Survival and Clinical Outcomes in Surgically Treated Patients With Metastatic Epidural Spinal Cord Compression: Results of the Prospective Multicenter AOSpine Study.

Published Ahead of Print on November 23, 2015 as 10.1200/JCO.2015.61.9338 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.61.9338

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Survival and Clinical Outcomes in Surgically Treated Patients With Metastatic Epidural Spinal Cord Compression: Results of the Prospective Multicenter AOSpine Study Michael G. Fehlings, Anick Nater, Lindsay Tetreault, Branko Kopjar, Paul Arnold, Mark Dekutoski, Joel Finkelstein, Charles Fisher, John France, Ziya Gokaslan, Eric Massicotte, Laurence Rhines, Peter Rose, Arjun Sahgal, James Schuster, and Alexander Vaccaro Michael G. Fehlings, Anick Nater, Lindsay Tetreault, and Eric Massicotte, University of Toronto; Joel Finkelstein and Arjun Sahgal, Sunnybrook Health Sciences Center, Toronto, Ontario; Charles Fisher, University of British Columbia and Vancouver Coastal Health, Vancouver, British Columbia, Canada; Branko Kopjar, University of Washington, Seattle, WA; Paul Arnold, University of Kansas, Kansas City, KS; Mark Dekutoski, The CORE Institute, Sun City West, AZ; John France, West Virginia University, Morgantown, WV; Ziya Gokaslan, Johns Hopkins University School of Medicine, Baltimore, MD; Laurence Rhines, MD Anderson Cancer Center, Houston, TX; Peter Rose, Mayo Clinic, Rochester, MN; James Schuster, University of Pennsylvania; and Alexander Vaccaro, Thomas Jefferson University, Philadelphia, PA. Published online ahead of print at www.jco.org on November 23, 2015. Supported by the Halbert Chair in Neural Repair and Regeneration and the Dezwirek Foundation (M.G.F.). Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Corresponding author: Michael G. Fehlings, MD, PhD, Toronto Western Hospital, 399 Bathurst St, 4W449, Toronto, Ontario M5T 2S8, Canada; e-mail: [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3399-1/$20.00

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Purpose Although surgery is used increasingly as a strategy to complement treatment with radiation and chemotherapy in patients with metastatic epidural spinal cord compression (MESCC), the impact of surgery on health-related quality of life (HRQoL) is not well established. We aimed to prospectively evaluate survival, neurologic, functional, and HRQoL outcomes in patients with MESCC who underwent surgical management. Patients and Methods One hundred forty-two patients with a single symptomatic MESCC lesion who were treated surgically were enrolled onto a prospective North American multicenter study and were observed at least up to 12 months. Clinical data, including Brief Pain Inventory, ASIA (American Spinal Injury Association) impairment scale, SF-36 Short Form Health Survey, Oswestry Disability Index, and EuroQol 5 dimensions (EQ-5D) scores, were obtained preoperatively, and at 6 weeks and 3, 6, 9, and 12 months postoperatively. Results Median survival time was 7.7 months. The 30-day and 12-month mortality rates were 9% and 62%, respectively. There was improvement at 6 months postoperatively for ambulatory status (McNemar test, P , .001), lower extremity and total motor scores (Wilcoxon signed rank test, P , .001), and at 6 weeks and 3, 6, and 12 months for Oswestry Disability Index, EQ-5D, and pain interference (paired t test, P , .013). Moreover, at 3 months after surgery, the ASIA impairment scale grade was improved (Stuart-Maxwell test P = .004). SF-36 scores improved postoperatively in six of eight scales. The incidence of wound complications was 10% and 2 patients required a second surgery (screw malposition and epidural hematoma). Conclusion Surgical intervention, as an adjunct to radiation and chemotherapy, provides immediate and sustained improvement in pain, neurologic, functional, and HRQoL outcomes, with acceptable risks in patients with a focal symptomatic MESCC lesion who have at least a 3 month survival prognosis. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

