- Email: [email protected]
Spinal Metastases in Breast Cancer: Single Center Experience
PEER-REVIEW REPORTS
Spinal Metastases in Breast Cancer: Single Center Experience Emilie Chan-Seng1,2, Marie Charissoux3, Ahmed Larbi4, Rapha¨el Te´treau5, Yannick Nicolas Gerber6, Delphine De Verbizier-Lonjon7, Franc¸ois Segnarbieux1, Nicolas Lonjon1,2
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Key words Breast cancer - Spinal metastasis - Survival - Treatment - Tumor board -
Abbreviations and Acronyms CT: Computed tomography Her2: Human epidermal growth factor receptor 2 HR: Hormonal receptor MRI: Magnetic resonance imaging SRE: Skeletal-related events UICC: Union for International Cancer Control From the Departments of 1 Neurosurgery and 7Nuclear Medicine, CHU Gui de Chauliac; 2INSERM U1051, Institut des Neurosciences de Montpellier; 3Department of Radiotherapy, Institute of Cancer from Montpellier Institut régional du cancer; 4Department of Radiology, CHU Lapeyronie; 5Department of Radiology, Institute of Cancer from Montpellier Institut régional du cancer, Montpellier, France; and 6John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom To whom correspondence should be addressed: Nicolas Lonjon, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014) 82, 6:1344-1350. http://dx.doi.org/10.1016/j.wneu.2014.08.010 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
- OBJECTIVE:
Metastases to the spine are a common manifestation of breast cancer leading to considerable reduction in the patient’s quality of life. Physicians must consider the different treatments available to decrease pain, reduce tumor burden, and ensure spinal stability to prevent neurological compromises. The first objective of this study is to analyze the epidemiology and outcomes of patients with spinal metastases from breast cancer and describe changes over time in these lesions. The second objective is to establish the current treatment of spinal metastases in this type of cancer.
- METHODS:
A total of 140 patients with breast cancer and spinal metastasis involvement were studied retrospectively. Demographic, clinical, and radiologic parameters were assessed, and the effects of systemic and local treatments on spinal metastasis were analyzed.
- RESULTS:
Median patient age at diagnosis of breast cancer was 50 years (19e86 years) and average follow-up was 100 months (4e384 months). Median overall survival after diagnosis of spinal metastasis was 18.6 months. Fractures were present in 24 patients (19.3%) at diagnosis and in up to 60 cases (48.6%) by the end of the study period.
- CONCLUSIONS:
The survival rate was better in patients with spinal metastases who received specific treatment. The evolution from lytic spinal metastasis to mixed and blastic subtypes is observed with adjunctive therapy for spinal metastases (bisphosphonates, radiotherapy). Increased attention must be given for high-grade breast cancer, as spinal metastases declare faster for these stages. This study provides evidence that a multidisciplinary tumor board specifically focusing on bone metastasis is essential to effectively manage patients with breast cancer and spinal metastasis.
INTRODUCTION About 20% of patients with breast cancer suffer from bone metastases (4). Skeletal involvement is present in more than half of the cases with distant metastases and spinal metastases are one of the most frequent sites of bony metastasis occurrence in this specific cancer (7, 19, 20, 22). The spinal involvement decreases dramatically the patient’s quality of life. Thus it is important to investigate different strategies to decrease pain, reduce tumor, and to correct sagittal spinal balance to prevent spinal cord injury. A multidisciplinary tumor board allows the coordination of all specialists to optimize treatment of spinal metastasis from breast cancer.
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Different clinical and skeletal-related events (SRE) such as pain, pathologic fracture, neurologic compression, hypercalcemia, and medullary insufficiency occur as a consequence of spinal metastasis evolution. At present there is no consensus guiding the follow-up of bone metastasis treatment from diagnosis through various available strategies. Recent (<3 months) computed tomography (CT) scan and magnetic resonance imaging (MRI) are essential to evaluate skeletal integrity and/ or the effect on spinal cord and nerve roots. Spinal metastasis can be diagnosed by an initial single photon emission CT. In case of positivity, a CT and/or MRI are
performed to evaluate the location and severity of the lesion(s) (21). Ongoing treatments of spinal metastasis from breast cancer include chemotherapy, hormonotherapy, bisphosphonates, radiotherapy, vertebroplasty, surgery (to ensure spinal stability, correct deformity, and decompress neural elements), and metabolic radiotherapy with samarium (15, 24). These interventions reduce tumor burden and pain, and can induce a spinal stabilization and a neural protection. The aim of the present study was to retrospectively analyze the epidemiology and outcomes of patients with spinal metastases from breast cancer and describe changes over time in these
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PEER-REVIEW REPORTS
lesions. The secondary objective was to show the interest of a mutlidisciplinary team tumor board. We compared the clinical and biologic evolution of breast cancer spinal metastasis treated with current methods guided by tumor board to previously published studies. METHODS Patient’s Data This retrospective cohort study included all patients diagnosed for breast cancer who were discussed in a multidisciplinary tumor board during the period 2009e2012 at one Regional Institute of Cancer (Institute of Cancer from Montpellier, France). This study was restricted to patients with spinal metastases from breast cancer to limit differences as a result of variation in primary cancer subtypes. For these patients, we retrospectively reviewed all the data from the initial diagnosis of breast cancer. For each patient, age at diagnosis of breast cancer, histologic subtype of breast cancer, stage (according to the Union for International Cancer Control [UICC] system), treatments, clinical/biologic evolution of cancer, spinal metastasis events, Tokuhashi and Tomita scoring system for preoperative evaluation of metastatic spine tumor prognosis, and date of death were recorded by electronic chart review. Radiologic characteristics of spinal involvement, such as lytic/osteoblastic/mixed lesion, presence of metastatic arachnoiditis, paravertebral extension, fractures, and/or kyphosis, were discussed after primary review of spine CT and/or MRI. Radiologic Characteristics Analysis Review of CT and MRI determined the topography of lesions (cervical, thoracic, lumbar), Tokuhashi and Tomita score, lytic, osteoblastic or mixed characteristics of spinal metastasis, presence of metastatic arachnoiditis and/or paravertebral extension, fractures, and/or spinal static imbalance. The same analyses were performed during the follow-up. The distribution rate of lytic, osteoblastic, and mixed spinal metastases was calculated just after the diagnosis and during follow-up. Statistical Analysis Data were analyzed using one-way analysis of variance when we compared more than
