Trends in bone metastasis treatments over recent decades and a historical comparison using the new Katagiri score system: future predictions based on pilot studies

doi:10.21203/rs.3.rs-3247077/v1

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Trends in bone metastasis treatments over recent decades and a historical comparison using the new Katagiri score system: future predictions based on pilot studies

https://doi.org/10.21203/rs.3.rs-3247077/v1

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Background

In 2016, the Comprehensive Guidelines for the Diagnosis and Treatment of Bone Metastasis was published. 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.

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%, which was a significant improvement from 2014 when the scoring system was developed. Other factors significantly affecting survival included thoracic and lumbar metastases, five or more bone metastases, and treatment with chemotherapy and immune checkpoint inhibitors.

Conclusions

The 1-year survival rate in patients with a poorer score was improved. These patients may be candidates for surgery in the future. Finally, updating the scoring system is required.

bone metastasis

new Katagiri scoring system

prognosis

immune check point inhibitors

survival

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. There are few epidemiological studies of bone metastasis. Based on the SEER database, 113,317 of 2,470,634 cancer patients in the United States from 2010 to 2016 experienced bone metastases (4.6%) [1]. A Danish cohort study reported that 7.5% of 10 major cancers have bone metastasis [2].

Bone metastasis occurs when a malignant tumor metastasizes through the blood to the bone marrow. It occurs most frequently in the spinal cord, which has abundant blood flow [3]. Osteoclasts are particularly important for the establishment of metastatic bone lesions, because bone must be destroyed to produce space for cancer cells to grow. Treatment of bone metastasis includes orthopedic surgery, radiotherapy, drug treatment, and palliative care [4]. The primary purpose of orthopedic treatment is to maintain and improve mobility [4]. Radiation therapy is highly effective at providing relief from painful bone metastases [4]. Drug therapy includes chemotherapy that inhibits the growth of cancer cells, hormone therapy, and bone modifying agents (BMA) that act on osteoclasts [4]. In recent years, immune check point inhibitors (ICIs) have been used to treat various cancers [5]. Palliative care is given not only to relieve pain, but to provide holistic support, so that the QOL of patients can be improved [4].

Invasiveness of these interventions varies from relatively high, such as surgery, to low, such as pain killers. Each treatment has clinical benefits, but care givers should determine which intervention is appropriate for each patient with bone metastases. Various scoring systems that determine the choice of intervention have also been developed [4]. The degree of invasiveness is an important issue in selecting treatment and a patient’s life expectancy is an important determinant.

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 (ECOG 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]. The survival rate was 91% at 1 year and 78% at 2 years with a prognostic score of ≤ 3 [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. However, prognosis is gradually improving for many cancer types. For example, in Japan, the 5-year relative survival rates for all malignancies in males and females were 59.1% and 66%, respectively, from 2006 to 2008, whereas they were 62% and 66.9% from 2009 to 2011, respectively [7]. The statistics are the same in the United States, in which the rate of cancer mortality has declined from approximately 1% per year during the late 1990s to 1.5% per year during the 2000s and 2% per year from 2015 through 2019 [8]. Nearly 10 years have passed since 2014 when the NKSS was published, so the decrease in cancer mortality or the increase in survival rate is expected to be approximately 20%. 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.

Purpose

The purpose of this study was to clarify the recent changes in the treatment of bone metastasis over the past 12 years.

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 (LDH), total bilirubin (T-Bil), 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. The survival rate and survival time were displayed as a Kaplan–Meier curve. Then, the median survival time (MST), the 6-month or the 1-year survival rates were determined. Statistical analyses were performed using BellCureve for Excel ver 4.04 (Social Survey Research Information Co., Ltd. Japan).

Ethics approval

This study was referred to as a fact-finding survey of bone metastases in Akita Prefecture. It was conducted as a part 1 of this study. It was certified and approved by the Ethics Committees of Akita University (#2814). All procedures were conducted according to the Declaration of Helsinki.

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 [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.

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 Supplemental 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 metastasis

Metastases were found in 96 cases by diagnostic imaging (70.5%) (Supplemental Table 2). Among). Of the 136 patients, 16.9% (n = 23) had pain, and 5.1% (n = 7) had neurological symptoms including paralysis, numbness, and muscle weakness, whereas 2.9% (n = 4) had bone symptoms, such as a fracture and swelling of the bone, and 2.9% (n = 4) had elevated serum alkaline phosphatase levels (Supplemental Table 2). Of 136 cases, 70% (n = 95) 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) (Fig. 1). This distribution reflects the characteristics of the Department of Clinical Oncology, which primarily treats advanced cancers. The survival of the middle-score and the higher-score groups was examined. The lower-score group was omitted because of the limited number of patients. The one-year survival rate was 56% for the middle-score group (Fig. 1). This was similar to that of the original paper, which reported 49.3%. The one-year survival rate was 20% in the higher-score group (Fig. 1). This result was greater than three times the difference from the original score, which was 6.0% (Fig. 1). The MST of the middle-score group (461 days) was significantly longer compared with that of the higher-score group (124 days, p < 0.001).

