A clinical model to predict the risk of synchronous bone metastasis in newly diagnosed colorectal cancer: a population-based study

Colorectal cancer (CRC) is the most commom cancer and the second most common cancer cause of death wordwide, leading to more than 1.8 million new cases and 881 thousand deaths in 2018 [1]. CRC is most likely to metastasize to liver, followed by lungs and peritoneal cavity, yet rarely to bone [2]. The incidence of bone metastasis (BM) among CRC patients has been reported to be 6.0–10.4% with higher rate of 8.6–23.7% in the autopsy results [3]. Nevertheless, the BM incidence rate from CRC has increased in recent years [4], and it is usually diagnosed at the advanced stages with a 5-year survival rate less than 5% [5].

In newly diagnosed CRC patients, systematic body screening including liver and lung examinations is routinely recommended by current guideline [6]. However, because of low incidence of BM, body imaging regarding to synchronous BM is mostly ignored during the primary diagnoses of CRC. And patients are often advised to perform radionuclide bone imaging or PET-CT only when they have suspicious symptoms of skeletal-related events (SREs), which are the concomitant complications of BM and exist high incidence within 1 year after BM [7]. At this time, the CRC are likely to have reached advanced stage or multiple metastases have occurred, thus the best chance of treatment for CRC patients will be missed [8]. In addition, the occurrence of SREs, including bone pain, pathological fracture, possible radiotherapy, spinal cord compression, fatal hypercalcemia could further lower the quality of life and survival of patients [9].

The identification of clinical and tumor factors related to synchronous BM will play an important role in the early detection of synchronous BM among newly diagnosed CRC patients. A clinical risk model of predicting BM appears to be a helpful way to clarify how likely a patient would suffer from BM. Several studies have identified the risk factors associated with BM [10, 11], however most of models tend to predict the risk of metachronous BM which is diagnosed after curative resection of CRC [12, 13]. To date, there is no statistical risk model has been developed for predicting the probability of synchronous BM at primary CRC diagnosis.

Thus, the aim of our study was to utilize the population-based data to identify the risk factors associated with high risk of synchronous BM and to develop a risk model to predict the likelihood of synchronous BM for newly diagnosed CRC patients, which could potentially alert clinicians to detect BM promptly in patients with CRC and further take appropriate measures to avoid the incidence of SREs.

Currently, CRC is a major cause of morbidity and mortality globally [1]. Liver and lung metastasis frequently occur in newly diagnosed CRC, which are routinely recommended to be identified by systematic body examination during the primary diagnosis of CRC [6]. Here we found the proportion of BM incidences in CRC patients in our study is much less than the national reported proportion of BM incidences in CRC patients [3]. Apart from the unrepresentative sample of the overall population in the national findings, this can be due to the rare incidence of synchronous BM recorded in the SEER database instead of metachronous BM seen through several decades in the national study. Synchronous BM diagnosed in CRC patients is very rare, which therefore lead to ignorance of this special clinical entity [15]. However, with the increased overall survival of CRC patients, the incidence of BM from CRC has been on the rising during the course of CRC [4]. Therefore, early identification of synchronous BM during the primary diagnosis of CRC will contribute to the accurate staging and improvement of prognosis for CRC patients. And in current clinical practice, the diagnosis of synchronous BM is mainly based on the clinical SREs, but the optimal theraputic opportunity for BM has already missed when SREs occur [8]. Therefore, early identification of synchronous BM during the primary diagnosis of CRC will also contribute to delay the progress of SREs and improve the quality of life of patients. To better address this issue, we used population-based database to generate a risk model based on clinical and tumor characteristics to predict the risk of synchronous BM in newly diagnosed CRC patients. The results showed that this risk model could precisely identified the synchronous BM from CRC patients with considerably high accuracy.

Previous studies have been reported identifying the risk factors of BM and developing risk models to predict BM after curative resection of CRC. Sun et al. evaluated 516 patients who received curative resection for CRC and found two independent risk factors contributing to BM during the follow-up, including lymph node involvement and tumor location [12]. Ang et al. have found that three independent risk factors of BM, including rectal cancer, lymph node metastasis and lung metastasis. A scoring system was then developed to predict BM based on these three risk factors, and CRC patient were divided into three groups with different risk of developing BM (1.5% vs. 6.6 and 10.5%, P < 0.001) [13].

In our study, we developed the first risk model to predict the probability of synchronous BM at primary CRC diagnosis. Here, we found that rectal cancer was an independent risk factor associated with synchronous BM, which accorded with research of other scholars [12, 13]. Rectal and colon cancers have differences of anatomical location and tissue sources from the beginning of embryonic development. There are some communicating branches between rectal vein and vertebral vein system, which probably is one of the mechanisms of BM [3]. It also be found that patients with poorly or undifferentiated tumor and signet-ring carcinoma were more prone to have BM. This might be because cancer cells have capability of invading surrounding tissues, capillaries and lymphatics with stronger growth potential to develop early metastasis [16]. The CEA in serum and lymph node metastasis would promote the infiltration and metastasis of CRC, leading to higher risk of synchronous BM in CRC patients [17, 18]. Besides, extraosseous metastasis could also increase the risk of synchronous BM. Thus, we use the above significant risk factors to develop the risk model to predict BM. Furthermore, this risk model showed good discriminations with the AUROC being 0.903 in the development and 0.889 in the validation cohort, which could be accurate to identify the newly diagnosed CRC patients who should require more comprehensive assessment to detect potential BM.

The strengths in this study include large sample size from SEER database and good accuracy for predicting synchronous BM in CRC patients. Furthermore, the prediction model consist of accessibly clinical and tumor characteristics, which suggested that this model should be more clinically acceptable. However, due to all patients in this study only representing the population in US, this risk model has the limitation in its widespread use, and the external validation involving the population from other countries should be needed to further confirm the accuracy of this risk model. Another limitation of this study is the lack of biological markers, which could be incorporated into this statistical model to improve the accuracy and its usefulness. Despite these limitations, this risk model remains a accurate and valuable clinical tool to predict the risk of developing synchronous BM in newly diagnosed CRC patients.

Although the patients with BM only accounted for a small proportion in CRC patients, early detection of synchronous BM with routine screening at the primary diagnose of CRC would be beneficial for high risk patients. Here, this clinical prediction model present high accuracy to identify the newly diagnosed CRC patients with high risk of BM and provide more individualized decision making to this group of patients.