SPINAL METASTASES IN BREAST CANCER
2 groups (e.g., to compare different characteristics according to the stage of breast cancer) and Fisher’s test to underline a difference between 2 groups within a category (e.g., to assess the effect of treatments on bone condensation). A P value < 0.05 was considered statistically significant (Graphpad Prism, version 6, La Jolla, California, USA). RESULTS Between 2009 and 2012, 140 patients with breast cancer and spinal metastasis involvement were treated. The average follow-up of our population was 100 months (range, 4e384 months). Median age at diagnosis of breast cancer was 50 years (range, 19e86 years). Anatomic and pathologic characteristics of our breast cancer population are shown in Table 1. Forty-eight deaths occurred during the follow-up period (34% of the population), with a median age at death of 59.5 years(range, 22e87 years). Diagnosis of spinal metastasis from breast cancer in asymptomatic patients was done during systematic routine follow-up in 35% of cases (bone scintigraphy [single photon emission CT-CT], whole-body CT scan, or MRI). Axial and/ or radicular pain prompted us to identify spinal metastasis for 63.3% of patients. In 2 cases (1.4%), an overt neurological deficit led to the diagnosis of spinal metastasis. During the follow-up period, 4 patients (2.8%) developed clinical symptoms of spinal cord compression. SREs were observed in 49 patients and included pain (73%), pathologic fracture (18%), and neurological deficit (9%). The average survival time without a SRE was 58.7 months (median, 28 months) after the spinal metastasis diagnosis. At the end of the study, 73 patients (52%) had no SRE. For patients with a second independent SRE, the median delay between 2 SREs was 13 months. The delay between breast cancer diagnosis and spinal metastasis diagnosis events significantly differed according to UICC stage criteria (overall P< 0.05, Fisher’s test). Spinal metastasis occurred after a median delay of 88.5 months for stage I, 74 months for stage II, 24 months for stage III, and 0 months for stage IV (Figure 1). This trend toward a shorter period to diagnosis of spinal metastasis
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Table 1. Histologic Characteristics and Breast Cancer Classification Number of Patients
Percentage (%)
Histologic characteristic Ductal carcinoma
89
62.2
Lobular carcinoma
26
18.2
4
2.8
Mixed Sarcoma
3
2.1
Unknown
21
14.7
þ
95
68
20
14
Unknown
25
18
21
14.7
Hormonodependance
Her2 protein þ
79
55.2
Unknown
43
30.1
TNM T0
2
1.4
T1
30
21.4
T2
36
25.7
T3
15
10.7
T4
17
12.2
Stage according to UICC I
16
11.4
II
32
22.9
III
19
13.6
IV
48
34.3
Unknown
25
17.9
Her2, human epidermal growth factor receptor 2; UICC, Union for International Cancer Control.
with worsening clinical status was similar if we partitioned by TNM classification. We analyzed our cohort according to the hormonal receptor (HR) and/or human epidermal growth factor receptor 2 (Her2) protein status (Table 2). We showed a longer delay of spinal metastasis diagnosis for the HR/Her2 group (median, 45.5 months) compared with HRþ/Her2 (median, 28 months) and HRþ/Her2þ (median, 3 months) groups
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PEER-REVIEW REPORTS EMILIE CHAN-SENG ET AL.
SPINE Figure 1. Delay onset of breast cancer metastasis (months) according to the stage (Union for International Cancer Control [UICC]) at diagnosis of breast cancer. Statistics: Fisher’s test. ##Statistical difference (P < 0.01) between delay onset of stage III and II; ***Statistical difference (P < 0.001) between delay onset of stage III and I; ###Statistical difference (P < 0.001) between stage IV and II; $$$Statistical difference (P < 0.001) between delay onset of stage IV and III.
(P< 0.05). We showed no significant differences considering only the HR status. However, the overall survival after spinal metastasis diagnosis was independent on breast cancer stage, HR status, or Her2 protein status (median, 18.6 months). In addition, age at breast cancer diagnosis had no significant consequence on the onset of spinal metastasis (Figure 2). A systematic review of spinal CT and MRI was performed to assess characteristics of bony metastases and to describe the evolution of these lesions (Tokuhashi and Tomita score, fractures, metastatic arachnoiditis, and paravertebral extension). Results are summarized in Table 3. During evolution of breast cancer, fractures were present in 24 patients (19.3%) at diagnosis and in 60 cases (48.6%) by the end of the study period. Paravertebral extension was noted in 6 patients (4.8%) initially and in 10 cases at the end (8.1%). Median age at diagnosis of breast cancer was 50 years (range, 19e86 years). We divided the patients in 2 groups according to this median age. In both age groups, the rate of lytic metastases decreased significantly during the follow-up period. Conversely, the rate of mixed metastases increased in the same period, regardless of the age at diagnosis. There were no
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SPINAL METASTASES IN BREAST CANCER
