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Prognostic value of low psoas muscle mass in patients with cervical spine metastasis
Journal of Clinical Neuroscience 66 (2019) 56–60
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Prognostic value of low psoas muscle mass in patients with cervical spine metastasis Sho Dohzono a,⇑, Ryuichi Sasaoka a, Kiyohito Takamatsu a, Masatoshi Hoshino b, Hiroaki Nakamura b a b
Department of Orthopaedic Surgery, Yodogawa Christian Hospital, 1-7-50 Kunijima Higasiyodogawa-ku, Osaka, Osaka 533-0024, Japan Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Osaka 545-8585, Japan
a r t i c l e
i n f o
Article history: Received 29 March 2019 Accepted 22 May 2019
Keywords: Prognosis Cervical spine metastases Psoas muscle Sarcopenia
a b s t r a c t Morphometric analyses have shown that the psoas muscle mass is associated with mortality in cancer patients. Because of the low incidence of cervical spine metastasis, few studies have been reported in this population. The present study aimed to identify the prognostic value of a psoas muscle mass in predicting overall survival. We also evaluated factors associated with surgical intervention for cervical spine metastases. We retrospectively evaluated 97 patients (mean age 65.2 years) diagnosed with cervical spine metastases between February 2009 and July 2016. The psoas muscle area was measured at the L3 level on computed tomography at the time nearest the diagnosis of cervical spine metastasis. Cox proportional hazards analyses were performed to evaluate the relation between overall survival and the psoas muscle’s composition. The mean overall survival for patients who underwent surgery was not significantly different from that for those without surgery. Multivariate analyses showed that the lowest percentage quartile (0%–25%) of the psoas muscle mass was associated with poor overall survival after adjusting for age and the prognostic predictive value (hazard ratio 1.93, 95% confidence interval 1.12–3.32; p = 0.017). Spinal cord compression, spinal instability, palsy, and the poor prognostic predictive value were factors associated with surgical intervention. In conclusion, a psoas muscle mass in the lowest quartile was independently associated with shorter survival among patients with cervical spine metastases. Although the poor prognostic predictive value was associated with surgical treatment, the overall survival was not different between patients who did or did not undergo surgery. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction After lung and liver, bone is the next most common site of metastases [1], with the spine the most common site of bone metastasis [2,3]. Spinal metastases have been found in 30%–70% of cancer patients in autopsy studies [4]. The proportion of cervical spine metastases is low, accounting for 8%–15% of vertebral metastases [5,6]. Several studies have revealed that cervical spine metastases have a poorer prognosis than metastases to other spinal sites [7–9]. In recent years, the psoas muscle had been attracting attention because of its relation to poor overall survival or surgical outcomes in patients with cancer. A meta-analysis and systematic review reported that lean skeletal muscle mass was associated with short overall survival in cancer patients [10]. Several studies have measured the total psoas muscle area at the level of the third lumbar vertebral body on cross-sectional computed tomography (CT) ⇑ Corresponding author. E-mail address: [email protected] (S. Dohzono). https://doi.org/10.1016/j.jocn.2019.05.024 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
images to evaluate low-area/density skeletal muscle masses [11,12]. Other studies have evaluated the association between psoas muscle size and overall survival in patients with spinal metastases [13,14]. Few studies, however, have focused on evaluating the prognostic value of the composition of the psoas muscle in patients with cervical spine metastases. Evaluating patients’ prognosis is important when deciding whether to undertake a surgical intervention in patients with cervical spine metastases. Although it has been established that surgical treatment could be considered in patients with neural compression and/or mechanical instability, few studies have addressed other factors that might be associated with the need for surgical intervention in patients with cervical spine metastases. The aim of this study was to evaluate the prognostic value of the psoas muscle mass and density in predicting overall survival in patients with cervical spine metastases. We also evaluated overall survival and factors associated with surgical intervention for cervical spine metastases.
