Recent trends in bone metastasis treatments: A historical comparison using the new Katagiri score system

Abstract

BACKGROUND

Bone metastasis has various negative impacts. Activities of daily living (ADL) and quality of life (QOL) can be significantly decreased, survival may be impacted, and medical expenses may increase. It is estimated that at least 5% cancer patients might be suffering from bone metastases. In 2016, we published the Comprehensive Guidelines for the Diagnosis and Treatment of Bone Metastasis. Since then, the therapeutic outcomes for patients have gradually improved. As life expectancy is a major determinant of surgical intervention, the strategy should be modified if the prolongation of survival is to be achieved.

AIM

To monitor how bone metastasis treatment has changed before and after launch of our guidelines for bone metastasis.

METHODS

For advanced cancer patients with bone metastasis who visited the Department of Clinical Oncology at Akita University hospital between 2012 and 2023, parameters including the site and number of bone metastases, laboratory data, and survival time, were extracted from electronic medical records and the Katagiri score was calculated. The association with survival was determined for each factor.

RESULTS

Data from 136 patients were obtained. The 1-year survival rate for the poor prognosis group with a higher Katagiri score was 20.0% in this study, which was 6% and an apparent improvement from 2014 when the scoring system was developed. Other factors significantly affecting survival included five or more bone metastases than less (P = 0.0080), and treatment with chemotherapy (P < 0.001), bone modifying agents (P = 0.0175) and immune checkpoint inhibitors (P = 0.0128). In recent years, advances in various treatment methods have extended the survival period for patients with advanced cancer. It is necessary not only to simply extend survival time, but also to maintain ADL and improve QOL.

CONCLUSION

Various therapeutic interventions including surgical approach for bone metastasis, which is a disorder of locomotor organs, are increasingly required. Guidelines and scoring system for prognosis need to be revised promptly.

Key Words: Bone metastasis; New Katagiri scoring system; Prognosis; Immune check point inhibitors; Survival

Core Tip: We investigated bone metastasis patients from 2012 to 2023 at Department of Clinical Oncology, Akita University Hospital to learn about recent trends in treatment methods and outcomes for patients with bone metastases. The prognosis of patients with bone metastases has improved recently. Now, there is a room for surgical interventions to the patients with bone metastases, which have been avoided due to their limited prognosis. These are expected to improve activities of daily living and quality of life and will benefit patients. Accordingly, guidelines and scoring system for prognosis need to be revised.

INTRODUCTION

Bone metastasis has various negative impacts. Activities of daily living (ADL) and quality of life (QOL) may be significantly decreased, survival may be impacted, and medical expenses may increase. Based on the SEER database, 113317 of 2470634 cancer patients in the United States from 2010 to 2016 experienced bone metastases[1].

Treatment of bone metastasis includes orthopedic surgery, radiotherapy, drug treatment including bone modifying agents (BMAs) and palliative care[2]. BMAs can suppress skeletal related events (SREs) composed of pathologic fracture, spinal cord compression, radiation or surgery to bone, and hypercalcemia of malignancy[2]. In recent years, the adjunctive treatments such as radiofrequency ablation are considered. Additionally, carrier-mediated drug delivery, bone substitutes to repair bone defects, and multifunctional scaffolds with bone tissue regeneration and antitumor properties are investigated[3]. In recent years, immune check point inhibitors (ICIs) have been used to treat various cancers[4]. There is a remarkable efficacy of ICIs in the treatment of tumors.

A large number of clinical trials reveal that ICIs have promising therapeutic effects, including overall survival (OS), objective effective rate and progression-free survival[4]. Despite the potential to improve cancer outcomes with use of ICIs, bone metastases remain may have different responses to ICIs than other disease sites[5]. The effects of ICI on bone metastasis should be understood, including elucidation of the bone microenvironment. Palliative care is given not only to relieve pain, but to provide holistic support, so that the QOL of patients can be improved[2].