differences in the rate of osteoblastic metastases in our cohort. Relative percentages of each tumor subtype changed, with a shift from lytic metastasis at diagnosis of breast cancer toward osteoblastic metastasis later in the disease course (Figure 3). Considering the UICC stage at diagnosis of breast cancer, patients with stage IV disease had a higher rate of lytic metastasis at diagnosis, but had a higher rate of mixed metastasis during follow-up (P< 0.01). This was also the case for stage I and III (P< 0.05). The rate of osteoblastic metastasis was not modified during the evaluation period. The evolution from lytic to mixed metastasis after combined treatment (chemotherapy, antiaromatases, bisphosphonates, and radiotherapy) was statistically significant (P< 0.001) (Figure 4). Chemotherapy alone resulted in decreased lytic metastasis and increased mixed metastasis (P< 0.01). Similar patterns were observed for radiotherapy and bisphosphonates. Finally, antiaromatase therapy only resulted in a decrease in lytic metastasis (P< 0.05). Then we compared the patients with unique metastasis (Tomita 1eTomita 5: group A) to patients with multiple metastases at spinal metastasis diagnosis (Tomita 6 and 7: group B). The median age at breast cancer diagnosis was 46 years (range, 25e70 years) in group A and 50 years (range, 19e86) in group B (P< 0.05). The median delay between spinal metastasis diagnosis and death did not significantly differ between group A (11 months) and group B (18.5 months). In group A, 58.8% of patients had metastatic events in more than 2 vertebral segments during evolution (70% mixed, 18% lytic, 12% osteoblastic). DISCUSSION According to the World Health Organization, worldwide, breast cancer is one of the most common cancer in women. With modern treatments, 5-year survival is more than 80%, according to the French cancer report issued in 2011 (National Institute of Cancer). Approximately 60% of new breast cancer cases arise in 50e74 years old women, with a median age at diagnosis of 61 years. Median age at diagnosis of primary breast cancer for our cohort was 50 years old. The relative 5-year survival rate decreases with age and cancer stage at
diagnosis (National Institute of Cancer). We observed similar trends in our population, with a mean survival of 122 months for patients with a stage I breast cancer, 111 months for stage II, 66.4 months for stage III, and 45.7 months for stage IV. Patients diagnosed for breast cancer at 50 years or less had an average survival of 117 months versus 82 months for patients diagnosed after 50 years. In our study, spinal metastasis was diagnosed during a systematic survey in asymptomatic patients in 35% of cases, which compares favorably with a recent study reporting 10% of cases (20). Spinal pain resulted in the diagnosis of spinal metastasis in 63.3% of patients, and neurological deficits in 1.4% of cases. Five to 10% of spinal metastases of various histologic types were diagnosed secondary to presentation with neurological signs (11, 20). For 15.7% of patients, spinal tumors were diagnosed before the primary breast cancer (6). A total of 50% of relapses of breast cancer arise during the first 2e4 years after primary diagnosis, but relapse can also be late (up to 20 years) (20). Delayed onset of spinal metastasis from breast cancer is not specifically described in the literature, but in our cohort we showed it occurs on average at 70 months after diagnosis and this might be extended to other cohort studies. In our case, onset of spinal metastasis was relatively short as the initial stage of breast cancer was high (stage III and IV, median delay of 24 and 0 months, respectively, against 88.5 months for stage I and 74 months for stage II). Previous reports support a relation between high stage of breast cancer and a high level of metastatic evolution, independent of location (7, 19, 20). Weber et al. (25) found in a retrospective study on 147 patients that the number of extraspinal organs involved by metastases was an independent prognostic factor of survival in patients with metastatic spinal cord compression from breast cancer. We confirm this data specifically for spinal metastasis from breast cancer. In addition, patients with diagnosis of breast cancer at 50 years old or less have a socalled “honeymoon” period without spinal metastasis (median, 55 months; range, 0e372 months), versus patients diagnosed after age 50 years (median, 36 months; range, 0e328 months). Several
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HRD/Her2D
HRD/Her2L
HRL/Her2D
HRL/Her2L
Un-known
HRD
HRL
16 (11.3)
67 (46)
4 (3)
12 (8.5)
44 (31.2)
93 (66)
22 (16)
Mean
56
51.8
58.5
46
52
53
48
Median
55
50
60
41.5
50.5
51
44
Maximal value
74
67
76
66
86
79
76
Minimal value
35
19
38
28
25
19
28
Mean
57.6
55.7
60
51.2
65
58
55
Median
56
56
60.5
44.5
64
59
52
Maximal value
74
79
76
72
90
79
78
Minimal value
37
19
43
30
28
19
30
Number of patients (percentage) Age of breast cancer diagnosis (years)
Age of spine metastasis diagnosis (years)
Delay onset of spine metastasis diagnosis after breast cancer diagnosis (months) Mean
14*
43*
16
56.8*
53.5
82.5
3*
28*
2
45.5*
31
62.5
Median Maximal value
60
245
60
216
372
288
Minimal value
0
0
0
0
0
0
41
74
40.8
98
81.5
120
Mean (years)
59.8
56
65
52.4
59
54.7
Median (years)
61
52
65
48
59
51
Maximal value (years)
66
81
78
76
81
78
Minimal value (years)
51
Long-term outcome after breast cancer diagnosis (months) Mean Death
Number (percentage of death inside the group)
4 (25)
22
52
30
22
30
23 (34)
2 (50)
9 (75)
30 (32)
11 (50)
Delay onset between spine metastasis diagnosis and death or end of outcome of our study (months) Mean
26.25
30.5
22.25
39
28
35.7
Median
20.5
26
21.5
23.5
24
27
Maximal value
84
115
45
113
116
123
Minimal value
4
2
1
1
2
1
Longer delay of spinal metastasis diagnosis after diagnosis of breast cancer for the HR/Her2 group (median, 45.5 months) compared with HRþ/Her2 (median, 28 months) and HRþ/Her2þ (median, 3 months) groups.
P value HRþ/Her2þ
HRD/Her2L
HRL/Her2L
P < 0.05
P < 0.05 P < 0.05
HRþ/Her2 HR, hormonal receptor; Her2, human epidermal growth factor receptor 2. *P< 0.05 (t-test).
investigators do not correlate age at diagnosis of breast cancer and age at diagnosis of spinal metastasis (27) and/or SRE (13). Early detection of breast cancer, because
of systematic campaign in target population, fosters to decrease the initial diagnostic stage of breast cancer, thereby delaying the appearance of spinal
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metastasis. Ongoing research tends to establish new therapeutics to limit the evolution of breast cancer and metastatic progression (9, 12, 16, 23). Thus, it is
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Table 2. Epidemiology of our Cohort According to Status of Hormonal Receptors and Her2
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SPINE Figure 3. Evolution of radiologic characteristics of breast cancer metastasis (lytic, mixed, osteoblastic) during outcome after diagnosis of breast cancer. T1: at diagnosis of spinal metastasis. T2: Evolution of spinal metastasis after specific treatment. T3: Evolution of spinal metastasis after specific treatment at the end of our study. Figure 2. Correlation between delay onset, diagnosis of breast cancer metastasis, diagnosis of breast cancer, age at diagnosis of breast cancer, and stage of cancer. Delay onset between diagnosis of breast cancer metastasis and diagnosis of breast cancer according to age and stage (Union for International Cancer Control) at diagnosis.