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S. Dohzono et al. / Journal of Clinical Neuroscience 66 (2019) 56–60
2. Methods 2.1. Study population The data from 106 patients who were diagnosed with cervical spine metastases at Yodogawa Christian Hospital from March 2009 to August 2016 were reviewed retrospectively. Spinal metastases were diagnosed radiologically with CT, magnetic resonance imaging, or positron emission tomography. The minimum followup period after a diagnosis of spinal metastasis was 2 years, except in cases of death before that time. The institutional review board of Yodogawa Christian Hospital approved this study. The requirement for written informed consent was waived because of the study’s retrospective design. 2.2. Outcome measures The primary outcome was the relation between the composition of the psoas muscle and overall survival in patients with cervical spine metastases. The secondary outcome was identification of the factors associated with surgical intervention for cervical spine metastases. 2.3. Measurements The bilateral psoas muscles were measured by aggregating the cross-sectional area (mm2) at the third lumbar level on CT images obtained at the time closest to the diagnosis of spinal metastasis. Muscle area was normalized for patient height (m2) to calculate the index for the psoas muscle in squared millimeters (crosssectional area) divided by the squared meters (height) (mm2/m2). Muscle density was measured according to the muscle radiation attenuation in Hounsfield units (HU). Adipose tissue and skeletal tissue areas were defined according to standard HU ranges (190 to 30 HU for adipose tissue and 29 to 150 HU for skeletal muscle) [15]. Because the measurements of trunk muscles were dependent on the patient’s sex, the muscle area and density were evaluated separately for male and female cohorts using different cutoff points (above or below the 25th percentile within each cohort). 2.4. Factors associated with spinal surgery The following variables were estimated for analyses of factors associated with spinal surgery: sex, age (<65 or 65 years), degree of metastatic epidural spinal cord compression (0,1 or 2,3), spinal instability estimated by the Spinal Instability Neoplastic Score [16] (12 or 13), the predictive values of the modified Katagiri score [17] (6 or 7), and palsy (Frankel scale A, B or C, D or E). The degree of spinal cord compression was estimated on axial T2-weighted magnetic resonance images at the site of the most severe compression [18]. 2.5. Statistical analysis A t-test was used to compare the average muscle area and density between men and women. Survival was estimated using the Kaplan–Meier method and the results compared using the logrank test. Cox proportional hazards analyses were performed to evaluate the relation between overall survival and the composition of the psoas muscle. In a multivariate analysis, adjustments were made for age and the predictive values of the modified Katagiri scoring system. Logistic regression analyses were performed to analyze factors associated with spinal surgery.
Data were censored on April 30, 2018. Patients who were lost to follow-up were censored at the date of the last contact/follow-up. Patients who were alive on April 30, 2018 were censored for overall survival analysis. Overall survival was calculated from the date of diagnosing cervical spine metastasis to the date of death. IBM SPSS Statistics, version 19 (IBM Corp., Armonk, NY, USA) was used for all statistical analyses. A value of p < 0.05 was considered to indicate statistical significance. 3. Results 3.1. Demographics From among the original 106 patients with cervical spine metastases, we excluded 9 patients because of incomplete radiological or clinical data. The remaining 97 patients were enrolled in the study. Table 1 shows patients’ demographic and clinical data. The mean patient age was 65.2 years (range 34–91 years), and 53% of patients were men. The primary site was the lung, followed by the breast, prostate, colorectum, stomach, pancreas, and ‘‘others” (Table 1). The most frequent metastasis location was C7T2 followed by C3-C6. Table 2 shows baseline characteristics and the distribution of prognostic factors in patients with cervical spine metastases. The psoas major muscle area was significantly greater in men than in women (p < 0.001), but the psoas major muscle density did not differ significantly between the sexes (Table 3). 3.2. Survival The overall median survival time was 14.2 months (range 0.4– 86.0 months). The overall median survival time in patients in the
Table 1 Demographic and clinical data. Characteristic
No.
Sex Male Female
51 (53%) 46 (47%)
Age (years) 65 <65
57 (59%) 40 (42%)
BMI (kg/m2) 30 25–30 20–25 <20
3 (3%) 19 (20%) 45 (46%) 30 (31%)
Primary site of metastasis Lung cancer Breast cancer Prostate cancer Colorectal cancer Gastric cancer Pancreatic cancer Others
36 (37%) 16 (16%) 15 (15%) 9 (9%) 5 (5%) 3 (3%) 13 (13%)
Main location Oc-C2 C3-C6 C7-T2 Diffuse type
9 (9%) 24 (25%) 41 (42%) 23 (24%)
SINS 13 7–12 6 Surgery for spinal metastasis Use of an anti-resorptive agent* Radiation therapy for spinal metastasis
16 55 26 14 66 33
SINS: Spinal Instability Neoplastic Score. * Zoledronic acid or denosmab.
(16%) (57%) (27%) (14%) (68%) (34%)
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S. Dohzono et al. / Journal of Clinical Neuroscience 66 (2019) 56–60
icantly different from that of patients without spinal surgery (Fig. 2).
Table 2 Baseline characteristics of prognostic factors. Prognostic factors
No.
*
Primary site Rapid growth Moderate growth Slow growth
41 (42%) 34 (35%) 22 (23%)
Abnormal laboratory datay Yes No
81 (84%) 16 (16%)
Visceral or cerebral metastasis Yes No
46 (47%) 51 (53%)
ECOG performance status 0–2 3–4
59 (61%) 38 (39%)
Previous chemotherapy Yes No
38 (39%) 59 (61%)
Multiple skeletal metastasis Yes No
62 (64%) 35 (36%)
Chemotherapy after spinal metastasis Yes No
38 (39%) 59 (61%)
3.3. Prognostic factors Table 4 shows the associations between the psoas major muscle area and density with overall survival. The multivariate analysis showed that the lowest quartile of the psoas muscle area was associated with poor overall survival after adjusting for age and the modified Katagiri score (hazard ratio 1.93, 95% confidence interval 1.12–3.32; p = 0.017).