INTRODUCTION

DOI: 10.1200/JCO.2015.61.9338

The spine is the most common location for osseous metastases.1,2 Metastatic epidural spinal cord compression (MESCC) is among the most debilitating complications of metastatic spine cancer, and can lead to severe pain, sensory and motor deficits, gait disturbance, and bladder, bowel, and sexual dysfunction.1,2 A recent populationbased study revealed that 3.4% of US patients with cancer are hospitalized as a result of MESCC.3

Among patients with cancer in their last year of life, those with MESCC are hospitalized for approximately twice as long as those patients without MESCC.4 MESCC is associated with reduced life expectancy and quality of life.2 Treatments for MESCC are palliative; they aim to maintain or improve quality of life by alleviating pain, preserving neurologic function, and assuring spinal stability. There are few prospective studies that focus on surgical outcomes in patients with MESCC. These have mainly examined outcome in terms of clinician-assessed criteria, © 2015 by American Society of Clinical Oncology

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Fehlings et al

such as survival,5-7 pain scores,7 and neurologic outcome, which are often defined by ambulatory status,7-9 or Frankel or ASIA (American Spinal Injury Association) impairment scale (AIS) grade.6,7 The AOSpine North America MESCC study was designed to prospectively evaluate the impact of surgery in patients with MESCC on both clinician-assessed criteria and patient-reported functional and healthrelated quality of life (HRQoL) outcomes by using several validated instruments, including the International Standards For Neurologic Classification of Spinal Cord Injury (ISNCSCI), Short Form 36 Health Survey version 2 (SF-36 v2), EuroQol 5 dimensions (EQ-5D), and the Oswestry Disability Index (ODI).

Research ethics boards from each participating hospital approved the study protocol. Between March 2008 and March 2013, 190 patients with MESCC were screened and 163 were enrolled onto the study. Of these, 142 patients who were treated with surgery for intractable pain, neurologic deficits, and imminent or overt spinal stability, were the object of this analysis (Fig 1). The type and extent of the surgery and postoperative radiation therapy (RT) protocol were at the discretion of the clinical team.

PATIENTS AND METHODS

Data Collection Clinical data were gathered via standardized questionnaires administered during clinic appointments or by phone, and by using physical examinations conducted by physicians, nurses, or trained research assistants. Outcome measures included the Brief Pain Inventory, the ISNCSCI, SF-36 v2, ODI, EQ-5D, and adverse events. Although patients were observed for different amounts of time, outcome data were collected preoperatively and at least at 6 weeks and 3, 6, 9, and 12 months postoperatively.

Design, Participants, and Setting The AOSpine MESCC study was a prospective, multicenter, observational, cohort study involving ten North American centers that are members of the AOSpine North American Clinical Research Network, and were selected for their high volume of patients presenting with spinal metastases as well as their expertise in the management of this condition.

Statistical Analyses Data were managed by the central Data Management Center (Seattle, WA). Paired or independent t tests were used to compare continuous data, as appropriate. Two-sided Fisher’s exact tests and McNemar and Stuart Maxwell tests were used to compare independent and paired categorical

From March 2008 to March 2013; 10 centers

(N = 190)

22 met

168 met

Exclusion criteria 1. Subject has multiple (≥ 2) symptomatic spinal metastases 2. Subject has radiosensitive tumors (eg, lymphoma, leukemia, multiple myeloma, germ cell tumor) 3. Subject has radioresistant tumor 4. The primary cancer site is in the CNS or spine 5. Subject has poor life expectancy (< 3 months) 6. Tumor that has compressed only the cauda equina or spinal nerve 7. Subject has history of substance abuse (recreational drugs, alcohol) within 12 months prior to screening 8. Subject is a prisoner 9. Subject is currently involved in another study that precludes/complicates participation in this study 10. Subject has a disease/condition precluding accurate evaluation (eg, significant psychiatric disease)

Inclusion criteria 1. Subject with single (solitary) symptomatic (neurological deficit or pain) metastatic epidural spinal compression at any level confirmed by MRI 2. Subject ≥ 18 years of age 3. Subject is able and willing to give written informed consent to participate in the study 4. Subject is able to read and write English on elementary level

147 met

Surgical indications 1. Intractable pain 2. Neurological deficits 3. Imminent/actual spinal instability Among 23 unknown preoperative MESCC histopathology — 5 excluded