essential to invoke spine surveys prophylactically for patients in stage III and/or IV
Table 3. Radiologic Characteristics at Time of Diagnosis of Breast Cancer Spinal Metastasis Number of Patients
Percentage
Metastatic characteristics Lytic
46
Osteoblastic
29
Mixed
31
Tomita’s score Tomita 1
10
8.0
Tomita 2
7
5.7
Tomita 3
1
0.8
Tomita 4
2
1.6
Tomita 5
1
0.8
Tomita 6
1
0.8
Tomita 7
100
82
Fractures
24
19.3
Epidural extension
17
13.7
6
4.8
Paravertebral extension
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at the time of breast cancer diagnosis and in those diagnosed after 50 years old. In our study we focus on the relationship between hormonal status and Her2 positivity in primary breast cancer and its consequences on spine metastasis. Patients with HR/Her2 had a delayed onset of spinal metastasis (median, 45.5 months) compared with patients who had HRþ/Her2 (median, 28 months) or HRþ/Her2þ status (median, 3 months) (P< 0.05). To our knowledge no previous studies have addressed this point, although it seems contradictory with the fact that triple positive breast cancer patients have a better prognosis than triple negative (2, 8). Wedin et al. (26) analyzed this parameters in bone metastasis. Progesterone receptor positivity in skeletal metastasis is associated with longer survival after pathologic fracture, but this finding may be related to the large panel of therapeutics available. The lifespan after spinal metastasis diagnosis was similar, regardless of the initial stage of breast cancer, hormonal status, and/or Her2 protein (median, 18.6 months). In our cohort, the mean survival time without SRE was evaluated at 58.7 months after spinal metastasis diagnosis. Of our population 52% had not shown any SRE after metastasis diagnosis. Thus, a SRE was revealed in 48% of our patients, with a
median delay of 13 months after spinal metastasis diagnosis. Jensen et al. (13) found a higher incidence of SRE during the first year after bony metastasis diagnosis, without correlations with the initial stage of breast cancer. Recurrence of SRE was especially higher (average, 3e4 SRE/ year, 0.65 spinal events/year) without treatment by bisphosphonates (3, 18). Three osteolytic lesions increased the risk of SRE (18). Treatment with zoledronate decreased the SRE risk by 31% compare with pamidronate (3). In our cohort, the onset of a second SRE was shorter for single spinal metastasis (average, 9.3 months) than for multiple spinal metastases (average, 20 months). Survival time was 15.5 months for patients with 1 spinal lesion versus 31 months for patients with multiple lesions. However, given the small number of patients with single spinal metastasis in our group (n ¼ 22), comparison with the literature (1) should be cautious. A single spinal metastasis has a better prognosis than multiple localizations. Of our cohort 5.7% showed neurological deficit during the follow-up. Lagrange et al. (14) reported about 5% of neurological deficits secondary to epidural compression in metastatic breast cancer, although Lewis et al. (17) more recently reported a rate of 15%e20%. In our cohort, neurological deficit appeared primarily during the later stages of breast cancer evolution, when few therapeutic options remain. This retrospective study does not allow us to discriminate the specific impact of
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Figure 4. Evolution of breast cancer metastasis (lytic, osteoblastic, mixed) during outcome according to specific treatments. (A) Evolution of spinal metastasis under antiaromatase. (B) Evolution of spinal metastasis under chemotherapy. (C) Evolution of spinal metastasis under bisphosphonates. (D) Evolution of spinal metastasis under radiotherapy. (E) Evolution of spinal metastasis under combined treatments. L, lytic; O, osteoblastic; M, mixed.
chemotherapy on spinal metastasis from breast cancer as our cohort underwent systematically this treatment. However, treatments based on bisphosphonates or radiotherapy support an osteoblastic evolution of spinal metastasis. Ren et al. (22) showed, in a retrospective study of 1585 patients, that radiotherapy and bisphosphonates decrease pain and increase the delay to analgesia, thereby improving quality of life. Our study confirms this beneficial effect of bisphosphonates to decrease the fracture risk process (5, 10).
CONCLUSION Treatments for patients with breast cancer and showing spinal metastasis surveyed by a multidisciplinary tumor board (oncologist, radiotherapist, interventional radiologist, spine surgeon, and nuclear medicine) allow the optimization of therapeutic sequences to potentialize their effects (tumoral reduction, alleviation of
pain, spinal stability, and neural protection) and thus improve the patient’s quality of life. Future work should aim to optimize the monitoring. A flow chart according to breast cancer stage at diagnosis as well as spinal metastasis could establish more efficient treatment. A standardized consensus for spinal metastasis management could be also improve coverage, care, and the quality of life of these patients. REFERENCES 1. Abrahm JL, Banffy MB, Harris MB: Spinal cord compression in patients with advanced metastatic cancer: “all I care about is walking and living my life”. JAMA 299:937-946, 2008. 2. Belkacemi Y, Penault-Llorca F, Gligorov J, Azria D: Intérêt des classifications moléculaires pour prédire la rechute locale et la diffusion métastatique des cancers du sein. Cancer Radiother 12:577-583, 2008. 3. Berenson JR, Rosen LS, Howell A, Porter L, Coleman RE, Morley W, Dreicer R, Kuross SA, Lipton A, Seaman JJ: Zoledronic acid reduces
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16. Lee YH, Hsieh PF, Huang HH, Chan KC: Upper airway obstruction after cervical spine fusion surgery: role of cervical fixation angle. Acta Anaesthesiol Taiwan 46:134-137, 2008.
24. Souchon R, Wenz F, Sedlmayer F, Budach W, Dunst J, Feyer P, Haase W, Harms W, SautterBihl ML, Sauer R: DEGRO practice guidelines for palliative radiotherapy of metastatic breast cancer:
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 3 March 2014; accepted 6 August 2014; published online 10 August 2014 Citation: World Neurosurg. (2014) 82, 6:1344-1350. http://dx.doi.org/10.1016/j.wneu.2014.08.010 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
WORLD FEDERATION OF NEUROSURGICAL SOCIETIES Mission Statement To facilitate the personal association of neurological surgeons throughout the world. To aid in the exchange and dissemination of knowledge and ideas in the field of neurological surgery. To encourage research in neurological surgery and allied sciences. To address issues of neurosurgical demography. To address issues of Public Health. To implement, improve and promote the standards of neurosurgical care and training worldwide.