3.4. Factors associated with spinal surgery Table 5 shows the factors associated with spinal surgery. Logistic regression analyses showed that spinal cord compression (Metastatic Epidural Spinal Cord Compression 2,3), spinal instability (SINS 13), palsy (Frankel scale A, B or C, D), and poor prognostic value (modified Katagiri score 7) were factors associated with cervical spinal surgery.
BMI: body mass index; ECOG: Eastern Cooperative Oncology Group. * Categorized according to Katagiri et al. [17]. C-reactive protein (CRP) 0.4 mg/dL; lactate dehydrogenase (LDH) 250 IU/L; serum albumin <3.7 g/dL; platelet count <100,000/lL; serum calcium 10.3 mg/dL; total bilirubin 1.4.
y
Table 3 Psoas major muscle area and density in men and women. Study group
Men Women
Muscle area (mm2/m2)
Muscle density (HU)
Mean (SD)
p
Mean (SD)
p
458.3 (112.6) 316.8 (93.5)
<0.001
40.9 (6.4) 40.6 (8.4)
0.783
HU, Hounsfield units; SD, standard deviation.
lowest quartile of the psoas muscle area was 5.2 months, which was significantly shorter than that of patients in the >25th percentile of the muscle area (18.1 months) (p = 0.015). Overall survival, however, was not significantly different among groups divided into quartiles of psoas muscle density (Fig. 1). The overall survival of patients who underwent spinal surgery was not signif-
Fig. 2. Overall survival of patients according to the surgical treatment for cervical spine metastases. MST median survival time; n number.
Fig. 1. Overall survival according to the percentage quartiles (0%–25%. 25%–50%, 50%–75%, 75%–100%) of the psoas muscle area and density.
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S. Dohzono et al. / Journal of Clinical Neuroscience 66 (2019) 56–60 Table 4 Associations between psoas major muscle area and density with overall survival periods. Parameter
Adjusted*
Unadjusted
Muscle area (<25th percentile) Muscle density (<25th percentile)
HR (95% CI)
p
HR (95% CI)
p
1.90 (1.12–3.21) 0.86 (0.50–1.49)
0.017 0.585
1.93 (1.12–3.32) 0.74 (0.42–1.29)
0.017 0.736
HR, hazard ratio; CI, confidence interval. * Adjusted for age and the modified Katagiri score.
Table 5 Factors associated with spinal surgery. Factors
Odds ratio (95% CI)
p
Sex Male Female
1.63 (0.54–4.89) Reference
0.387
Age (years) 65 <65
1.21 (0.40–3.64) Reference
0.740
MESCC 0,1 2,3
Reference 7.70 (2.37–25.1)
0.001
SINS 13 12
12.2 (3.47–42.8) Reference
< 0.001
Modified Katagiri score 7 6
4.50 (1.47–13.8) Reference
0.008
Palsy (Frankel scale) A,B C,D E
35.4 (4.31–290) 28.0 (2.50–313) Reference
0.001 0.007
CI: confidence interval; MESCC: Metastatic Epidural Spinal Cord Compression, SINS: Spine Instability Neoplastic Score, ECOG: Eastern Cooperative Oncology Group.