Included for analysis (n = 142)

Deaths during follow-up (n = 88)

Censored Alive at the time of censoring Patient withdrew from the study Patient was withdrawn from the study for noncompliance Loss in follow-up

Postoperative histological diagnosis revealed: Inclusion criterion not met: metastatic spinal cord lesion Langerhans cell histiocytosis Exclusion criterion met: radiosensitive metastatic lesion Non-Hodgkin lymphoma Burkett lymphoma Plasma cell neoplasm

(n = 2)

(n = 54) (n = 45) (n = 7) (n = 7) (n = 7)

Fig 1. AOSpine North America MESCC study patient selection and censoring flow chart. MESCC, metastatic epidural spinal cord compression; MRI, magnetic resonance imaging.

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Survival and Clinical Outcomes in Surgical Patients With MESCC

Table 1. Preoperative and Surgical Characteristics of Patients (N = 142) Characteristic Mean age, years SD (range) Female gender Comorbidities Total Cardiovascular Myocardial infarction Angina/coronary artery disease Arrhythmia Congestive heart failure Hypertension Peripheral arterial disease End-stage renal disease Diabetes Psychiatric Stroke Site of primary tumor Lungs Kidney Breast Prostate Gastrointestinal Unknown Skin Liver Ovarian Uterus Other Treatment history for MESCC lesion before surgery Received conservative oncologic treatment (any) Radiation therapy Chemotherapy Hormone therapy Metastasis located outside the spine Bone metastases (only) Visceral metastases (only) Both bone and visceral metastases MESCC spinal segment location Cervical Cervico-thoracic Thoracic No. of vertebral body involved 1 2 3 $4 Ability to walk four steps independently Bladder dysfunction Bowel dysfunction Spinal stability Stable Unstable Imminent instability Principal indication for surgical procedure Intractable pain Neurologic deficits Instability/imminent instability No. of level operated on Mean (SD; median; range) 1 2 3 4 5 6 7 (continued in next column)

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Value 59.4 11.97 (29-85) 59 (41.5) 108 80 5 15 9 2 66 3 1 16 15 1

(76.0) (74.0) (4.6) (13.9) (8.3) (1.8) (61.1) (2.8) (0.9) (14.8) (13.9) (0.9)

34 22 21 19 10 17 7 3 1 1 7

(23.9) (15.5) (14.8) (13.4) (7.0) (12.0) (4.9) (2.1) (0.7) (0.7) (4.9)

46 37 8 6 86 18 44 24

(32.4) (80.4) (17.4) (13.0) (60.6) (20.9) (51.2) (27.9)

22 (15.5) 4 (2.8) 116 (81.7) 99 17 19 7 102 24 17

(69.7) (12.0) (13.4) (4.9) (71.8) (16.9) (12.0)

50 (35.2) 69 (48.6) 23 (16.2) 55 (38.7) 57 (40.2) 30 (21.1) 5.3 3 8 27 19 29 16 19

(2.56; 5; 1-18) (2.1) (5.6) (19.0) (13.4) (20.4) (11.3) (13.4)

Table 1. Preoperative and Surgical Characteristics of Patients (N = 142) (continued) Characteristic

Value

8 9 10; 11; 12; 13; 15; 18, respectively Surgical procedures Anterior decompression and reconstruction only Posterior-only approach Combined anterior and posterior approach Spinal device used Total (any) Plates Pedicle screws Rods Cage Other spine device Other material used Total (any) Bone graft Bone substitute Bone cement Other

12 (8.4) 3 (2.1) 1 (0.7) 10 (7.0) 83 (58.5) 49 (34.5) 134 (94.4) 19 124 110 36 22 112 (78.9) 56 34 45 15

NOTE. All data are given as No. (%) unless otherwise indicated. Operative time from opening to closure in minutes: mean, 291.44; SD, 148.16; median, 272.0; range, 80-1,065. Information is missing for three patients. Abbreviations: MESCC, metastatic epidural spinal cord compression; SD, standard deviation.

variables, respectively. The Kaplan-Meier (K-M) method was used to analyze survival rate, and log-rank tests were conducted for statistical significance; the date of surgery was the starting date, and death or the last known contact date was the censor date. Type I error was set at P ,.05. All analyses were performed using SAS (SAS/STAT User’s Guide, Version 9.4; SAS Institute, Cary, NC).

