Abstract
Background/Aim: Individualization of treatment may improve the outcome of patients with bone metastases from breast cancer. To support physicians when selecting individualized programs for these patients, a simple instrument for predicting survival was created. Patients and Methods: In 126 female patients with breast cancer irradiated for bone metastases, 11 characteristics were evaluated with respect to survival. Results: On Cox regression analysis, Eastern Cooperative Oncology Group performance score (0-1 vs. ≥2; p=0.032) and visceral metastases (absence vs. presence; p=0.017) were independently associated with survival and incorporated into the scoring instrument. Three prognostic groups (0, 1 or 2 points) were designated with 12-month survival rates of 38%, 57% and 91%, and 24-month survival rates of 32%, 36% and 80%, respectively (p<0.001). Conclusion: This easy-to-use scoring instrument allows physicians to estimate the lifespan of patients irradiated for bone metastases from breast cancer and can facilitate individualization of their treatment.
Bone metastases are very common in patients with breast cancer and can be found in up to 70% of these patients during their lifetimes (1, 2). Although patients with bone metastases from breast cancer have more favorable prognoses than those with bone metastases from other types of solid cancer, their outcomes should be improved further (1). In addition to the administration of novel anticancer agents, this goal may be achieved with the comparatively new approach of personalized care including treatment regimens tailored to the specific needs of each patient. To choose the best possible treatment for an individual, one should be aware of the life expectancy. For patients with a short-expected lifespan, the treatment program should be as least onerous and as short as is practical. For patients with a longer expected lifetime, long-term local control and late treatment-related sequelae need to be considered to a greater extent.
To estimate a patient's life expectancy, survival scores have been established for different oncological situations, including metastatic disease (3-12). Considering the variations in biological behavior of the different cancer types, it is generally agreed that diagnosis-specific scoring instruments for each major entity would be desirable, ideally for each type of metastasis. For patients with metastatic breast cancer, specific prognostic instruments have already been developed for radiotherapy of brain metastases and vertebral metastasis associated with epidural spinal cord compression (13-19). This study was performed to contribute to optimal individualization of the treatment for patients with breast cancer. The goal was to add a specific survival score for those with breast cancer requiring radiation treatment for bone metastases not associated with spinal cord compression.
Patients and Methods
Eleven characteristics were retrospectively analyzed for potential associations with survival in a series of 126 females who received conventional multi-fraction longer-course radiotherapy for bone metastases from breast cancer. Dose-fractionation programs included 10×3 Gy over 2 weeks (n=77), 12-13×3.0 Gy over 2.5 weeks (n=4), 14-15×2.5 Gy (n=26) or 15×2.0 Gy (n=5) over 3 weeks and 18-20×2.0 Gy over 3.5-4 weeks (n=14). Patients with spinal metastases associated with cord compression were not included in this study, which was approved by the Ethics Committee of the University of Lübeck (18-254A, extension in 2019). The 11 potential prognostic characteristics, which are summarized in Table I, included: i) age on the first day of radiotherapy (≤65 years vs. ≥66 years, median=65 years), ii) performance score according to the Eastern Cooperative Oncology Group (ECOG 0-1 vs. ≥2), iii) period from breast cancer diagnosis until irradiation of bone metastases (≤39 vs. ≥40 months, median=39.5 months), iv) visceral metastases (no vs. yes) or v) additional non-irradiated bone (no vs. yes) metastases, vi) location of bone metastases (spine vs. other and both), vii) number of irradiated metastatic sites (1 site vs. ≥2 sites), viii) pathological fracture(s) (no vs. yes), ix) preceding surgery of bone metastases (no vs. yes), x) pre-radiotherapy treatment with bisphosphates or denosumab (no vs. yes), and xi) pre-radiotherapy systemic treatment (no vs. yes).
The potential prognostic factors and their distribution.
The time to death was referenced from the first day of radiotherapy. Statistical analyses were performed with the Kaplan-Meier method and the log-rank test (univariate analyses). Factors that proved to be significant (p<0.05) or showed a strong trend (p<0.06) for an association with survival were also evaluated in a multivariate manner (Cox regression model). Those characteristics that proved to be independently associated with survival were incorporated in the scoring instrument.
Results
Median follow up times were 16.5 (1-129) months in the entire series and 22 (3-102) months in those patients who were alive at their last follow-up visit. For the entire cohort, the median survival was 27 months. At 6, 12, 18 and 24 months, the survival rates were 80%, 66%, 57% and 51%, respectively. An ECOG performance score of 0-1 (p=0.003), and absence of visceral metastases (p=0.005) were significantly positively associatend with survival in the univariate analyses. Additionally, the absence of pathological fracture(s) showed a strong trend for being associated with better survival (p=0.058). The univariate analyses of all 11 investigated characteristics are summarized in Table II.
Survival curves obtained with the Kaplan-Meier method for groups of patients with 0 points, 1 point and 2 points.
On Cox regression analysis, the ECOG performance score [risk ratio (RR)=1.70, 95% confidence interval (CI)=1.05-2.72), p=0.032) and visceral metastases (RR=1.75, 95% CI=1.11-2.79, p=0.017) maintained significance. Pathological fracture(s) did not achieve significance (RR=1.40, 95% CI=0.86-2.23, p=0.17) in the Cox regression analysis.