4. Discussion This study investigated the relation between the composition of psoas muscle and overall survival, and it sought to identify factors associated with surgical intervention for cervical spine metastases. The psoas muscle area was categorized according to sex-specific quartile cutoff points. The results showed that the lowest quartile of psoas muscle mass was associated with shorter survival—independent of known prognostic factors. Although a poor prognostic predictive value was associated with surgical treatment, overall survival of patients who underwent surgery was not significantly different from that of patients who did not undergo surgery. Previous studies showed that the prognosis was worse for patients with cervical spine metastases than for those with metastases at other spinal sites [7–9], with a median survival time of 6– 7 months [9,19] and a mean survival time of 9.5–16.9 months [20,21]. Compared with those studies, the present study showed a longer survival time. Our median and mean survival times were 14.2 and 26.3 months, respectively. This difference may be because of the improvements in chemotherapy and hormonal therapy and the advent of novel targeted therapy. Recently, a growing number of studies have reported an association between skeletal muscle mass evaluated by CT and outcomes for patients with cancer. A meta-analyses and systematic review that included 38 studies revealed that low skeletal muscle mass was related to short overall survival [10]. Similarly, our study explored an association between low psoas muscle mass and poor overall survival in patients with cervical spine metastases. Such patients typically present with neurological symptoms, neck pain, and/or signs of mechanical instability. Hence, rehabilitation is important to regaining functional ability, regardless of whether
surgery is necessary. A retrospective study showed that rehabilitation improved functional outcomes in patients with spinal metastasis. Furthermore, those who achieved high functional gain after rehabilitation had longer survival [22]. In contrast, a randomized controlled trial found that paravertebral muscle training did not improve overall survival in patients with spinal metastases [23]. Thus, further studies are needed to evaluate whether the interventions aimed at preserving psoas muscle improved overall survival in patients with metastasis in the cervical spine. Indications for surgical intervention in patients with cervical spine metastases are progressive neurological compromise, neck pain, and spinal instability. Evaluation of the prognosis is important during the decision-making process regarding surgical treatment because major operations for patients with limited life expectancy should be avoided. The present study showed that a poor prognostic predictive value was associated with the need for surgical treatment, but overall survival in patients who underwent surgery was not significantly different from those without surgery. These results indicate that surgical intervention for cervical metastases may lead to extended overall survival. A randomized trial of patients with metastatic epidural spinal cord compression revealed the superiority of surgery followed by radiation therapy over irradiation alone. However, a subgroup analysis on cervical spine metastasis was not undertaken in that study [24]. Further studies are required to elucidate whether surgical intervention for cervical spine metastases affect overall survival. Several limitations of the present study must be acknowledged. First, its retrospective nature is a limitation, and the treatment of cervical spine metastases and systemic treatments for primary cancer were not uniform. Multivariate analysis reduces bias in prognostic estimates, but the analyses remain subject to biases resulting from unobserved confounding factors. Second, only a small number of patients (14%) underwent surgery for cervical spine metastases. Further studies with a larger sample size should be conducted to confirm the present results. In conclusion, psoas muscle with a low mass was independently associated with shorter survival in patients with cervical spine metastases. Although a poor prognostic predictive value was associated with surgical treatment, overall survival was not different between the patients who underwent surgery and those who did not. Acknowledgment We thank Nancy Schatken, BS, MT(ASCP), from Edanz Group (www.edanzediting.com/ac), for editing a draft of this manuscript. Declaration of Competing Interest We declare that the authors report no conflict of interest concerning the materials or methods used in this paper. Role of funding source This study received no specific grant from any funding agency in public, commercial or not-for-profit sectors.
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Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.05.024.
[13]
[14]
References [15] [1] Aaron AD. The management of cancer metastatic to bone. JAMA 1994;272:1206–9. [2] Ortiz Gomez JA. The incidence of vertebral body metastases. Int Orthop 1995;19:309–11. [3] Wong DA, Fornasier VL, MacNab I. Spinal metastases: the obvious, the occult, and the impostors. Spine 1990;15:1–4. [4] Jacobs WB, Perrin RG. Evaluation and treatment of spinal metastases: an overview. Neurosurg Focus 2001;11:e10. [5] Brihaye J, Ectors P, Lemort M, Van Houtte P. The management of spinal epidural metastases. Adv Tech Stand Neurosurg 1988;16:121–76. [6] Constans JP, de Divitiis E, Donzelli R, Spaziante R, Meder JF, Haye C. Spinal metastases with neurological manifestations. Review of 600 cases. J Neurosurg 1983;59:111–8. [7] Bartels RH, Feuth T, van der Maazen R, Verbeek AL, Kappelle AC, Andre Grotenhuis J, et al. Development of a model with which to predict the life expectancy of patients with spinal epidural metastasis. Cancer 2007;110:2042–9. [8] North RB, LaRocca VR, Schwartz J, North CA, Zahurak M, Davis RF, et al. Surgical management of spinal metastases: analysis of prognostic factors during a 10year experience. J Neurosurg Spine 2005;2:564–73. [9] Sciubba DM, Gokaslan ZL, Suk I, Suki D, Maldaun MV, McCutcheon IE, et al. Positive and negative prognostic variables for patients undergoing spine surgery for metastatic breast disease. Eur Spine J 2007;16:1659–67. [10] Shachar SS, Williams GR, Muss HB, Nishijima TF. Prognostic value of sarcopenia in adults with solid tumours: A meta-analysis and systematic review. Eur J Cancer 2016;57:58–67. [11] Shen W, Punyanitya M, Wang Z, Gallagher D, St-Onge MP, Albu J, et al. Total body skeletal muscle and adipose tissue volumes: estimation from a single abdominal cross-sectional image. J Appl Physiol 1985;2004(97):2333–8. [12] Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care.
