Abstract
Background/Aim: This study aimed to investigate the clinical influence of the growth speed of primary lesions on appendicular skeletal metastases to provide an optimal treatment strategy for the metastases. Patients and Methods: Fifty-seven patients who underwent surgery for appendicular skeletal metastases between 2008 and 2020 were included. According to the growth speed of primary lesions, the patients were divided into the S group (slow-to-moderate, n=34) and the R group (rapid, n=23), and the outcomes were investigated. Results: The period from diagnosis of skeletal metastases to pathological fracture (PF) was shorter in the R group than in the S group (p=0.24). The overall survival of the S group was significantly better than that of the R group (p=0.02). Conclusion: The appendicular skeletal metastases of the primary tumor with rapid growth speed have a high risk of PFs developed early from the diagnosis of skeletal metastases, and the prognosis may be poor.
- Appendicular skeletal metastases
- tumor growth speed
- pathological fracture
- impending fracture
- prophylactic surgery
In cancer treatment, the progress of systemic treatment involving chemotherapy, radiotherapy, and surgery and the development of new treatments such as immunotherapy have improved the life expectancy of patients with cancer (1). However, due to this improvement, the incidence of skeletal metastases has increased and has become a clinical problem (2-4). The bone is the third most common metastatic site of malignant tumors after the lungs and liver (2, 3, 5), and the prognosis of malignant tumors with bone metastasis is demonstrably poor (6). Although the overall incidence of skeletal metastases has not been clarified (7), Jiang et al. have reported that 29.81% (67,605/226,816) of patients diagnosed with malignancy with distant metastasis had skeletal metastases (8). Various studies have reported that metastatic sites involve the vertebrae (69%), pelvis (41%), femur (25%), upper extremities (15%), and cranium (14%) (9). Although the incidence of metastasis in the long bones of the upper or lower extremities is not very high, the incidence of pathological fractures (PFs) of the long bones is approximately 10% in patients with skeletal metastases (10-12). Skeletal-related events (SREs), such as PF, cord compression, severe skeletal pain, and hypercalcemia (13), are associated with a decline in the quality of life (7). Moreover, overall survival (OS) is shorter among patients with SREs than in those with skeletal metastases without SREs (14). In particular, PFs have been reported to have significant implications for morbidity and mortality in patients with appendicular skeleton metastases (15-17). Therefore, providing appropriate treatment for cancer patients with appendicular skeletal metastases is critically important in improving their prognosis and limb function.
Katagiri’s score (18) and Mirels’ score (19) have been commonly used in the clinical practice of evaluating skeletal metastases. Katagiri’s score has been used to estimate patient prognosis, and Mirels’ score is a parameter for the treatment of appendicular skeleton metastasis. Katagiri’s score is used in general clinical practice for skeletal metastases, but not in selecting a specific treatment plan for skeletal metastases in the appendicular skeleton. Meanwhile, Mirels’ score does not consider the primary lesion and the patient’s life expectancy. Thus, in the treatment of skeletal metastases, although the treatment guideline according to each primary lesion is ideal, there is no such specific index. Therefore, we focused on the tumor growth speed of the primary lesions described by Katagiri’s score. This study aimed to clarify the clinical influence of tumor growth speed of primary lesions in patients who underwent surgical treatment for appendicular skeletal metastases.
Patients and Methods
This was a retrospective study based on the database and medical information of our institution (Kanazawa University Hospital, Kanazawa city, Ishikawa, Japan). Between 2008 and 2020, 57 patients [30 male and 27 female; mean age, 64.2±12.3 years (range=33-87 years)] who underwent surgery for appendicular skeletal metastases were included. The indications for surgery in this study was a PF or an impending fracture (IF) with a Mirels’ score of >9 points (19). Patients who could not be followed-up for over 6 months or underwent surgery for primary malignant bone tumors or recurrent tumors were excluded.
First, the participants were divided into the PF group and the prophylactic surgery group including the IF group, and the OS after the diagnosis of skeletal metastases was investigated to clarify the influence of the timing of surgery on prognosis. Additionally, the Eastern Cooperative Oncology Group performance status (PS) before and after surgery was investigated to evaluate postoperative function. The preoperative PS was at the time of diagnosis of skeletal metastases, and the postoperative PS was at the time of the final follow-up. Subsequently, a comparison between radical surgery (wide resection and reconstruction) and palliative surgery (tumor curettage, cement replacement, and osteosynthesis) was performed to investigate the differences in surgical procedures. Then, based on the factor of tumor growth speed of primary lesions of Katagiri’s score (18), the participants were divided into the S group (slow-to-moderate growth speed) and the R group (rapid growth speed). Among the groups, the period from diagnosis of skeletal metastases to PF and OS were investigated. Finally, to evaluate predictive factors implicated in the prognosis of appendicular skeletal metastasis, univariate analysis was performed on the patient's characteristics, and variables with p<0.05 in the univariate analysis were used for multivariate analysis.
Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama city, Japan) (20). The two groups were compared using the t-test, Mann–Whitney U-test, and chi-square test. OS was performed using the Kaplan–Meier curve and compared using the log-rank test. The univariate and multivariate analyses were performed using the log-rank test and Cox proportional hazards analysis, respectively. In all statistical analyses, the significance was set at p<0.05.
This study was approved by the ethics committee of Kanazawa University Hospital, and individual patient consent was obtained using the opt-out method.
Results
The characteristics of the participants are summarized in Table I. Renal cell carcinoma (RCC) was the most common primary lesion (n=16), followed by breast cancer (n=11), lung cancer (n=7), and hepatocellular carcinoma (HCC; n=7). The most common skeletal metastatic sites were the femur at 73.7% and the humerus at 26.3%, and 82.5% of the participants had other organ (visceral or brain) metastases. The characteristics of the PF and IF groups are summarized in Table I. The skeletal metastatic lesions and treatment with bone modifying agents (BMA) showed a significant difference between the two groups. In the IF group, the median survival time was 92.6 months, and the 1-, 2-, and 5-year OS rates were 88.4%, 79.3%, and 52.4%, respectively. Meanwhile, in the PF group, the median survival time was 8.7 months, and the 1-, 2-, and 5-year OS rates were 43.6%, 36.4%, and 7.3%, respectively. The OS of the IF group was significantly better than that of the PF group (p<0.005) (Figure 1A). Postoperative PS showed a significant improvement compared to preoperative PS in both groups (p<0.001 in the PF group and p=0.001 in the IF group) (Figure 2). In the surgical procedure, palliative surgery was common in the PF group, while radical surgery was common in the IF group, and the OS was significantly better in the latter (p<0.005) (Figure 1B).
Characteristics of all patients in the impending fracture (IF) and pathological fracture (PF) groups. The p-value is the result of the statistical analysis performed on both groups.
Kaplan–Meier survival curves. (A) The survival curve of all patients in the impending fracture (IF) and pathological fracture (PF) groups. The survival rate of the IF group was significantly higher than that of the PF group (p<0.005). (B) The survival curve of patients who underwent radical surgery and palliative surgery. The survival rate of patients who underwent radical surgery was significantly higher than those who underwent palliative surgery (p<0.005). (C) The survival curve of slow-moderate growth speed of primary lesion (S group) and rapid growth speed (R group). The survival rate of the S group was significantly higher than that of the R group (p=0.02).
Performance status of both groups. Postoperative performance statuses (PS) were significantly better than preoperative performance statuses in both pathological fracture (PF) (left) and impending fracture (IF) groups (right) (p<0.001 and p=0.001, respectively).
The characteristics of the S and R groups are summarized in Table II, and no significant differences were observed. The period from the diagnosis of skeletal metastases to PF was shorter in the R group (p=0.24) (Figure 3). In the S group, the median survival time was 43.3 months, and the 1-, 2-, and 5-year OS rates were 82.6%, 74.7%, and 38.1%, respectively, and those in the R group were 7.3 months and 41.5%, 33.2%, and 33.2%, respectively. The OS of the S group was significantly better than that of the R group (p=0.02) (Figure 1C).
Characteristics of the slow-to-moderate growth speed (S) group and the rapid growth speed (R) group. The p-value is the result of the statistical analysis performed on both groups.
The period from diagnosis of skeletal metastases to pathological fracture. The period from diagnosis of skeletal metastases to pathological fracture had no significant difference between the slow-to-moderate growth speed of primary lesion (S group) and rapid growth speed (R group) (p=0.24).
In the univariate analysis of prognostic factors for appendicular skeletal metastases, another-organ metastasis, treatment history of BMA and drugs, PF, surgical procedure, and tumor growth speed of the primary lesion were significantly different (Table III). In the multivariate analysis incorporating the prognostic factors with p<0.05 in the univariate analysis, only another-organ metastasis was an independent poor prognostic factor (Table IV).
Univariate analysis of prognostic factors on appendicular skeletal metastases.
Discussion
The Mirels’ score is commonly used for predicting PFs and deciding the treatment plan for appendicular skeletal metastases in clinical practice (21). Although this scoring system is based on clinical symptoms and radiological parameters, the primary lesions and the patient’s life expectancy are not considered. The incidence of skeletal metastases and metastatic type, such as blastic or lytic, differs depending on the primary tumors, and skeletal metastases often appear after the disease stage has progressed. The influence of primary tumors and the patient’s life expectancy should be considered when predicting the risk of PFs and selecting a treatment plan for appendicular skeletal metastases. Therefore, this study focused on the tumor growth speed of primary lesions and investigated its clinical influence on appendicular skeletal metastases.