Membership Services (www.wfns.org) Teresa Chen Hsiao-Hui (Teresa) Chen Office Manager, WFNS Central Office World Federation of Neurosurgical Societies 5 Rue du Marché 1260 Nyon, Vaud, Switzerland Tel: +41 (0) 22 3624303 Fax: +41 (0) 22 3624352 Email: [email protected]
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Spinal Metastases in Breast Cancer: Single Center Experience Emilie Chan-Seng1,2, Marie Charissoux3, Ahmed Larbi4, Rapha¨el Te´treau5, Yannick Nicolas Gerber6, Delphine De Verbizier-Lonjon7, Franc¸ois Segnarbieux1, Nicolas Lonjon1,2
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Key words Breast cancer - Spinal metastasis - Survival - Treatment - Tumor board -
Abbreviations and Acronyms CT: Computed tomography Her2: Human epidermal growth factor receptor 2 HR: Hormonal receptor MRI: Magnetic resonance imaging SRE: Skeletal-related events UICC: Union for International Cancer Control From the Departments of 1 Neurosurgery and 7Nuclear Medicine, CHU Gui de Chauliac; 2INSERM U1051, Institut des Neurosciences de Montpellier; 3Department of Radiotherapy, Institute of Cancer from Montpellier Institut régional du cancer; 4Department of Radiology, CHU Lapeyronie; 5Department of Radiology, Institute of Cancer from Montpellier Institut régional du cancer, Montpellier, France; and 6John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom To whom correspondence should be addressed: Nicolas Lonjon, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2014) 82, 6:1344-1350. http://dx.doi.org/10.1016/j.wneu.2014.08.010 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
- OBJECTIVE:
Metastases to the spine are a common manifestation of breast cancer leading to considerable reduction in the patient’s quality of life. Physicians must consider the different treatments available to decrease pain, reduce tumor burden, and ensure spinal stability to prevent neurological compromises. The first objective of this study is to analyze the epidemiology and outcomes of patients with spinal metastases from breast cancer and describe changes over time in these lesions. The second objective is to establish the current treatment of spinal metastases in this type of cancer.
- METHODS:
A total of 140 patients with breast cancer and spinal metastasis involvement were studied retrospectively. Demographic, clinical, and radiologic parameters were assessed, and the effects of systemic and local treatments on spinal metastasis were analyzed.
- RESULTS:
Median patient age at diagnosis of breast cancer was 50 years (19e86 years) and average follow-up was 100 months (4e384 months). Median overall survival after diagnosis of spinal metastasis was 18.6 months. Fractures were present in 24 patients (19.3%) at diagnosis and in up to 60 cases (48.6%) by the end of the study period.
- CONCLUSIONS:
The survival rate was better in patients with spinal metastases who received specific treatment. The evolution from lytic spinal metastasis to mixed and blastic subtypes is observed with adjunctive therapy for spinal metastases (bisphosphonates, radiotherapy). Increased attention must be given for high-grade breast cancer, as spinal metastases declare faster for these stages. This study provides evidence that a multidisciplinary tumor board specifically focusing on bone metastasis is essential to effectively manage patients with breast cancer and spinal metastasis.
INTRODUCTION About 20% of patients with breast cancer suffer from bone metastases (4). Skeletal involvement is present in more than half of the cases with distant metastases and spinal metastases are one of the most frequent sites of bony metastasis occurrence in this specific cancer (7, 19, 20, 22). The spinal involvement decreases dramatically the patient’s quality of life. Thus it is important to investigate different strategies to decrease pain, reduce tumor, and to correct sagittal spinal balance to prevent spinal cord injury. A multidisciplinary tumor board allows the coordination of all specialists to optimize treatment of spinal metastasis from breast cancer.
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Different clinical and skeletal-related events (SRE) such as pain, pathologic fracture, neurologic compression, hypercalcemia, and medullary insufficiency occur as a consequence of spinal metastasis evolution. At present there is no consensus guiding the follow-up of bone metastasis treatment from diagnosis through various available strategies. Recent (<3 months) computed tomography (CT) scan and magnetic resonance imaging (MRI) are essential to evaluate skeletal integrity and/ or the effect on spinal cord and nerve roots. Spinal metastasis can be diagnosed by an initial single photon emission CT. In case of positivity, a CT and/or MRI are
performed to evaluate the location and severity of the lesion(s) (21). Ongoing treatments of spinal metastasis from breast cancer include chemotherapy, hormonotherapy, bisphosphonates, radiotherapy, vertebroplasty, surgery (to ensure spinal stability, correct deformity, and decompress neural elements), and metabolic radiotherapy with samarium (15, 24). These interventions reduce tumor burden and pain, and can induce a spinal stabilization and a neural protection. The aim of the present study was to retrospectively analyze the epidemiology and outcomes of patients with spinal metastases from breast cancer and describe changes over time in these
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lesions. The secondary objective was to show the interest of a mutlidisciplinary team tumor board. We compared the clinical and biologic evolution of breast cancer spinal metastasis treated with current methods guided by tumor board to previously published studies. METHODS Patient’s Data This retrospective cohort study included all patients diagnosed for breast cancer who were discussed in a multidisciplinary tumor board during the period 2009e2012 at one Regional Institute of Cancer (Institute of Cancer from Montpellier, France). This study was restricted to patients with spinal metastases from breast cancer to limit differences as a result of variation in primary cancer subtypes. For these patients, we retrospectively reviewed all the data from the initial diagnosis of breast cancer. For each patient, age at diagnosis of breast cancer, histologic subtype of breast cancer, stage (according to the Union for International Cancer Control [UICC] system), treatments, clinical/biologic evolution of cancer, spinal metastasis events, Tokuhashi and Tomita scoring system for preoperative evaluation of metastatic spine tumor prognosis, and date of death were recorded by electronic chart review. Radiologic characteristics of spinal involvement, such as lytic/osteoblastic/mixed lesion, presence of metastatic arachnoiditis, paravertebral extension, fractures, and/or kyphosis, were discussed after primary review of spine CT and/or MRI. Radiologic Characteristics Analysis Review of CT and MRI determined the topography of lesions (cervical, thoracic, lumbar), Tokuhashi and Tomita score, lytic, osteoblastic or mixed characteristics of spinal metastasis, presence of metastatic arachnoiditis and/or paravertebral extension, fractures, and/or spinal static imbalance. The same analyses were performed during the follow-up. The distribution rate of lytic, osteoblastic, and mixed spinal metastases was calculated just after the diagnosis and during follow-up. Statistical Analysis Data were analyzed using one-way analysis of variance when we compared more than