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Appl Physiol, Nutr, Metabol = Physiologie appliquee, nutrition et metabolisme. 2008;33:997–1006. Zakaria HM, Basheer A, Boyce-Fappiano D, Elibe E, Schultz L, Lee I, et al. Application of morphometric analysis to patients with lung cancer metastasis to the spine: a clinical study. Neurosurg Focus 2016;41:E12. Gakhar H, Dhillon A, Blackwell J, Hussain K, Bommireddy R, Klezl Z, et al. Study investigating the role of skeletal muscle mass estimation in metastatic spinal cord compression. Eur Spine J 2015;24:2150–5. Mitsiopoulos N, Baumgartner RN, Heymsfield SB, Lyons W, Gallagher D, Ross R. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J Appl Physiol 1985;1998 (85):115–22. Fisher CG, DiPaola CP, Ryken TC, Bilsky MH, Shaffrey CI, Berven SH, et al. A novel classification system for spinal instability in neoplastic disease: an evidence-based approach and expert consensus from the Spine Oncology Study Group. Spine 2010;35:E1221–9. Katagiri H, Okada R, Takagi T, Takahashi M, Murata H, Harada H, et al. New prognostic factors and scoring system for patients with skeletal metastasis. Cancer Med 2014;3:1359–67. Bilsky MH, Laufer I, Fourney DR, Groff M, Schmidt MH, Varga PP, et al. Reliability analysis of the epidural spinal cord compression scale. J Neurosurg Spine 2010;13:324–8. Quan GM, Vital JM, Pointillart V. Outcomes of palliative surgery in metastatic disease of the cervical and cervicothoracic spine. J Neurosurg Spine 2011;14:612–8. Wu X, Ye Z, Pu F, Chen S, Wang B, Zhang Z, et al. Palliative surgery in treating painful metastases of the upper cervical spine: case report and review of the literature. Medicine (Baltimore) 2016;95:e3558. Cho W, Chang UK. Neurological and survival outcomes after surgical management of subaxial cervical spine metastases. Spine 2012;37:E969–77. Tang V, Harvey D, Park Dorsay J, Jiang S, Rathbone MP. Prognostic indicators in metastatic spinal cord compression: using functional independence measure and Tokuhashi scale to optimize rehabilitation planning. Spinal Cord 2007;45:671–7. Rief H, Omlor G, Akbar M, Welzel T, Bruckner T, Rieken S, et al. Feasibility of isometric spinal muscle training in patients with bone metastases under radiation therapy – first results of a randomized pilot trial. BMC Cancer 2014;14:67. Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366:643–8.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical study
Prognostic value of low psoas muscle mass in patients with cervical spine metastasis Sho Dohzono a,⇑, Ryuichi Sasaoka a, Kiyohito Takamatsu a, Masatoshi Hoshino b, Hiroaki Nakamura b a b
Department of Orthopaedic Surgery, Yodogawa Christian Hospital, 1-7-50 Kunijima Higasiyodogawa-ku, Osaka, Osaka 533-0024, Japan Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Osaka 545-8585, Japan
a r t i c l e
i n f o
Article history: Received 29 March 2019 Accepted 22 May 2019
Keywords: Prognosis Cervical spine metastases Psoas muscle Sarcopenia
a b s t r a c t Morphometric analyses have shown that the psoas muscle mass is associated with mortality in cancer patients. Because of the low incidence of cervical spine metastasis, few studies have been reported in this population. The present study aimed to identify the prognostic value of a psoas muscle mass in predicting overall survival. We also evaluated factors associated with surgical intervention for cervical spine metastases. We retrospectively evaluated 97 patients (mean age 65.2 years) diagnosed with cervical spine metastases between February 2009 and July 2016. The psoas muscle area was measured at the L3 level on computed tomography at the time nearest the diagnosis of cervical spine metastasis. Cox proportional hazards analyses were performed to evaluate the relation between overall survival and the psoas muscle’s composition. The mean overall survival for patients who underwent surgery was not significantly different from that for those without surgery. Multivariate analyses showed that the lowest percentage quartile (0%–25%) of the psoas muscle mass was associated with poor overall survival after adjusting for age and the prognostic predictive value (hazard ratio 1.93, 95% confidence interval 1.12–3.32; p = 0.017). Spinal cord compression, spinal instability, palsy, and the poor prognostic predictive value were factors associated with surgical intervention. In conclusion, a psoas muscle mass in the lowest quartile was independently associated with shorter survival among patients with cervical spine metastases. Although the poor prognostic predictive value was associated with surgical treatment, the overall survival was not different between patients who did or did not undergo surgery. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction After lung and liver, bone is the next most common site of metastases [1], with the spine the most common site of bone metastasis [2,3]. Spinal metastases have been found in 30%–70% of cancer patients in autopsy studies [4]. The proportion of cervical spine metastases is low, accounting for 8%–15% of vertebral metastases [5,6]. Several studies have revealed that cervical spine metastases have a poorer prognosis than metastases to other spinal sites [7–9]. In recent years, the psoas muscle had been attracting attention because of its relation to poor overall survival or surgical outcomes in patients with cancer. A meta-analysis and systematic review reported that lean skeletal muscle mass was associated with short overall survival in cancer patients [10]. Several studies have measured the total psoas muscle area at the level of the third lumbar vertebral body on cross-sectional computed tomography (CT) ⇑ Corresponding author. E-mail address: [email protected] (S. Dohzono). https://doi.org/10.1016/j.jocn.2019.05.024 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