Various scoring systems that determine the choice of intervention have also been developed[2]. The new Katagiri scoring system (NKSS), which was developed in 2014, is very good tool to predict the life expectancy of bone metastatic patients[6]. The NKSS consists of six items, including: (1) The characteristics of primary cancers; (2) The existence of visceral, brain, and peritoneal dissemination; (3) Laboratory data; (4) Eastern Cooperative Oncology Group performance status (PS); (5) History of chemotherapy; and (6) The existence of multiple bone metastasis. Scores range from 0 to 10[6]. In the NKSS, the survival rate was 27% at 6 months, and 6% at 1 year with an overall prognostic score of ≥ 7[6]. Based on the Japanese comprehensive guidelines for diagnosis and treatment of bone metastasis, published in 2016, surgery is not recommended when prognosis is predicted within 6 months. The prognosis is gradually improving, for example, the 5-year survival rate improved by 2% each year from 2015 to 2019 in the United States[7]. It is also necessary to consider the impact on the scoring system from changes in treatment regimens, such as approval of the ICIs. Therefore, we examined the factors impacting cancer patients with bone metastases from 2012 to 2023.

MATERIALS AND METHODS

Patients

We retrospectively examined the clinical status of patients with bone metastases who underwent treatment at the Department of Clinical Oncology at Akita University hospital from December 2010 to March 2023.

Methods

Patient data included gender, age, site and number of bone metastases, site of primary tumor, metastasis other than bone, symptoms, opportunity for diagnosis, treatment history including radiotherapy, anticancer drugs, opioids, BMA and ICIs was extracted from their electronic medical records. Laboratory data at their visit included serum levels of C-reactive protein, lactate dehydrogenase, total bilirubin, calcium, and the number of platelets. Information regarding PS and ADL were also extracted from the medical records. Furthermore, the patient’s life and death were examined as well as their survival time from the day visiting our department, and a score was calculated by the NKSS.

Statistical analyses were performed using BellCureve for Excel Ver 4.04 (Social Survey Research Information Co., Ltd., Japan).

All procedures were conducted according to the Declaration of Helsinki.

RESULTS

Patient characteristics

For 12 years and 4 months, 136 patients were enrolled in this study (Table 1). This number includes 13% of the patients presenting to the Department of Clinical Oncology. Of these, 86 were male (63.2%). Ages ranged from 24 to 84 years, with a median age of 64 years. The primary sites of bone metastases are listed in Table 1. Cancer of unknown primary (CUP) [n = 31 (22.8%)] was the most common, followed by gastric cancer [n = 24 (17.6%)], colorectal cancer, [n = 21 (15.4%)] sarcoma [n = 10 (7.4%)], and pancreatic cancer [n = 9 (6.6%)]. The MST for all cancer patients with bone metastases was 8.6 months [95% confidence interval (95%CI): 6-10 months]. MSTs by primary sites were as follows: CUP (8.6 months, 95%CI: 1-16 months), gastric cancer (6.0 months, 95%CI: 5-7 months), colorectal cancer (8.5 months, 95%CI: 6-11 months), sarcoma (9.2 months, 95%CI: 0-24 months), and pancreatic cancer (9.3 months, 95%CI: 3-16 months). The relatively short survival period may reflect the nature of the Department of Clinical Oncology, which treats very advanced cancers.

Table 1 Characteristics of the participants.

Primary site	n	Median survival time (95%CI, month)
CUP	31	8.6 (1-16)
Gastric cancer	24	6.0 (5-7)
Colorectal cancer	21	8.5 (6-11)
Sarcoma	10	9.2 (0-24)
Pancreatic cancer	9	9.3 (3-16)
NET	7	4.0 (2-7)
Esophageal cancer	6	2.9 (1-4)
Skin cancer	4	34.7 (4-66)
Thymic cancer	3	14.0 (14-14)
Hematologic malignancy	3	Not reached
Urological cancer	3	8.1 (0-17)
Others	6	6.4 (3-10)
Overall	136	8.1 (6-10)

CUP: Cancer of unknown primary; NET: Neuroendocrine tumor; CI: Confidence interval.

