Prognostic factors in patients with breast cancer metastasis in the femur treated surgically

BACKGROUND:  Breast carcinoma is a common malignancy in the developed world. Late diagnosis of the disease is associated with bone metastasis. The femur is commonly affected. Prognostic factors of mortality in patients with bone metastases originating from cancers in general have been reported. However, there is no specific report of prognostic factors in relation to breast cancer metastasis in the surgically treated femur. The determination of prognostic factors in patients with bone metastasis can assist in therapeutic decisions.

OBJECTIVE:  To determine clinical and orthopedic factors related to mortality in patients with breast cancer and metastases to the femur treated surgically.

METHOD:  This was a retrospective study and included 41 patients undergoing surgical treatment of femoral metastases. We analyzed the following variables: (i) number and location of bone metastases, (ii) visceral metastases, (iii) presence of pathological fracture, (iv) fixation method, and (v) laboratory tests. These factors were correlated with mortality using Cox Multivariate Logistic regression and Kaplan-Meier curves.

RESULTS:  There was a high prevalence of multiple metastases associated with pathological fractures at the time of surgery. Mortality was high and early. Subtrochanteric location, the presence of fractures, anemia, and alterations in renal function were associated with higher mortality. The fixation method, the number of bone metastases, and the presence of metastasis in other organs did not affect mortality.

CONCLUSIONS:  Breast cancer with metastasis to the femur is an advanced disease with early mortality. Clinical and orthopedic factors should be considered. Surgery is recommended when lesions occur, regardless of the type of implant used.

KEYWORDS: Breast Cancer; Femur Metastasis; Prognosis; Mortality

RESUMO

INTRODUÇÃO:  O carcinoma de mama é um tumor maligno comum no mundo desenvolvido. O diagnóstico tardio da doença está associada com metástases ósseas. O fêmur é comumente afetado. Fatores prognósticos de mortalidade em pacientes com metástases ósseas provenientes de cânceres em geral têm sido relatados. No entanto, não há nenhum relatório específico de fatores prognósticos em relação à metástase do câncer de mama no fêmur tratados cirurgicamente. A determinação de fatores prognósticos em pacientes com metástases ósseas pode auxiliar a tomada de decisões terapêuticas.

OBJETIVO:  Determinar os fatores clínicos e ortopédicos relacionados com a mortalidade em pacientes com câncer de mama e metástases ao fêmur tratados cirurgicamente.

MÉTODO:  Foi realizado um estudo retrospectivo que incluiu 41 pacientes submetidos ao tratamento cirúrgico de metástases femorais. Foram analisadas as seguintes variáveis: (i) número e a localização das metástases ósseas, (ii) metástases viscerais, (iii) presença de fratura patológica, (iv) método de fixação e (v) testes de laboratório. Esses fatores foram correlacionados com a mortalidade por meio de regressão logística multivariada Cox e curvas Kaplan-Meier.

RESULTADOS:  Houve uma alta prevalência de metástases múltiplas associadas com fraturas patológicas, no momento da cirurgia. A mortalidade foi alta e precoce. Localização subtrocantéricas, a presença de fraturas, anemia e alterações na função renal foram associados a maior mortalidade. O método de fixação, o número de metástases ósseas, e a presença de metástases em outros órgãos não alterou a mortalidade.

CONCLUSÕES:  O câncer de mama com metástase para o fêmur é uma doença avançada, com mortalidade precoce. Factores clínicos e ortopédicas deve ser considerado. A cirurgia é recomendada quando ocorrem lesões, independente do tipo de implante utilizado.

INTRODUCTION

Breast carcinoma is a common disease in the developed world. In the presence of metastases, the bone is affected in more than 50% of patients¹. In the appendicular skeleton, the femur is most commonly affected^2,3.

Although metastases to the axial skeleton are more frequent, metastases to the lower limbs cause greater loss of function. Bone metastases in the lower limb, even in the absence of fractures, lead to pain, functional limitations, and reduced quality of life for patients, due to strict bed rest and its complications, such as deep vein thrombosis, pneumonia, and decubitus sores⁴. The presence of fractures leads to a further increase in morbidity and mortality in these patients⁵. In practical terms, there is no specific clinical treatment for metastatic lesions in the femur^4,6.

Prognostic factors for mortality in cancer patients in general and for bone metastases have been reported. The presence of multiple bone metastasis, visceral metastasis, low hemoglobin, presence of fractures, and prosthetic replacement therapy are associated with higher mortality in this population^7-10. However, we are aware of no report of specific prognostic factors related to metastases derived from breast cancer that occur in the femur. Thus, the aim of this study was to determine factors related to clinical orthopedic issues and mortality in this cohort of patients.