images to evaluate low-area/density skeletal muscle masses [11,12]. Other studies have evaluated the association between psoas muscle size and overall survival in patients with spinal metastases [13,14]. Few studies, however, have focused on evaluating the prognostic value of the composition of the psoas muscle in patients with cervical spine metastases. Evaluating patients’ prognosis is important when deciding whether to undertake a surgical intervention in patients with cervical spine metastases. Although it has been established that surgical treatment could be considered in patients with neural compression and/or mechanical instability, few studies have addressed other factors that might be associated with the need for surgical intervention in patients with cervical spine metastases. The aim of this study was to evaluate the prognostic value of the psoas muscle mass and density in predicting overall survival in patients with cervical spine metastases. We also evaluated overall survival and factors associated with surgical intervention for cervical spine metastases.
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2. Methods 2.1. Study population The data from 106 patients who were diagnosed with cervical spine metastases at Yodogawa Christian Hospital from March 2009 to August 2016 were reviewed retrospectively. Spinal metastases were diagnosed radiologically with CT, magnetic resonance imaging, or positron emission tomography. The minimum followup period after a diagnosis of spinal metastasis was 2 years, except in cases of death before that time. The institutional review board of Yodogawa Christian Hospital approved this study. The requirement for written informed consent was waived because of the study’s retrospective design. 2.2. Outcome measures The primary outcome was the relation between the composition of the psoas muscle and overall survival in patients with cervical spine metastases. The secondary outcome was identification of the factors associated with surgical intervention for cervical spine metastases. 2.3. Measurements The bilateral psoas muscles were measured by aggregating the cross-sectional area (mm2) at the third lumbar level on CT images obtained at the time closest to the diagnosis of spinal metastasis. Muscle area was normalized for patient height (m2) to calculate the index for the psoas muscle in squared millimeters (crosssectional area) divided by the squared meters (height) (mm2/m2). Muscle density was measured according to the muscle radiation attenuation in Hounsfield units (HU). Adipose tissue and skeletal tissue areas were defined according to standard HU ranges (190 to 30 HU for adipose tissue and 29 to 150 HU for skeletal muscle) [15]. Because the measurements of trunk muscles were dependent on the patient’s sex, the muscle area and density were evaluated separately for male and female cohorts using different cutoff points (above or below the 25th percentile within each cohort). 2.4. Factors associated with spinal surgery The following variables were estimated for analyses of factors associated with spinal surgery: sex, age (<65 or 65 years), degree of metastatic epidural spinal cord compression (0,1 or 2,3), spinal instability estimated by the Spinal Instability Neoplastic Score [16] (12 or 13), the predictive values of the modified Katagiri score [17] (6 or 7), and palsy (Frankel scale A, B or C, D or E). The degree of spinal cord compression was estimated on axial T2-weighted magnetic resonance images at the site of the most severe compression [18]. 2.5. Statistical analysis A t-test was used to compare the average muscle area and density between men and women. Survival was estimated using the Kaplan–Meier method and the results compared using the logrank test. Cox proportional hazards analyses were performed to evaluate the relation between overall survival and the composition of the psoas muscle. In a multivariate analysis, adjustments were made for age and the predictive values of the modified Katagiri scoring system. Logistic regression analyses were performed to analyze factors associated with spinal surgery.
Data were censored on April 30, 2018. Patients who were lost to follow-up were censored at the date of the last contact/follow-up. Patients who were alive on April 30, 2018 were censored for overall survival analysis. Overall survival was calculated from the date of diagnosing cervical spine metastasis to the date of death. IBM SPSS Statistics, version 19 (IBM Corp., Armonk, NY, USA) was used for all statistical analyses. A value of p < 0.05 was considered to indicate statistical significance. 3. Results 3.1. Demographics From among the original 106 patients with cervical spine metastases, we excluded 9 patients because of incomplete radiological or clinical data. The remaining 97 patients were enrolled in the study. Table 1 shows patients’ demographic and clinical data. The mean patient age was 65.2 years (range 34–91 years), and 53% of patients were men. The primary site was the lung, followed by the breast, prostate, colorectum, stomach, pancreas, and ‘‘others” (Table 1). The most frequent metastasis location was C7T2 followed by C3-C6. Table 2 shows baseline characteristics and the distribution of prognostic factors in patients with cervical spine metastases. The psoas major muscle area was significantly greater in men than in women (p < 0.001), but the psoas major muscle density did not differ significantly between the sexes (Table 3). 3.2. Survival The overall median survival time was 14.2 months (range 0.4– 86.0 months). The overall median survival time in patients in the
Table 1 Demographic and clinical data. Characteristic
No.