In various studies, PFs, primary tumors, multiple skeletal metastases and visceral metastasis have been reported as prognostic factors for appendicular skeletal metastases (16, 17, 22, 23). In this study, the OS of patients with PFs was significantly poor (Figure 1A), which is consistent with previous reports. However, in our multivariate analysis, although visceral or brain metastasis was an independent poor prognostic factor, no significant difference was observed in the PFs (Table IV). In the multivariate analysis, the prognostic factors for appendicular skeletal metastasis are occasionally different depending on the literature due to the heterogeneous nature of the sample populations and study designs (24); here, the small number of participants may have influenced the results of the multivariate analysis. In the univariate analysis, the PFs showed a significant difference, indicating them as a factor that adversely affects prognosis.
Multivariate analysis of prognostic factors for appendicular skeletal metastases.
Various reports have indicated primary tumors as a prognostic factor, and that breast cancer, RCC, lymphoma, and myeloma have a favorable prognosis, while lung cancer and HCC have a poor prognosis (16, 22, 25). When these were applied to the factor of the tumor growth speed of primary lesions in the Katagiri score, those with a favorable prognosis had a slow-to-moderate growth speed, and those with a poor prognosis had a rapid growth rate. Regarding the relationship between the primary tumor growth speed and the prognosis of appendicular skeletal metastases, Sørensen et al. have reported that a rapid growth speed was associated with a poorer prognosis, and the rapidly growing cancer was a poor prognostic factor in the multiple regression analysis (26). In this study, although the participants were divided into the rapid tumor growth group and the slow-to-moderate growth speed group, the results of the prognosis were almost the same as in that report, and the rapid tumor growth of the primary lesion was a poor prognostic factor in the univariate analysis (Table III). Hence, the tumor growth rate of the primary lesion is considered a prognostic factor for appendicular skeletal metastases.
Moreover, the primary tumors with a rapid growth rate in this study tended to have a short period from diagnosis of skeletal metastases to PFs and a high risk of developing PFs (Table II, Figure 3). This was considered one of the reasons for the poor prognosis of appendicular skeletal metastases with a rapid growth of primary lesions. Therefore, after diagnosis of appendicular skeletal metastases with rapid tumor growth of the primary lesions, follow-up in short intervals should be performed to prevent PFs, and if the patient's general condition is favorable and stable, early prophylactic surgery may be a better treatment plan.
Based on Mirels’ score, prophylactic surgery is recommended for patients who score more than 9 points (19). Ward et al. have reported that prophylactic surgery had the advantages of less bleeding, shorter inpatient stay, and superior improvement of postoperative function compared to surgery for PFs (27). In this study, radical surgery was significantly performed in the prophylactic surgery group, and the prognosis was significantly better than that of palliative surgery (Figure 1B). Some studies have reported that radical surgery is a better prognostic factor for appendicular skeletal metastases (28, 29). Considering these results, prophylactic radical surgery before PFs may be a treatment plan that can predict the best prognosis for appendicular skeletal metastases. Additionally, postoperative PS showed a significant improvement over preoperative PS in prophylactic surgery (Figure 2); thus, functional improvement can also be expected.
This study has some limitations. First, this was a retrospective study involving a small number of patients in a single institution. Second, this study included only patients who were treated with surgery, and the outcomes of patients who were treated conservatively were not considered. In the future, we plan to further study the optimal treatment strategy for appendicular skeletal metastases, including patients treated conservatively.
Conclusion
The appendicular skeletal metastases of the primary tumor with rapid growth speed may have a high risk of PFs developed early from the diagnosis of skeletal metastases and a poor prognosis than those of slow-to-moderate growth speed. In the treatment for cancer patients with those bone metastases, if the general condition is favorable and stable, prophylactic radical surgery before PF may be expected to improve the prognosis and functional outcomes.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
Conceptualization: Yohei Asano; Data curation: Yohei Asano, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Hirotaka Yonezawa, Yoshihiro Araki, Sei Morinaga, Shiro Saito; Investigation: Yohei Asano; Project administration: Yohei Asano; Writing – original draft: Yohei Asano; Writing – review and editing: Norio Yamamoto, Takayuki Nojima, and Hiroyuki Tsuchiya. All Authors approved the final version of the manuscript.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received October 8, 2021.
- Revision received November 3, 2021.
- Accepted November 9, 2021.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.