RESULTS

Preoperative Demographic Data The cohort consisted of 59 women and 83 men with a mean age of 59.4 years (range, 29 to 85 years). One hundred eight patients (76.0%) had at least one reported comorbidity, and cardiovascular comorbidities were the most common type (80 patients; 74.0%). Of patients with cardiovascular comorbidities, 66 patients (61.1%) had hypertension and 15 patients (13.9%) had coronary artery disease. The most frequent sites of primary tumor were lung (34 patients; 23.9%), kidney (22 patients; 15.5%), breast (21 patients; 14.8%), and prostate (19 patients; 13.4%). Seventeen patients (12.0%) had MESCC from an unknown primary site of origin. Eighty-six patients (60.6%) presented with metastasis in addition to the MESCC lesion: 18 patients (20.9%) had skeletal metastasis outside the spine; 44 patients (51.2%) had visceral metastasis; and 24 patients (27.9%) had both skeletal and visceral metastasis. MESCC mostly involved the thoracic spine (116 patients; 81.7%), and 99 patients (69.7%) had involvement at one vertebral body. One hundred two patients (71.8%) were able to walk four steps independently. Of 46 patients (32.4%) who received preoperative, nonsurgical oncologic treatment of their MESCC lesion, 37 (80.4%) received RT (Table 1). © 2015 by American Society of Clinical Oncology


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Surgical and Postoperative Treatment Data Neurologic deficit (57 patients; 40.2%) and intractable pain (55 patients; 38.7%) were the main indications for surgery, whereas 92 patients (64.8%) underwent surgery for actual spinal instability (69 patients; 48.6%) or imminent spinal instability (23 patients; 16.2% [Table 1]). Median operative time from skin opening to closure was 272 minutes and ranged from 80 to 1,065 minutes. Surgeries involved a median of five vertebral levels (range, one to 18). Ten patients (7.0%) underwent an anterior procedure (one cervical single level and seven cervical, one cervico-thoracic, and one thoracic multiple levels), whereas 83 patients (58.5%) were treated via a posterior-only approach and 49 patients (34.5%) underwent combined anterior and posterior approaches. The surgeries were classified into 22 and 32 distinct procedural techniques for posterior-only and combined surgeries, respectively. Spinal reconstruction using spinal devices was performed in 134 patients (94.4%) and involved plates (19 patients), pedicle screws (124 patients), rods (110 patients), cages (36 patients), or other spine devices (22 patients), such as k-wires or lateral mass screws. Spinal reconstruction using other materials was performed in 112 patients (78.9%), including bone graft (56 patients), bone substitute (34 patients), or bone cement (45 patients). Postoperative RT was considered for all patients and was deemed beneficial and administered to 121 patients (85.2% [Table 1]). Postoperative Outcomes Compared with preoperative status, the proportion of patients who were able to walk four steps independently postoperatively was higher at 6 weeks and 3, 6, and 12 months. Although fewer patients suffered from bladder or bowel dysfunction at all followups, the difference was significant for bladder dysfunction at 6 months only (McNemar P = .019; Table 2). ISNCSCI motor scores for lower extremities and total were improved at 6 weeks and 3, 6, and 12 months postoperatively (Table 3). Twenty-nine patients (33.3%) had a preoperative, mild neurologic grade (AIS D) and 47 patients (54.0%) had a preoperative, normal neurologic grade (AIS E). At 3 months, the AIS grade was improved (Stuart-Maxwell test P = .004) but was not improved at 6 weeks and 6 and 12 months (Table 4). Changes in AIS grade at 6 weeks are illustrated in Appendix Table A1 (online only).