SPINAL METASTASES IN BREAST CANCER
2 groups (e.g., to compare different characteristics according to the stage of breast cancer) and Fisher’s test to underline a difference between 2 groups within a category (e.g., to assess the effect of treatments on bone condensation). A P value < 0.05 was considered statistically significant (Graphpad Prism, version 6, La Jolla, California, USA). RESULTS Between 2009 and 2012, 140 patients with breast cancer and spinal metastasis involvement were treated. The average follow-up of our population was 100 months (range, 4e384 months). Median age at diagnosis of breast cancer was 50 years (range, 19e86 years). Anatomic and pathologic characteristics of our breast cancer population are shown in Table 1. Forty-eight deaths occurred during the follow-up period (34% of the population), with a median age at death of 59.5 years(range, 22e87 years). Diagnosis of spinal metastasis from breast cancer in asymptomatic patients was done during systematic routine follow-up in 35% of cases (bone scintigraphy [single photon emission CT-CT], whole-body CT scan, or MRI). Axial and/ or radicular pain prompted us to identify spinal metastasis for 63.3% of patients. In 2 cases (1.4%), an overt neurological deficit led to the diagnosis of spinal metastasis. During the follow-up period, 4 patients (2.8%) developed clinical symptoms of spinal cord compression. SREs were observed in 49 patients and included pain (73%), pathologic fracture (18%), and neurological deficit (9%). The average survival time without a SRE was 58.7 months (median, 28 months) after the spinal metastasis diagnosis. At the end of the study, 73 patients (52%) had no SRE. For patients with a second independent SRE, the median delay between 2 SREs was 13 months. The delay between breast cancer diagnosis and spinal metastasis diagnosis events significantly differed according to UICC stage criteria (overall P< 0.05, Fisher’s test). Spinal metastasis occurred after a median delay of 88.5 months for stage I, 74 months for stage II, 24 months for stage III, and 0 months for stage IV (Figure 1). This trend toward a shorter period to diagnosis of spinal metastasis
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Table 1. Histologic Characteristics and Breast Cancer Classification Number of Patients
Percentage (%)
Histologic characteristic Ductal carcinoma
89
62.2
Lobular carcinoma
26
18.2
4
2.8
Mixed Sarcoma
3
2.1
Unknown
21
14.7
þ
95
68
20
14
Unknown
25
18
21
14.7
Hormonodependance
Her2 protein þ
79
55.2
Unknown
43
30.1
TNM T0
2
1.4
T1
30
21.4
T2
36
25.7
T3
15
10.7
T4
17
12.2
Stage according to UICC I
16
11.4
II
32
22.9
III
19
13.6
IV
48
34.3
Unknown
25
17.9
Her2, human epidermal growth factor receptor 2; UICC, Union for International Cancer Control.
with worsening clinical status was similar if we partitioned by TNM classification. We analyzed our cohort according to the hormonal receptor (HR) and/or human epidermal growth factor receptor 2 (Her2) protein status (Table 2). We showed a longer delay of spinal metastasis diagnosis for the HR/Her2 group (median, 45.5 months) compared with HRþ/Her2 (median, 28 months) and HRþ/Her2þ (median, 3 months) groups
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SPINE Figure 1. Delay onset of breast cancer metastasis (months) according to the stage (Union for International Cancer Control [UICC]) at diagnosis of breast cancer. Statistics: Fisher’s test. ##Statistical difference (P < 0.01) between delay onset of stage III and II; ***Statistical difference (P < 0.001) between delay onset of stage III and I; ###Statistical difference (P < 0.001) between stage IV and II; $$$Statistical difference (P < 0.001) between delay onset of stage IV and III.
(P< 0.05). We showed no significant differences considering only the HR status. However, the overall survival after spinal metastasis diagnosis was independent on breast cancer stage, HR status, or Her2 protein status (median, 18.6 months). In addition, age at breast cancer diagnosis had no significant consequence on the onset of spinal metastasis (Figure 2). A systematic review of spinal CT and MRI was performed to assess characteristics of bony metastases and to describe the evolution of these lesions (Tokuhashi and Tomita score, fractures, metastatic arachnoiditis, and paravertebral extension). Results are summarized in Table 3. During evolution of breast cancer, fractures were present in 24 patients (19.3%) at diagnosis and in 60 cases (48.6%) by the end of the study period. Paravertebral extension was noted in 6 patients (4.8%) initially and in 10 cases at the end (8.1%). Median age at diagnosis of breast cancer was 50 years (range, 19e86 years). We divided the patients in 2 groups according to this median age. In both age groups, the rate of lytic metastases decreased significantly during the follow-up period. Conversely, the rate of mixed metastases increased in the same period, regardless of the age at diagnosis. There were no
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SPINAL METASTASES IN BREAST CANCER