Characteristics of bone metastases

The frequency of bone metastases was as follows: single (n = 33, 24.3%), 2 or more and 4 or less (n = 44, 32.4%), and 5 or more (n = 58, 42.6%). The frequency of bone metastasis by site is shown in Supplementary Table 1. Metastases to the spine were the most frequent (n = 97, 71%) and the frequencies were as follows: cervical spine (n = 28, 21%), thoracic spine (n = 71, 52%), and lumbar spine (n = 64, 47%). Metastases to the pelvic bones, including the sacrum, ilium, and pubis were the next most frequent (n = 72, 53%). Metastases to other bones including ribs, scapula, and long bones, such as the femur, were third (n = 67, 49%).

Opportunity for diagnosing bone metastases

Metastases were found in 96 cases by diagnostic imaging (70.5%) (Supplementary Table 2). Of the 136 patients, 16.9% had pain, and 5.1% had neurological symptoms, whereas 2.9% had bone symptoms, such as a fracture and 2.9% had elevated serum alkaline phosphatase levels (Supplementary Table 2). Of 136 cases, 70% were asymptomatic.

Classification by NKSS classification

Calculation by NKSS calculations were conducted on the visiting day. Of the 136 patients, only 3 patients (2.2%) scored 0-3 (lower score), 62 patients (45.6%) scored 4-6 (middle score), and 71 patients (52.2%) scored 7-10 (higher score) (Figure 1A). The survival of the middle-score group (MSG) and the higher-score group (HSG) was examined. The 1-year survival rate was 56% for the MSG (Figure 1A and Table 2). This was similar to that of the original paper, which reported 49.3%. The 1-year survival rate was 20.0% in the HSG (Figure 1A and Table 2). This was greater than three times in the original paper, which was 6.0% (Figure 1A and Table 2). In this study, the MST of the MSG (461 d) was significantly longer compared with that of the HSG (124 d, P < 0.001).

Figure 1 Overall survival of patients with bone metastasis. A: Overall survival by the new Katagiri score. The survival by the new Katagiri score: Middle (4-6), and higher (7-10) is indicated; B: Overall survival of patients with bone metastasis by the number of metastases. Meta: Number of metastases, n: Number of patients, MST: Median survival time; CI: Confidence interval.

Table 2 Historical comparison of survival outcomes between the periods ranging from 2005 to 2008 and 2020 to 2023.

NKSS	n	1-yr-survival rate in this study (2010-2023) (95%CI)	1-yr-survival rate in the original study (2005-2008) (95%CI)
0-3	3	-	91.4 (85.9–96.9)
4-6	62	56 (43-70)	49.3 (44.0-54.6)
7-10	71	20 (10-31)	6.0 (3.5–8.5)

NKSS: New Katagiri scoring system; CI: Confidence interval.

Other factors affecting patient survival

Survival with and without symptoms of bone metastasis were compared. The MST was 192 d with symptoms and 254 d without (Supplementary Figure 1). There was no significant difference (P = 0.4794). Bone metastases symptoms may not affect the survival of patients.

Next, we examined the effect of the number of bone metastases on survival. The MSTs for patients with ≤ 4 oligo-metastases were 288 d (Figure 1B). However, the MST of patients with at least 5 bone metastases was 180 d (Figure 1B). There was a significant survival difference between ≥ 5 multiple metastases and ≤ 4 oligo-metastases (P = 0.0080) (Figure 1B). This indicates that ≥ 5 bone metastases may negatively impact survival.