Both pain severity and pain interference scores on the Brief Pain Inventory were lower at 6 weeks and 3, 6, and 12 months than preoperatively (Table 3). Similarly, both ODI and EQ-5D scores improved at 6 weeks and 3, 6, and 12 months postoperatively (Table 3). There was improvement between preoperative SF-36 scores and 6-week and 3-, 6- and 12-month follow-ups for the bodily pain scale; 3-, 6-, and 12-month follow-ups for the emotional wellbeing scale; 3-, 6-, and 12-month follow-ups for the social functioning scale; and 6-month follow-ups for both the mental component score (MCS) and the role limitations as a result of emotional problems scale (Table 3). However, postoperative scores declined for the general health scale at 6-week and 3- and 6-month follow-ups, and for the physical component score, physical functioning scale, and role limitations as a result of physical problems scale at 6-week follow-ups (Table 3). There were no differences between pre- and postoperative scores for the energy/fatigue scale.

Survival During follow-up, 88 patients died and 54 patients were censored (45 patients survived, seven patients self-withdrew from the study, one patient was withdrawn for lack of compliance, and one patient was lost to follow-up); the K-M survival estimate at 1 year postoperatively was 38.0%. Of 88 patients who died, eight patients (9.1%) died within 30 days and 40 patients (45.5%) died within 3 months postoperatively. The median survival time (MST) was 230.5 days (7.7 months). Figure 2 shows the K-M survival curve with 95% confidence limits. Survival differed (P , .001) on the basis of primary tumor site: lung (n = 34; MST, 135 days), breast (n = 21; MST, 368 days), kidney (n = 22; MST, 271 days), and prostate (n = 19; MST, 200 days). Surgical Complications A total of 96 complications occurred in 42 patients (29.6%) within 30 days after surgery. Three patients had CSF leakage postoperatively that was not associated with wound dehiscence or infection or required a second surgery. There were 24 infections in 20 patients (25.0%); urinary tract infections and wound infections each accounted for 10 patients (10.4%). Postoperative wound

Table 2. Pre- and Postoperative Status of Ability to Walk Four Steps Independently With or Without Aid, and Bladder and Bowel Dysfunction Follow-Up Time per Variable Ability to walk four steps independently 6 weeks 3 months 6 months 12 months Bladder dysfunction 6 weeks 3 months 6 months 12 months Bowel dysfunction 6 weeks 3 months 6 months 12 months

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No. of Patients

Preoperative (%)

P (McNemar)

Postoperative (%)

79 66 55 31

57 51 41 23

(72.2%) (77.3%) (74.6%) (74.2%)

69 63 53 29

(87.3%) (95.5%) (96.4%) (93.6%)

.007 .003 .001 .034

79 66 55 30

11 (13.9%) 7 (10.6%) 8 (14.6%) 5 (16.7%)

6 2 1 2

(7.6%) (3.0%) (1.8%) (6.7%)

.166 .096 .019 .257

79 66 55 30

8 7 8 5

3 (3.8%) 2 (3.0%) 0 1 (33%)

.096 .096 N/A .103

(10.1%) (10.6%) (14.6%) (16.7%)




Table 3. Pre- and Postoperative Scores by Follow-Up Visit Follow-Up Time ISNCSCI motor score: upper extremities 6 weeks 3 months 6 months 12 months ISNCSCI motor score: lower extremities 6 weeks 3 months 6 months 12 months ISNCSCI motor score: total 6 weeks 3 months 6 months 12 months BPI: pain severity 6 weeks 3 months 6 months 12 months BPI: pain interference 6 weeks 3 months 6 months 12 months ODI 6 weeks 3 months 6 months 12 months EQ-5D 6 weeks 3 months 6 months 12 months SF-36: PCS t score 6 weeks 3 months 6 months 12 months SF-36: MCS t score 6 weeks 3 months 6 months 12 months SF-36: physical functioning t score 6 weeks 3 months 6 months 12 months SF-36: bodily pain t score 6 weeks 3 months 6 months 12 months SF-36: general health t score 6 weeks 3 months 6 months 12 months SF-36: energy/fatigue t score 6 weeks 3 months 6 months 12 months

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No.