differences in the rate of osteoblastic metastases in our cohort. Relative percentages of each tumor subtype changed, with a shift from lytic metastasis at diagnosis of breast cancer toward osteoblastic metastasis later in the disease course (Figure 3). Considering the UICC stage at diagnosis of breast cancer, patients with stage IV disease had a higher rate of lytic metastasis at diagnosis, but had a higher rate of mixed metastasis during follow-up (P< 0.01). This was also the case for stage I and III (P< 0.05). The rate of osteoblastic metastasis was not modified during the evaluation period. The evolution from lytic to mixed metastasis after combined treatment (chemotherapy, antiaromatases, bisphosphonates, and radiotherapy) was statistically significant (P< 0.001) (Figure 4). Chemotherapy alone resulted in decreased lytic metastasis and increased mixed metastasis (P< 0.01). Similar patterns were observed for radiotherapy and bisphosphonates. Finally, antiaromatase therapy only resulted in a decrease in lytic metastasis (P< 0.05). Then we compared the patients with unique metastasis (Tomita 1eTomita 5: group A) to patients with multiple metastases at spinal metastasis diagnosis (Tomita 6 and 7: group B). The median age at breast cancer diagnosis was 46 years (range, 25e70 years) in group A and 50 years (range, 19e86) in group B (P< 0.05). The median delay between spinal metastasis diagnosis and death did not significantly differ between group A (11 months) and group B (18.5 months). In group A, 58.8% of patients had metastatic events in more than 2 vertebral segments during evolution (70% mixed, 18% lytic, 12% osteoblastic). DISCUSSION According to the World Health Organization, worldwide, breast cancer is one of the most common cancer in women. With modern treatments, 5-year survival is more than 80%, according to the French cancer report issued in 2011 (National Institute of Cancer). Approximately 60% of new breast cancer cases arise in 50e74 years old women, with a median age at diagnosis of 61 years. Median age at diagnosis of primary breast cancer for our cohort was 50 years old. The relative 5-year survival rate decreases with age and cancer stage at
diagnosis (National Institute of Cancer). We observed similar trends in our population, with a mean survival of 122 months for patients with a stage I breast cancer, 111 months for stage II, 66.4 months for stage III, and 45.7 months for stage IV. Patients diagnosed for breast cancer at 50 years or less had an average survival of 117 months versus 82 months for patients diagnosed after 50 years. In our study, spinal metastasis was diagnosed during a systematic survey in asymptomatic patients in 35% of cases, which compares favorably with a recent study reporting 10% of cases (20). Spinal pain resulted in the diagnosis of spinal metastasis in 63.3% of patients, and neurological deficits in 1.4% of cases. Five to 10% of spinal metastases of various histologic types were diagnosed secondary to presentation with neurological signs (11, 20). For 15.7% of patients, spinal tumors were diagnosed before the primary breast cancer (6). A total of 50% of relapses of breast cancer arise during the first 2e4 years after primary diagnosis, but relapse can also be late (up to 20 years) (20). Delayed onset of spinal metastasis from breast cancer is not specifically described in the literature, but in our cohort we showed it occurs on average at 70 months after diagnosis and this might be extended to other cohort studies. In our case, onset of spinal metastasis was relatively short as the initial stage of breast cancer was high (stage III and IV, median delay of 24 and 0 months, respectively, against 88.5 months for stage I and 74 months for stage II). Previous reports support a relation between high stage of breast cancer and a high level of metastatic evolution, independent of location (7, 19, 20). Weber et al. (25) found in a retrospective study on 147 patients that the number of extraspinal organs involved by metastases was an independent prognostic factor of survival in patients with metastatic spinal cord compression from breast cancer. We confirm this data specifically for spinal metastasis from breast cancer. In addition, patients with diagnosis of breast cancer at 50 years old or less have a socalled “honeymoon” period without spinal metastasis (median, 55 months; range, 0e372 months), versus patients diagnosed after age 50 years (median, 36 months; range, 0e328 months). Several
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HRD/Her2D
HRD/Her2L
HRL/Her2D
HRL/Her2L
Un-known
HRD
HRL
16 (11.3)
67 (46)
4 (3)
12 (8.5)
44 (31.2)
93 (66)
22 (16)
Mean
56
51.8
58.5
46
52
53
48
Median
55
50
60
41.5
50.5
51
44
Maximal value
74
67
76
66
86
79
76
Minimal value
35
19
38
28
25
19
28
Mean
57.6
55.7
60
51.2
65
58
55
Median
56
56
60.5
44.5
64
59
52
Maximal value
74
79
76
72
90
79
78
Minimal value
37
19
43
30
28
19
30
Number of patients (percentage) Age of breast cancer diagnosis (years)
Age of spine metastasis diagnosis (years)
Delay onset of spine metastasis diagnosis after breast cancer diagnosis (months) Mean
14*
43*
16
56.8*
53.5
82.5
3*
28*
2
45.5*
31
62.5
Median Maximal value
60
245
60
216
372
288
Minimal value
0
0
0
0
0
0
41
74
40.8
98
81.5
120
Mean (years)
59.8
56
65
52.4
59
54.7
Median (years)
61
52
65
48
59
51
Maximal value (years)
66
81
78
76
81
78
Minimal value (years)
51
Long-term outcome after breast cancer diagnosis (months) Mean Death
Number (percentage of death inside the group)
4 (25)
22
52
30
22
30
23 (34)
2 (50)
9 (75)
30 (32)
11 (50)
Delay onset between spine metastasis diagnosis and death or end of outcome of our study (months) Mean
26.25
30.5
22.25
39
28
35.7
Median
20.5
26
21.5
23.5
24
27
Maximal value
84
115
45
113
116
123
Minimal value
4
2
1
1
2
1
Longer delay of spinal metastasis diagnosis after diagnosis of breast cancer for the HR/Her2 group (median, 45.5 months) compared with HRþ/Her2 (median, 28 months) and HRþ/Her2þ (median, 3 months) groups.
P value HRþ/Her2þ
HRD/Her2L
HRL/Her2L
P < 0.05
P < 0.05 P < 0.05
HRþ/Her2 HR, hormonal receptor; Her2, human epidermal growth factor receptor 2. *P< 0.05 (t-test).
investigators do not correlate age at diagnosis of breast cancer and age at diagnosis of spinal metastasis (27) and/or SRE (13). Early detection of breast cancer, because
of systematic campaign in target population, fosters to decrease the initial diagnostic stage of breast cancer, thereby delaying the appearance of spinal
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metastasis. Ongoing research tends to establish new therapeutics to limit the evolution of breast cancer and metastatic progression (9, 12, 16, 23). Thus, it is
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Table 2. Epidemiology of our Cohort According to Status of Hormonal Receptors and Her2
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SPINE Figure 3. Evolution of radiologic characteristics of breast cancer metastasis (lytic, mixed, osteoblastic) during outcome after diagnosis of breast cancer. T1: at diagnosis of spinal metastasis. T2: Evolution of spinal metastasis after specific treatment. T3: Evolution of spinal metastasis after specific treatment at the end of our study. Figure 2. Correlation between delay onset, diagnosis of breast cancer metastasis, diagnosis of breast cancer, age at diagnosis of breast cancer, and stage of cancer. Delay onset between diagnosis of breast cancer metastasis and diagnosis of breast cancer according to age and stage (Union for International Cancer Control) at diagnosis.
