findings. The incidence of bone-only metastasis is high in NSCLC (NOS/others), SCLC, ADC, bladder cancer, and esophageal cancer. So, for patients with these cancers, we must find a specific metastasis status. Because the treatment of bone-only metastasis is different from other sites or multiple sites metastasis (60), identifying bone-only metastasis may help clarify the clinical course, improve the prognosis for patients with bone-only metastasis, and estimate median survival time more accurately (64,65).

Our data also have value for the design of clinical trials. The data in our study may help investigators quantify the specific number of patients needed to be excluded from the trial enrollment, with bone metastasis as an exclusion criterion. Moreover, for studies or trials which are related to bone metastases, our study can provide generalizable estimates of incidence and prognosis for use in calculations and some trial design.

Limitations

The present study has some potential limitations. Firstly, we only identified bone metastases at initial cancer diagnosis, and, because SEER cannot provide information relating to disease recurrence, we could not screen patients with bone metastases after initial diagnosis. Secondly, we do not have information relating to the number size and exact location of the bone metastases. Thirdly, screening was not conducted across all malignancies, and therefore some data of metastases might have been missed. Finally, treatment information for the metastatic sites was not provided, so we could not study the treatment received by each patient.

Although this study has several limitations, it provides new information regarding the epidemiology of bone metastasis. Incidence of bone metastasis and the specific proportion of patients with bone metastases among different cancer types could help in the development of the formation of screening paradigms for bone metastases, clinical treatment and trial design, and counseling of different subsets of patients with cancer.

Conclusions

The results of this study provide population-based estimates of the incidence of bone metastasis and the specific incidence proportion of patients with bone metastasis diagnosis of solid tumors. We have shown that prostate cancer and breast cancer are most likely to occur with bone metastases. Additionally, the rate of bone metastasis was more than 20% in patients with lung, renal, bladder, thyroid, and esophageal cancers. We also found that the median survival time was more than 20 months in bone metastatic breast cancer, prostate cancer, and thyroid cancer. Conversely, the median survival time was the shortest in gastrointestinal, lung, and gynecologic cancer with bone metastases. These data may help clinicians in their justification of using of bone screening, which may also have an important role in clinical trial design and better prognosis. The findings can support the decision of screening of the bone and extracranial metastases for patients with high-risk primary malignancy.

Acknowledgments

Funding: This work was funded by the National Natural Science Foundation of China (No. 81501933), the Zhejiang Provincial Medical and Health Technology Foundation of China (No. 2018KY129), Wenzhou Leading Innovative Talent Project (No. RX2016004) and the Wenzhou Municipal Science and Technology Bureau (No. Y20170389). The funders had no role in the design, execution, or writing of the study.

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm.2020.03.55). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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