Sex Male Female
51 (53%) 46 (47%)
Age (years) 65 <65
57 (59%) 40 (42%)
BMI (kg/m2) 30 25–30 20–25 <20
3 (3%) 19 (20%) 45 (46%) 30 (31%)
Primary site of metastasis Lung cancer Breast cancer Prostate cancer Colorectal cancer Gastric cancer Pancreatic cancer Others
36 (37%) 16 (16%) 15 (15%) 9 (9%) 5 (5%) 3 (3%) 13 (13%)
Main location Oc-C2 C3-C6 C7-T2 Diffuse type
9 (9%) 24 (25%) 41 (42%) 23 (24%)
SINS 13 7–12 6 Surgery for spinal metastasis Use of an anti-resorptive agent* Radiation therapy for spinal metastasis
16 55 26 14 66 33
SINS: Spinal Instability Neoplastic Score. * Zoledronic acid or denosmab.
(16%) (57%) (27%) (14%) (68%) (34%)
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S. Dohzono et al. / Journal of Clinical Neuroscience 66 (2019) 56–60
icantly different from that of patients without spinal surgery (Fig. 2).
Table 2 Baseline characteristics of prognostic factors. Prognostic factors
No.
*
Primary site Rapid growth Moderate growth Slow growth
41 (42%) 34 (35%) 22 (23%)
Abnormal laboratory datay Yes No
81 (84%) 16 (16%)
Visceral or cerebral metastasis Yes No
46 (47%) 51 (53%)
ECOG performance status 0–2 3–4
59 (61%) 38 (39%)
Previous chemotherapy Yes No
38 (39%) 59 (61%)
Multiple skeletal metastasis Yes No
62 (64%) 35 (36%)
Chemotherapy after spinal metastasis Yes No
38 (39%) 59 (61%)
3.3. Prognostic factors Table 4 shows the associations between the psoas major muscle area and density with overall survival. The multivariate analysis showed that the lowest quartile of the psoas muscle area was associated with poor overall survival after adjusting for age and the modified Katagiri score (hazard ratio 1.93, 95% confidence interval 1.12–3.32; p = 0.017).
3.4. Factors associated with spinal surgery Table 5 shows the factors associated with spinal surgery. Logistic regression analyses showed that spinal cord compression (Metastatic Epidural Spinal Cord Compression 2,3), spinal instability (SINS 13), palsy (Frankel scale A, B or C, D), and poor prognostic value (modified Katagiri score 7) were factors associated with cervical spinal surgery.
BMI: body mass index; ECOG: Eastern Cooperative Oncology Group. * Categorized according to Katagiri et al. [17]. C-reactive protein (CRP) 0.4 mg/dL; lactate dehydrogenase (LDH) 250 IU/L; serum albumin <3.7 g/dL; platelet count <100,000/lL; serum calcium 10.3 mg/dL; total bilirubin 1.4.
y
Table 3 Psoas major muscle area and density in men and women. Study group
Men Women
Muscle area (mm2/m2)
Muscle density (HU)
Mean (SD)
p
Mean (SD)
p
458.3 (112.6) 316.8 (93.5)
<0.001
40.9 (6.4) 40.6 (8.4)
0.783
HU, Hounsfield units; SD, standard deviation.
lowest quartile of the psoas muscle area was 5.2 months, which was significantly shorter than that of patients in the >25th percentile of the muscle area (18.1 months) (p = 0.015). Overall survival, however, was not significantly different among groups divided into quartiles of psoas muscle density (Fig. 1). The overall survival of patients who underwent spinal surgery was not signif-
Fig. 2. Overall survival of patients according to the surgical treatment for cervical spine metastases. MST median survival time; n number.
Fig. 1. Overall survival according to the percentage quartiles (0%–25%. 25%–50%, 50%–75%, 75%–100%) of the psoas muscle area and density.
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S. Dohzono et al. / Journal of Clinical Neuroscience 66 (2019) 56–60 Table 4 Associations between psoas major muscle area and density with overall survival periods. Parameter
Adjusted*
Unadjusted
Muscle area (<25th percentile) Muscle density (<25th percentile)
HR (95% CI)
p
HR (95% CI)
p
1.90 (1.12–3.21) 0.86 (0.50–1.49)
0.017 0.585
1.93 (1.12–3.32) 0.74 (0.42–1.29)
0.017 0.736
HR, hazard ratio; CI, confidence interval. * Adjusted for age and the modified Katagiri score.