essential to invoke spine surveys prophylactically for patients in stage III and/or IV
Table 3. Radiologic Characteristics at Time of Diagnosis of Breast Cancer Spinal Metastasis Number of Patients
Percentage
Metastatic characteristics Lytic
46
Osteoblastic
29
Mixed
31
Tomita’s score Tomita 1
10
8.0
Tomita 2
7
5.7
Tomita 3
1
0.8
Tomita 4
2
1.6
Tomita 5
1
0.8
Tomita 6
1
0.8
Tomita 7
100
82
Fractures
24
19.3
Epidural extension
17
13.7
6
4.8
Paravertebral extension
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at the time of breast cancer diagnosis and in those diagnosed after 50 years old. In our study we focus on the relationship between hormonal status and Her2 positivity in primary breast cancer and its consequences on spine metastasis. Patients with HR/Her2 had a delayed onset of spinal metastasis (median, 45.5 months) compared with patients who had HRþ/Her2 (median, 28 months) or HRþ/Her2þ status (median, 3 months) (P< 0.05). To our knowledge no previous studies have addressed this point, although it seems contradictory with the fact that triple positive breast cancer patients have a better prognosis than triple negative (2, 8). Wedin et al. (26) analyzed this parameters in bone metastasis. Progesterone receptor positivity in skeletal metastasis is associated with longer survival after pathologic fracture, but this finding may be related to the large panel of therapeutics available. The lifespan after spinal metastasis diagnosis was similar, regardless of the initial stage of breast cancer, hormonal status, and/or Her2 protein (median, 18.6 months). In our cohort, the mean survival time without SRE was evaluated at 58.7 months after spinal metastasis diagnosis. Of our population 52% had not shown any SRE after metastasis diagnosis. Thus, a SRE was revealed in 48% of our patients, with a
median delay of 13 months after spinal metastasis diagnosis. Jensen et al. (13) found a higher incidence of SRE during the first year after bony metastasis diagnosis, without correlations with the initial stage of breast cancer. Recurrence of SRE was especially higher (average, 3e4 SRE/ year, 0.65 spinal events/year) without treatment by bisphosphonates (3, 18). Three osteolytic lesions increased the risk of SRE (18). Treatment with zoledronate decreased the SRE risk by 31% compare with pamidronate (3). In our cohort, the onset of a second SRE was shorter for single spinal metastasis (average, 9.3 months) than for multiple spinal metastases (average, 20 months). Survival time was 15.5 months for patients with 1 spinal lesion versus 31 months for patients with multiple lesions. However, given the small number of patients with single spinal metastasis in our group (n ¼ 22), comparison with the literature (1) should be cautious. A single spinal metastasis has a better prognosis than multiple localizations. Of our cohort 5.7% showed neurological deficit during the follow-up. Lagrange et al. (14) reported about 5% of neurological deficits secondary to epidural compression in metastatic breast cancer, although Lewis et al. (17) more recently reported a rate of 15%e20%. In our cohort, neurological deficit appeared primarily during the later stages of breast cancer evolution, when few therapeutic options remain. This retrospective study does not allow us to discriminate the specific impact of
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Figure 4. Evolution of breast cancer metastasis (lytic, osteoblastic, mixed) during outcome according to specific treatments. (A) Evolution of spinal metastasis under antiaromatase. (B) Evolution of spinal metastasis under chemotherapy. (C) Evolution of spinal metastasis under bisphosphonates. (D) Evolution of spinal metastasis under radiotherapy. (E) Evolution of spinal metastasis under combined treatments. L, lytic; O, osteoblastic; M, mixed.
chemotherapy on spinal metastasis from breast cancer as our cohort underwent systematically this treatment. However, treatments based on bisphosphonates or radiotherapy support an osteoblastic evolution of spinal metastasis. Ren et al. (22) showed, in a retrospective study of 1585 patients, that radiotherapy and bisphosphonates decrease pain and increase the delay to analgesia, thereby improving quality of life. Our study confirms this beneficial effect of bisphosphonates to decrease the fracture risk process (5, 10).
CONCLUSION Treatments for patients with breast cancer and showing spinal metastasis surveyed by a multidisciplinary tumor board (oncologist, radiotherapist, interventional radiologist, spine surgeon, and nuclear medicine) allow the optimization of therapeutic sequences to potentialize their effects (tumoral reduction, alleviation of
pain, spinal stability, and neural protection) and thus improve the patient’s quality of life. Future work should aim to optimize the monitoring. A flow chart according to breast cancer stage at diagnosis as well as spinal metastasis could establish more efficient treatment. A standardized consensus for spinal metastasis management could be also improve coverage, care, and the quality of life of these patients. REFERENCES 1. Abrahm JL, Banffy MB, Harris MB: Spinal cord compression in patients with advanced metastatic cancer: “all I care about is walking and living my life”. JAMA 299:937-946, 2008. 2. Belkacemi Y, Penault-Llorca F, Gligorov J, Azria D: Intérêt des classifications moléculaires pour prédire la rechute locale et la diffusion métastatique des cancers du sein. Cancer Radiother 12:577-583, 2008. 3. Berenson JR, Rosen LS, Howell A, Porter L, Coleman RE, Morley W, Dreicer R, Kuross SA, Lipton A, Seaman JJ: Zoledronic acid reduces
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10. Hamaoka T, Madewell JE, Podoloff DA, Hortobagyi GN, Ueno NT: Bone imaging in metastatic breast cancer. J Clin Oncol 22:2942-2953, 2004.
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18. Major PP, Cook RJ, Lipton A, Smith MR, Terpos E, Coleman RE: Natural history of malignant bone disease in breast cancer and the use of cumulative mean functions to measure skeletal morbidity. BMC Cancer 9:272, 2009.
25. Weber A, Bartscht T, Karstens JH, Schild SE, Rades D: Breast cancer patients with metastatic spinal cord compression. Number of extraspinal organs involved by metastases influences survival. Strahlenther Onkol 190:283-286, 2014.
12. Hsu YH, Hsing CH, Li CF, Chan CH, Chang MC, Yan JJ, Chang MS: Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models. J Immunol 188: 1981-1991, 2012.
19. McLain RF: Cancer in the Spine: Comprehensive Care. Cancer of the Spine: How Big Is the Problem?, Kai-Uwe Lewandrowski, Gordon R. Bell, and Robert F. McLain. Totowa, NJ: Humana Press; 2006:392.
26. Wedin R, Skoog L, Bauer HC: Proliferation rate, hormone receptor status and p53 expression in skeletal metastasis of breast carcinoma. Acta Oncol 43:460-466, 2004.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 3 March 2014; accepted 6 August 2014; published online 10 August 2014 Citation: World Neurosurg. (2014) 82, 6:1344-1350. http://dx.doi.org/10.1016/j.wneu.2014.08.010 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2014 Elsevier Inc. All rights reserved.
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