Mean Preoperative Score (SD)

Mean Postoperative Score (SD)

P

73 56 45 22

48.63 48.61 48.56 47.05

(4.01) (4.73) (4.89) (7.05)

48.82 49.20 49.64 49.91

(4.45) (3.54) (1.72) (0.43)

.951* .581* .227* .063*

71 55 44 22

44.75 45.04 45.34 45.41

(10.28) (10.18) (9.55) (7.71)

47.01 48.51 49.45 50.00

(7.91) (7.00) (1.80) (0)

.016* .004* .002* .008*

71 55 44 22

93.37 93.65 93.91 92.45

(11.85) (12.08) (12.03) (12.96)

95.80 97.69 99.23 99.91

(10.77) (8.48) (3.15) (0.43)

.042* .013* , .001* .002*

94 69 46 17

6.41 6.49 6.64 5.62

(2.68) (2.76) (2.57) (2.82)

4.39 4.07 4.32 3.06

(2.38) (2.47) (2.68) (1.97)

, .001† , .001† , .001† .019†

94 69 46 17

7.16 7.05 6.83 6.70

(2.63) (2.69) (2.47) (2.42)

4.82 4.13 4.18 3.82

(2.46) (2.56) (2.68) (2.61)

, .001† , .001† , .001† .009†

73 58 43 33

54.10 52.55 54.47 48.79

(21.74) (21.46) (21.12) (21.00)

46.34 35.40 29.37 33.09

(19.45) (19.79) (15.88) (19.83)

.002† , .001† , .001† .001†

74 59 46 34

0.44 0.49 0.50 0.52

(0.26) (0.27) (0.26) (0.26)

0.57 0.67 0.74 0.68

(0.24) (0.20) (0.15) (0.22)

, .001† , .001† , .001† .006†

74 61 47 34

30.69 31.66 32.31 35.89

(9.74) (9.73) (8.74) (8.97)

27.91 32.21 33.37 35.60

(13.44) (9.68) (11.22) (11.09)

.016† .713† .596† .417†

74 61 47 34

43.71 44.55 43.44 43.83

(11.21) (11.37) (10.60) (11.58)

45.72 47.86 50.77 47.89

(12.52) (11.18) (11.10) (13.21)

.247† .051† , .001† .124†

75 61 47 34

30.68 31.53 31.96 34.44

(13.78) (14.58) (14.96) (15.28)

26.62 31.12 34.84 35.43

(10.23) (10.73) (12.54) (13.38)

.020† .835† .323† .760†

75 61 48 34

29.92 30.17 30.76 31.53

(8.02) (8.06) (7.00) (7.85)

36.61 40.08 41.59 40.22

(8.59) (10.32) (10.65) (12.02)

75 61 48 34

43.56 45.63 45.36 46.55

(10.22) (9.16) (9.81) (9.65)

40.09 41.13 40.25 42.95

(10.59) (11.00) (11.13) (12.27)

.008† .004† .003† .094†

74 43.23 61 44.36 48 44.81 34 46.86 (continued on following page)

(10.93) (10.64) (9.05) (9.74)

41.92 44.82 45.78 46.86

(10.14) (9.22) (10.67) (11.34)

.398† .805† .546† 1.000†

, , , ,

.001† .001† .001† .001†



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Fehlings et al

Table 3. Pre- and Postoperative Scores by Follow-Up Visit (continued) Follow-Up Time

No.

SF-36: social functioning t score 6 weeks 3 months 6 months 12 months SF-36: role limitations as a result of physical problems t score 6 weeks 3 months 6 months 12 months SF-36: role limitations as a result of emotional problems t score 6 weeks 3 months 6 months 12 months SF-36: emotional well-being t score 6 weeks 3 months 6 months 12 months

Mean Preoperative Score (SD)

Mean Postoperative Score (SD)

P

75 61 48 34

31.40 31.90 32.31 31.18

(12.43) (12.92) (12.58) (11.36)

30.31 36.20 40.37 37.76

(13.00) (11.70) (12.04) (12.90)

.538† .019† , .001† .024†

75 61 47 34

30.04 31.24 30.96 31.64

(10.55) (10.24) (9.89) (10.79)

25.70 31.24 33.58 34.93

(9.09) (10.70) (12.02) (12.69)