SUBJECT AND METHODS

We conducted a retrospective cohort study involving 41 women diagnosed with breast cancer metastasis in the femur who underwent surgery between 1994 and 2007. We analyzed the following orthopedic variables: (i) the number of bone metastases, (ii) the presence of pathological fractures, (iii) the fixation method used in the treatment of the metastasis (synthesis or prostheses/endoprostheses), and (iv) the topography of the metastasis in the femur. The number and location of bone metastases was determined by scintigraphy and RX. In order to establish the topography of the lesions, in the femur was divided into proximal (transtrochanteric region and femoral neck), subtrochanteric region, distal, and diaphysis. The clinical parameters studied were serum hemoglobin (Hb) levels, serum creatinine (Cr) and urea (Ur) values, as well as the presence of metastasis in other organs. The staging of the tumor in relation to parenchymal and/or visceral metastasis was performed with the aid of computed tomography or MRI. We calculated the correlation of mortality with these preoperative variables using Cox multivariate logistic regression model. We also calculated survival curves with censored data by the Kaplan-Meier method (tested by a log-Rank method, with p < 0,05 as the limit for significance).

RESULTS

Patient follow-up ranged from 8 to 63 months (average, 37 months). One patient was lost to follow-up. The mean age was 53.8 years. The average number of bone metastases, including the femur, was 10.8. The proximal femur proved to be the most common location of bone metastases and fractures. Most of the patients (30) had pathological fracture at the time of surgery.

Clinical variables evaluated were the preoperative values of Cr and Ur (for renal function) and serum Hb. On average, the values were within normal limits. The presence of at least one visceral/parenchymal metastasis (most commonly a pulmonary metastasis) associated with the bone metastasis was detected in 24 patients (58%).

In the surgical treatment of bone metastases, femoral prosthetic replacement and syntheses (intramedullary nails or plates) were typically used.

Mortality was 70% (29 patients), primarily in the first year after surgery. The median survival was 8.1 ± 6.6 months as illustrated in Fig. 1. The location of the lesion, the presence of fractures, and clinical variables (Creatinine and Hemoglobin) were correlated with mortality. However, treatment method, presence of metastases in visceral organs, and the number of bone metastases were not, as shown in Table 1.

Figure 1
Kaplan-Meyer curve for overall mortality. The median survival was 8.1 months, with 70% of deaths occurring during the first year after surgery.

Table 1
Mortality estimates obtained by Cox multivariate logistic regression

				95% confidence interval
	Variables	regression coefficient	hazard ratio (HR)	lower	upper	p value
Topography of lesions	proximal(1) diaphysis distal	- 1.088	2.969(2)	1.010	4.929	0.050
		- 1.20	3.322(2)	1.362	5.820	0.050
		- 0.443	1.557(2)	- 0.462	3.517	0.610
Hemoglobin		- 0.233	1.263(3)	0.697	3.223	0.002
Urea		0.026	1.026	0.934	1.968	0.090
Creatinine		1.295	3.650(4)	1.690	5.610	0.002
Presence of fracture		1.14	3.130	1.170	5.060	0.016
Prosthetic replacement/osteosynthesis		- 0.251	0.900	- 1.006	2.806	0.996
Metastasis in other organs		0.419	0.400	- 1.560	2.306	1.520
Number of bone metastasis		0.030	0.910	- 1.010	2.900	0.987

• ⁽¹⁾
  neck and transtrochanteric region of femur;
• ⁽²⁾
  HR subtrochanteric reference;
• ⁽³⁾
  HR with a drop 1 mg/dl of hemoglobin;
• ⁽⁴⁾
  HR with an increase 1 mg/dl of creatine.

For statistical purposes, the subtrochanteric region was used as a reference. The presence of metastasis in this region increased mortality by 3- to 3.3-fold in comparison to those located in the proximal femur and diaphysis, respectively (Table 1). Figure 2 shows the distribution of mortality according to the location of the femoral lesion.

Figure 2
The Kaplan Meyer curves for distribution of mortality according to the location of the femoral lesion. Subtrochanteric lesions are significantly worse than all other femoral locations.

Clinical data showed that a 1 mg/dL increase in serum Creatinine was associated with about a 3.6-fold increased risk of death (Table 1). Creatinine values above 1.2 mg/dL also increased mortality (Fig. 3A). Urea levels did not appear to affect mortality.

Figure 3
Kaplan Meyer for distribution of mortality according to blood levels of creatinine (A) and hemoglobin (B). High levels of creatinine and low levels of hemoglobin significantly worsen prognosis.

A drop in the hemoglobin value of 1 mg/dL increased the risk of death by approximately 1.2 fold (Table 1). In patients with Hb < 11 mg/dL, mortality was significantly increased (Fig. 3B).

The presence of fractures was associated with increased mortality, especially in the first 12 months postoperatively (Table 1). However, after 24 months, there was no statistical difference in mortality (Fig. 4).

Figure 4
Kaplan Meyer distribution of mortality according to the presence or absence of femoral fractures. The presence of fractures significantly affects mortality during the first year after surgery, but not after that.

Mortality was not influenced by the number of bone metastases or the presence of multiple lesions (Table 1, Fig. 5B). Moreover, the presence of metastasis in other organs was not associated with increased mortality (Table 1, Fig. 5A). The type of procedure performed (osteosynthesis or arthroplasty) did not affect mortality (Table 1, Fig. 6).