Other factors affecting patient survival

Survival with and without symptoms of bone metastasis were compared. The MST was 192 days with symptoms and 254 days without (Supplemental Fig. 1). There was no significant difference (p = 0.4794). Bone metastases symptoms may not affect the survival of patients. Next, we examined the differences in survival depending on the site of bone metastasis. We compared the survival with and without spinal metastases (including cervical, thoracic, and lumbar spine). The MST was 244 days with spinal metastases and 279 days without, indicating that the MST with spinal metastases was significantly shorter (p = 0.0013) (Fig. 2A). In contrast, there was no significant difference between with and without pelvic bone metastases, or with and without other bone metastases (Fig. 2B, C). This indicates that spinal metastases alone may have a negative impact on survival. With respect to cervical spine metastases, there was no significant difference between with and without bone metastases (p = 0.258) (Fig. 2D); however, there was a significant difference between with and without bone metastases in the thoracic spine (p = 0.0087) (Fig. 2E) and lumbar spine (p = 0.0174) (Fig. 2F).

Next, we examined the effect of the number of bone metastases on survival. The MSTs for patients with ≤ 4 oligo-metastases were 288 days (Fig. 3). However, the MST of patients with at least 5 bone metastases was 180 days (Fig. 3). There was a significant survival difference between ≧ 5 multiple metastases and ≤ 4 oligo-metastases (p = 0.0080) (Fig. 3). This indicates that ≧ 5 bone metastases may negatively impact survival.

Survival impact of bone metastases treatments

Of the 136 patients with bone metastases, 98 (72.1%) received radiotherapy, whereas 38 did not. The MST was 263 days with radiotherapy and 168 days without (Fig. 4A). There was no significant difference between the two groups (p = 0.145) (Fig. 4A). Radiotherapy may not confer a survival benefit for patients with bone metastases. The main purpose of radiotherapy is to relief pain, not necessarily to prolong survival. Of the 137 patients, 126 (92.6%) received chemotherapy, whereas 9 did not. The MST was 263 days with chemotherapy and 82 days without (Fig. 4B). There was significant difference between the two groups (p < 0.001) (Fig. 4B). A subgroup analysis was performed based on the number of lines of chemotherapy received. The MSTs for single, two lines, and three or more lines were 124 days, 263 days and 420 days, respectively (Fig. 4C). Chemotherapy for advanced cancer, if the physical condition of the patient was acceptable, was sequential, so the more lines of treatments may simply represent longer survival. Of the 136 patients, 100 (73.5%) received BMA, whereas 36 did not. The MST was 276 days with BMA and 99 days without (Fig. 4D). There was a significant difference between the two groups (p = 0.0175) (Fig. 4D). In July 2014, nivolumab, an anti-programmed cell death-1 (PD-1) antibody, was approved in Japan as the first ICI for the treatment of unresectable malignant melanoma. [9]. As a result, it has gradually been used to treat various types of malignancies. Of the 136 patients, 19 (14.0%) received ICIs, and 117 did not. The MST was 1146 days with ICIs and 222 days without (Supplemental Fig. 2). There was a significant difference between the two groups (p = 0.0128) (Supplemental Fig. 2). ICIs may have some survival benefits on the patients with bone metastases.