Survival impact of bone metastases treatments

Of the 136 patients with bone metastases, 72.1% received radiotherapy. The MST was 263 d with radiotherapy and 168 d without (Figure 2A). There was no significant difference between the two groups (P = 0.145) (Figure 2A). The main purpose of radiotherapy is to relief pain, not necessarily to prolong survival. Of the 137 patients, 92.6% received chemotherapy. The MST was 263 d with chemotherapy and 82 d without (P < 0.001) (Figure 2B). Chemotherapy for advanced cancer, if the patient was acceptable, may represent longer survival. Of the 136 patients, 73.5% received BMA. The MST was 276 d with BMA and 99 d without (P = 0.0175) (Figure 2C). The purpose of using BMAs is to prevent the onset of SREs[2], and as a result, it is expected that the QOL and ADL of the patients with bone metastases will be maintained. Improvements in the QOL and ADL of patients may indirectly contribute to prolonging survival. Of the 136 patients, 14.0% received ICIs. The MST was 1146 d with ICIs and 222 d without (P = 0.0128) (Figure 2D). ICIs may have some survival benefits on the patients with bone metastases.

Figure 2 Overall survival of patients with bone metastasis by the type of treatment. A: Radiation; B: Chemotherapy; C: Bone modifying agent; D: Immune check point inhibitors. n: Number of patients; Rad: Radiation; Cx: Chemotherapy; BMA: Bone modifying agent; ICI: Immune check point inhibitors.

DISCUSSION

The 1-year survival rate for the MSG was almost the same as the original data, but it was not the same in the HSG, which was 6.0% and 20.0% in the original study and this study, respectively[6]. It is important to identify patients with bone metastasis and predict their survival rate. This information can guide the subsequent treatment and management. The predictive systems should be updated promptly. This study indicates the necessity of updating. Scoring system such as NKSS is used the most commonly, but in the future, machine learning might be preferred because of its innovation and accuracy[8]. It was suggested that chemotherapy, BMA and ICIs may contribute to prolonging survival. In this study, ICI was used in 8 cases (42.1%) of gastric cancer with bone metastases and 6 cases (31.6%) of lung cancer. Generally, patients with bone metastasis have a poor prognosis, so it is difficult to suggest the effectiveness of ICI. Combination therapy of nivolumab and ipilimumab for non-small cell lung cancer (NSCLC) has been shown to be more effective than platinum combination chemotherapy, regardless of the presence or absence of bone metastases[9]. The hazard ratio was higher for patients with bone metastases than those without bone metastases in spite the 95% confidential interval was slightly greater than 1.0[9]. On the other hand, the patients with NSCLC and bone metastases who received ICIs had a higher hazard of death[10]. In the pivotal trial of ICIs for gastric cancer, there is no description of bone metastasis[11]. The ICIs prolong survival in malignant tumors with bone metastasis in CheckMate 025, a randomized phase 3 trial of nivolumab vs everolimus in previously treated advanced renal cell carcinoma, in which a subgroup analysis revealed that median OS in patients with bone metastases was 18.5 months with nivolumab vs 13.8 months with everolimus[12]. Thus, ICIs might prolong the survival time of patients with bone metastasis, although it was not significant[12]. The effect on bone metastasis with ICIs is still debatable. The generalizability of our study might be limited as this study is retrospective from a single institute.

Currently, orthopedic interventions are largely inappropriate if the expected survival time is 6 months or less[2]. In this study, the 6-month survival rate of the HSG was 75.3% (Figure 1A). Much more patients in the HSG may have a chance of benefiting from orthopedic treatment. Recently, patient surveillance studies indicated that many patients desire survival with preserved ADL rather than simply prolonging survival[13]. It is very important to keep patients’ ADL with bone metastases by various interventions. This study is a retrospective survey at one facility and there were some limitations. It is necessary to expand the scale of such kinds of surveillance to verify the results in the future.

CONCLUSION

In recent years, advances in various treatment methods have extended the survival period for patients with advanced cancer. It is necessary not only to simply extend survival time, but also to maintain ADL and improve QOL. For this purpose, various therapeutic interventions including surgical approach for bone metastasis, which is a disorder of locomotor organs, are increasingly required. Scoring system for the individual patient prognosis should be updated promptly because this system is the starting point for the treatment of bone metastasis.