Figure 5
Kaplan Meyer distribution of mortality according to the presence metastases in other organs (A), or according to the number of bone metastases (B). Both significantly enhance early mortality.

Figure 6
Kaplan Meyer distribution of mortality according to the surgical procedure. Survival is not affected by the selection of procedure.

DISCUSSION

Metastasis of breast cancer to the femur requires, in most cases, surgical intervention because conservative treatments and radiotherapy are not effective in preventing pathological fractures. The study population had advanced neoplasia, because the presence of bone metastasis indicates disseminated disease in stage IV. The average age here was 56 years, lower than that reported in the literature¹.

The average number of bone metastases at the time of treatment of a femoral lesion was high, so there was a tendency to also find metastasis elsewhere, an observation consistent with the literature⁹. In this series, femoral metastasis was associated with lesions in other organs in 58% of cases, an indicator of advanced disease. Thus, the staging of the disease is important because there is a high likelihood of finding other bone lesions and/or metastases in other organs at the time of diagnosis of a femoral lesion. These factors are important in preoperative planning and overall treatment of the disease.

In terms of topographic distribution, the femoral lesions were predominantly located in the proximal region, which is consistent with published reports¹¹. The proximal location of the lesion results in a higher probability of fracture due to mechanical forces acting on the hip³. Additionally, a proximal lesion more often needs prosthetic replacement, reflecting an increase in the duration of the surgery and its complications, thereby increasing mortality¹². However, in this study, the subtrochanteric region resulted in worse prognosis, in contrast to reported data¹³. This difference may be due to the fact that other reports considered this region to be part of the proximal femur. Thus, differentiation between lesions in the subtrochanteric proximal, intertrochanteric, and neck regions is important because of different associated mortalities. Thus, a subtrochanteric location, which is associated with reduced survival, may be treated with palliative procedures and, eventually, minimally invasive procedures to improve the quality of life.

In our study, the type of surgery (osteosynthesis or prosthetic replacement) had no effect on mortality. This divergence from the literature^14,15 may be due to the surgeon's level of expertise with arthroplasty. In the literature, fixation was associated with a greater chance of implant failure and revision surgery. These techniques should therefore be used in patients with reduced life expectancies. Prosthetic replacements should be reserved for patients with a better prognosis due to the reduced possibility of implant failure⁸.

Fractures were associated with high mortality in the first 12 postoperative months (Fig. 5), in agreement with the literature ² Fractures caused increased mortality due to restriction to bed rest and associated complications. Prophylactic treatment of bone lesions can result in shorter hospital stay and reduced blood loss during surgery, leading to lower mortality⁵. Fractures associated with bone metastasis of breast cancer have higher mortality than do other cancers, such as those of the lung or kidney^9,15.

Clinically, renal function parameters and hemoglobin levels were, on average, normal. Renal insufficiency and anemia are important in recovery and postoperative mortality^2,17. Anemia leads to slower wound healing, with an increased possibility of infection. An Hb level < 11 mg/dL is associated with poor prognosis and higher mortality¹⁷. In this study, Hb < 11 mg/dL (Fig. 4) and Cr > 1.2 g/dL (Fig. 3) were independent predictors of mortality, which is consistent with the literature¹⁷.

Visceral metastases occurred in 58% of the patients. The lung was most commonly affected, and liver and brain metastases were next. Distant metastasis is a relevant comorbidity because it leads to organ failure and frequent hospitalizations. Thus, it is associated with poor prognosis and higher mortality^2,12. However, in this cohort, there was no statistical relationship between the presence of visceral metastasis and higher mortality. There may be a bias in this result, as only patients who underwent surgery were included in our sample; we excluded patients with visceral metastases and other metastasis who did not undergo femoral surgery. Further studies are necessary to examine this.

Overall, 29 patients (70%) died after a minimum two months of follow-up. The average time between surgery and death was 8.1 months. This high mortality and early deaths reflects the typical behavior of an aggressive disease.

In conclusion, surgeons should assess these patients globally (orthopedic and clinical factors) before a surgical procedure is decided upon, because in most cases, a palliative surgical treatment should be considered. The surgical treatment of metastasis in the femur should be performed as soon as possible and allow rapid rehabilitation so that the patient can enjoy the last months of survival with the best possible quality of life.

ACKNOWLEDGEMENTS

The authors declare that they have no conflict of interest. There was no external funding source for this study.

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• ² Narazaki DK, Alvarenga Neto CC, Caiero MT, Camargo OP. Prognostic factors in pathologic fractures secondary to metastatic tumors. Clinics. 2006;61(4):313-20.
• ³ Keene JS, Sellinger DS, Mcbeath AA, Engber WD. Metastatic breast cancer in femur. A search for the lesion at risk of fracture. Clin Orthop Relat Res. 1986;203:282-8.
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Publication Dates

• Publication in this collection
  Oct 2014

History

• Received
  10 May 2014
• Reviewed
  21 May 2014
• Accepted
  22 June 2014