In 2016, we developed comprehensive guidelines for the management of bone metastases [4]. Seven years have passed since then and cancer treatment has experienced great progress during this period. The greatest advance in treatment is the development of ICIs [5]), which continues to today. What impacts will these developments have? We examined the effect on prolonging the survival time of patients with bone metastases. The NKSS is a widely used method in Japan that uses six factors to predict prognosis [6]. The NKSS scores were calculated for 136 patients who visited the Department of Clinical Oncology of the Akita University hospital. Only 3 patients were in the lower-score group; however, 62 and 71 were in the middle-score and higher-score groups, respectively. There was a significant difference in survival time between these latter two groups, indicating that the NKSS remains an effective tool for predicting the prognosis of patients with bone metastasis. The 1-year survival rate for the middle-score group was almost the same as the original data, but it was not the same in the higher-score group, which was 6% and 20% in the original study, respectively [6]. The results were similar to US statistics, in which the 5-year survival rate improved by 2% each year from 2015 to 2019 [8]. This was greater than a threefold improvement. Therefore, we examined the factors involved in prolonging survival by treatment intervention. It was suggested that radiation therapy does not prolong survival, but chemotherapy and BMA may contribute to prolonging survival. In addition, it was shown that ICIs may significantly contribute to prolonging survival. There are no studies yet showing that ICIs prolong survival in malignant tumors with bone metastasis, except CheckMate 025 [10]. CheckMate 025 was a randomized phase 3 trial of nivolumab versus everolimus in previously treated advanced renal cell carcinoma [10], in which significantly improved overall survival (OS) was observed [10]. A subgroup analysis revealed that median OS in patients with bone metastases was 18.5 months with nivolumab versus 13.8 months with everolimus [hazard ratio: 0.72 (95% CI: 0.47–1.09)] [10]. Thus, ICIs prolong the survival time of patients with bone metastasis [10], although it was not significant [10]. Currently, orthopedic interventions are largely inappropriate if the expected survival time is 6 months or less [4]. The 6-month survival rate of the higher-score group was 75.3% in this study. Much more patients in the higher-score group may have a chance of benefiting from orthopedic treatment. In addition, the presence of upper spinal metastases and ≧ 5 bone metastases would be candidates for poorer prognostic factors. However, a previous study indicated that there was no significant difference in survival among the sites of the spine, including the cervical, thoracic, or lumbar regions (p = 0.08) [11]. For the NKSS, survival was compared between the axial bone only and the axial bone plus a limb; however, there was no significant survival benefit between the two (p = 0.148 ~ 0.347) [11]. This issue remains controversial, and it should be confirmed in the future. For the NKSS, the number of bone metastases was divided into two groups: solitary and multiple bone metastases [6]. The hazard ratio for multiple bone metastases was 1.55 (p < 0.001) [6]; however, whether a much higher number of bone metastases has a negative impact on survival should be determined. The previous finding that multiple bone metastases tend to occur more frequently compared with single- or oligo-metastases was also evident in the present study [12]. Bone metastases occur in the blood-rich spine, especially in the thoracic spine. In most cases, bone metastases are diagnosed by imaging while asymptomatic. This may be based on the hypothesis that even if a metastatic tumor reaches the bone marrow, it remains dormant for a certain period [13]. These results indicate that surveillance using imaging techniques may be important to detect dormant bone metastasis earlier. Symptomatic bone metastases do not reduce patient survival, whereas spinal metastases may decrease patient prognosis, perhaps because spinal cord paralysis progresses to disuse syndrome. Maintenance of ADL appears to prolong survival time [4]. Recently, patient surveillance studies indicated that many patients desire survival with preserved ADL rather than simply prolonging survival [14]. Thus, the maintenance of ADL and QOL is an important outcome for cancer patients. This study is a retrospective survey by one clinical department at one facility and there were some limitations. However, the results appear to show a certain tendency, because our department is the largest high-volume center in Akita Prefecture. Nonetheless, it is necessary to expand the scale of this study to verify the results in the future.

Acknowledgments

We thank Enago (https://www.enago.jp) for their critical English editing.

Compliance with Ethical Standards

Consent for this study was not obtained directly from each patient because the study was conducted using only medical information. Notification about the purpose and the implementation of the research was made public and an "opt-out" system was implemented to guarantee the opportunity to refuse as much as possible.

Conflict of Interest

No author has any conflict of interest concerning this publication.

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Table 1 is available in the Supplementary Files section.

SFig.1.pdf
Supplemental Figure 1. OS of patients with bone metastasis by the presence of symptoms
SFig.2.pdf
Supplemental Figure 2. OS of patients with bone metastasis by treatment with immune check point inhibitors ICI: immune check point inhibitor, n: number of patients
sTab.1.pdf
Supplemental Table 1. Frequency of bone metastasis by site
STab.2.pdf
Supplemental Table 2. Opportunity of finding of bone metastasis using a diagnostic measure
Table.pdf
Table 1. Patient characteristics CUP: Cancer of Unknown Primary, NET: Neuroendocrine Tumor, n: number, CI: confidence interval

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Trends in bone metastasis treatments over recent decades and a historical comparison using the new Katagiri score system: future predictions based on pilot studies

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Patients and Methods

Results

Discussion

Declarations

References

Tables

Supplementary Files

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