Table 5 Factors associated with spinal surgery. Factors
Odds ratio (95% CI)
p
Sex Male Female
1.63 (0.54–4.89) Reference
0.387
Age (years) 65 <65
1.21 (0.40–3.64) Reference
0.740
MESCC 0,1 2,3
Reference 7.70 (2.37–25.1)
0.001
SINS 13 12
12.2 (3.47–42.8) Reference
< 0.001
Modified Katagiri score 7 6
4.50 (1.47–13.8) Reference
0.008
Palsy (Frankel scale) A,B C,D E
35.4 (4.31–290) 28.0 (2.50–313) Reference
0.001 0.007
CI: confidence interval; MESCC: Metastatic Epidural Spinal Cord Compression, SINS: Spine Instability Neoplastic Score, ECOG: Eastern Cooperative Oncology Group.
4. Discussion This study investigated the relation between the composition of psoas muscle and overall survival, and it sought to identify factors associated with surgical intervention for cervical spine metastases. The psoas muscle area was categorized according to sex-specific quartile cutoff points. The results showed that the lowest quartile of psoas muscle mass was associated with shorter survival—independent of known prognostic factors. Although a poor prognostic predictive value was associated with surgical treatment, overall survival of patients who underwent surgery was not significantly different from that of patients who did not undergo surgery. Previous studies showed that the prognosis was worse for patients with cervical spine metastases than for those with metastases at other spinal sites [7–9], with a median survival time of 6– 7 months [9,19] and a mean survival time of 9.5–16.9 months [20,21]. Compared with those studies, the present study showed a longer survival time. Our median and mean survival times were 14.2 and 26.3 months, respectively. This difference may be because of the improvements in chemotherapy and hormonal therapy and the advent of novel targeted therapy. Recently, a growing number of studies have reported an association between skeletal muscle mass evaluated by CT and outcomes for patients with cancer. A meta-analyses and systematic review that included 38 studies revealed that low skeletal muscle mass was related to short overall survival [10]. Similarly, our study explored an association between low psoas muscle mass and poor overall survival in patients with cervical spine metastases. Such patients typically present with neurological symptoms, neck pain, and/or signs of mechanical instability. Hence, rehabilitation is important to regaining functional ability, regardless of whether
surgery is necessary. A retrospective study showed that rehabilitation improved functional outcomes in patients with spinal metastasis. Furthermore, those who achieved high functional gain after rehabilitation had longer survival [22]. In contrast, a randomized controlled trial found that paravertebral muscle training did not improve overall survival in patients with spinal metastases [23]. Thus, further studies are needed to evaluate whether the interventions aimed at preserving psoas muscle improved overall survival in patients with metastasis in the cervical spine. Indications for surgical intervention in patients with cervical spine metastases are progressive neurological compromise, neck pain, and spinal instability. Evaluation of the prognosis is important during the decision-making process regarding surgical treatment because major operations for patients with limited life expectancy should be avoided. The present study showed that a poor prognostic predictive value was associated with the need for surgical treatment, but overall survival in patients who underwent surgery was not significantly different from those without surgery. These results indicate that surgical intervention for cervical metastases may lead to extended overall survival. A randomized trial of patients with metastatic epidural spinal cord compression revealed the superiority of surgery followed by radiation therapy over irradiation alone. However, a subgroup analysis on cervical spine metastasis was not undertaken in that study [24]. Further studies are required to elucidate whether surgical intervention for cervical spine metastases affect overall survival. Several limitations of the present study must be acknowledged. First, its retrospective nature is a limitation, and the treatment of cervical spine metastases and systemic treatments for primary cancer were not uniform. Multivariate analysis reduces bias in prognostic estimates, but the analyses remain subject to biases resulting from unobserved confounding factors. Second, only a small number of patients (14%) underwent surgery for cervical spine metastases. Further studies with a larger sample size should be conducted to confirm the present results. In conclusion, psoas muscle with a low mass was independently associated with shorter survival in patients with cervical spine metastases. Although a poor prognostic predictive value was associated with surgical treatment, overall survival was not different between the patients who underwent surgery and those who did not. Acknowledgment We thank Nancy Schatken, BS, MT(ASCP), from Edanz Group (www.edanzediting.com/ac), for editing a draft of this manuscript. Declaration of Competing Interest We declare that the authors report no conflict of interest concerning the materials or methods used in this paper. Role of funding source This study received no specific grant from any funding agency in public, commercial or not-for-profit sectors.
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Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.05.024.
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