The two independent prognostic factors, i.e. ECOG performance score and visceral metastases, were incorporated into the scoring instrument. Taking into account the corresponding survival rates, 0 points were given for an ECOG performance score of ≥2 and for the presence of visceral metastases, and 1 point was given for an ECOG performance score of 0-1 and for absence of visceral metastases. Based on these points, three groups were created, namely: 0 points, 1 point and 2 points. The survival rates of these groups at 6, 12, 18 and 24 months are summarized in Table II. The corresponding Kaplan-Meier curves are shown in Figure 1.
Discussion
During recent years, several studies have been carried out to improve the outcomes of patients with metastatic breast cancer (20-24). For patients with breast cancer who require irradiation for bone metastases, a variety of dose-fractionation regimens are available (1). A radiotherapy regimen can be extremely short, such as a single fraction of 8 Gy or 10 Gy, or longer, lasting for several weeks. These fractionated programs include lower dose per fraction (mainly 2-4 Gy) and higher total doses (mainly 20-40 Gy). When treating a patient with a fractionated regimen, physicians can choose between short-course (e.g. 5×4 Gy in 1 week) and longer-course (e.g. 10×3 Gy in 2 weeks or 20×2 Gy in 4 weeks) programs. It is generally agreed that for the majority of patients with bone metastases associated with impending or existing pathological fractures, metastatic spinal cord compression or an extensive soft-tissue component (so-called complicated bone metastases), fractionated radiotherapy is appropriate (1). The situation is different when a patient presents with uncomplicated painful bone metastases, i.e. without the above stated complications. For alleviating osseous pain in these patients, 1×8 Gy is as effective as fractionated radiotherapy programs. This has been demonstrated in several meta-analyses of randomized trials (25-28). Single-fraction irradiation appears particularly appropriate for patients with a limited survival time to avoid spending much of their short lifespan with radiation treatment. However, following irradiation with 1×8 Gy, a recurrence of the irradiated painful bone metastases was observed about 2.5 to 3 times more often than after fractionated, particularly after longer-course radiotherapy (25, 28). This aspect is particularly important for longer-term survivors, since according to randomized trials, median duration of control of pain may be longer than 1 year (29, 30).
Univariate analyses: Survival rates at 6, 12, 18 and 24 months.
Survival rates of the different prognostic groups.
In addition, remineralization and stabilization of osteolytic metastases following radiotherapy generally takes several months. According to a prospective randomized trial of 107 patients irradiated for bone metastases with either 1×8 Gy or 10×3 Gy, remineralization (relative increase in bone density) was significantly less pronounced after the single-fraction program, i.e. 120% compared to 173% (p<0.001) (31). Taking into account that longer-course radiotherapy is superior to single-fraction treatment with respect to local control and successful remineralization, it becomes clear that patients with more favorable survival prognoses appear to be good candidates for longer-course radiation programs with higher total doses such as 10×3 Gy and 20×2 Gy.
To make sure that each patient requiring irradiation for uncomplicated painful bone metastases from breast cancer receives the best personalized regimen, one should be able to estimate survival as precisely as possible. To facilitate this process, a new scoring system was developed particularly for these patients. Patients of the group with 2 points had excellent survival prognoses, with survival rates of 91% at 1 year and 80% at 2 years, respectively. Therefore, these patients can be considered suitable candidates for longer-course radiotherapy. For patients with vertebral metastases leading to spinal cord compression, longer-course programs with doses higher than 30 Gy were reported to result in better local control than 10×3 Gy (32). If this finding also applies to patients with uncomplicated bone metastases, patients achieving 2 points in the current study might be optimally irradiated with 15×2.5 Gy or 20×2 Gy. Of the patients of the 1-point group, 57% survived for 1 year or longer, but only 36% for 2 years or more. These patients may also benefit from radiotherapy with a longer-course; however, 10×3 Gy may be more appropriate. Patients of the group with 0 points had the least favorable survival prognoses, only 38% survived for 1 year or more. Therefore, these patients may be considered for single-fraction or short-course multifraction radiotherapy. When physicians consider these recommendations, it must be noted that the scoring system was created from retrospective data. This may have led to hidden selection biases, although we aimed to reduce such a risk by including only patients who received longer-course radiotherapy.
In summary, this new scoring instrument allows physicians to estimate the lifespan of breast cancer patients to be irradiated for bone metastases and may facilitate individualization of their treatment. This instrument may also contribute to proper stratification of patients to be included in future clinical trials.
Footnotes
Authors' Contributions
S.J., R.H., S.E.S. and D.R. participated in the design of the study. R.H., S.J. and D.R. provided data. D.R. and S.E.S. performed the analyses of the data. S.J., S.E.S. and D.R. drafted the manuscript, which has been reviewed and approved by all Authors.
Conflicts of Interest
On behalf of all Authors, the corresponding Author states that there is no conflict of interest related to this study.
- Received November 29, 2019.
- Revision received December 5, 2019.
- Accepted December 12, 2019.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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