.004† , .001† .206† .168†

75 61 47 34

37.01 39.37 37.60 37.70

(15.99) (15.07) (15.46) (17.27)

38.15 40.39 45.13 40.90

(16.11) (15.28) (13.66) (16.27)

.634† .631† .010† .323†

74 61 48 34

43.54 43.41 43.08 44.38

(9.93) (10.23) (10.23) (10.58)

46.29 48.35 50.30 49.18

(11.43) (9.53) (10.95) (12.26)

.062† .003† , .001† .046†

Abbreviations: BPI, Brief Pain Inventory; EQ-5D, EuroQol 5 dimensions; ISNCSCI, International Standards for Neurologic Classification of Spinal Cord Injury; MCS, mental component score; ODI, Oswestry Disability Index; PCS, physical component score; SD, standard deviation; SF-36, Short Form 36 Health Survey. *Wilcoxon signed rank test. †Paired t test.

infection developed in two of 17 patients who were not administered preoperative RT as well as in eight of 69 patients who received preoperative RT. The rate of postoperative wound infection was not associated with the administration of preoperative RT to the MESCC lesion before its surgical treatment (Fisher’s exact test P = 1.000). Two patients required a second spinal surgery: one for progressive neurologic deficits as a result of a spinal hematoma and one for screw malposition.

DISCUSSION

Treatment of metastatic spinal disease requires careful consideration of the life expectancy, function, and overall HRQoL of the patient. Surgical intervention is proposed for patients with MESCC for whom the anticipated improvement in HRQoL outweighs the potential risks. Given the relatively low incidence of MESCC, the frailty and poor survival, statistical research of appropriate power has been challenging to achieve. Although several retrospective studies10-16 and a few prospective studies5-7,9,17 have evaluated the

impact of surgery on survival and function, HRQoL was assessed in few prospective studies.18-20 Two meta-analyses concluded that decompressive surgery followed by RT was associated with improved ambulatory status21,22 and survival22 than with RT alone in selected patients with MESCC. In addition, a recent economic systematic review performed by the Fehlings et al23 reported that treatment with surgery combined with RT was more effective but costlier than RT alone. Moreover, surgery has the conceptual benefit of providing direct spinal cord decompression, reduction of local tumor burden, and the opportunity for mechanical stabilization of the diseased spine. In addition, surgical decompression provides cytoreduction and a margin around neural elements, that is, separation surgery, allowing subsequent adjuvant therapy, which is associated with improved local tumor control.24-29 Because it is now largely recognized that modern spinal surgery combined with RT provides improved clinical outcomes compared with RT alone, and is cost-effective in selected patients, surgery is usually the preferred initial treatment. We lack medical equipoise to conduct a randomized clinical trial that compares

Table 4. AIS Grades Preoperatively and at Each Postoperative Follow-Up Time AIS Grade

Preoperative (n = 136)

A 2 B 3 C 17 D 48 E 66 P (Stuart Maxwell test) Preoperative v follow-up

(1.5) (2) (12.5) (35) (48)

6 Weeks (n = 87; 64%) 1 1 2 19 64

(1) (1) (2) (22) (74)

.178

3 Months (n = 59; 43%)

6 Months (n = 38; 28%)

12 Months (n = 10; 7%)

1 (2) 0 0 7 (12) 51 (86)

0 0 0 2 (5) 36 (95)

0 0 0 0 10 (100)

.004

.173

.532

NOTE. All data are given as No. (%) unless otherwise specified. Abbreviation: AIS, American Spinal Injury Association impairment scale.

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Survival Probability

1.0

0.8

0.6

0.4

0.2

0

200

400

600

800

1,000

1,200

Postoperative Follow-Up Time (days) Fig 2. Kaplan-Meier overall survival curve with 95% CLs. CLs end at 466 days, that is, survival time of the next to last patient censored. The last patient censored was at 1,085 days. CL, confidence limit.

surgical treatment versus conservative treatment in patients with MESCC. Given the variability of patient, tumor, and physician determinants that influence surgical decision making (eg, habits, beliefs, and experience), we assert that the optimal study design to evaluate surgical outcomes for patients with MESCC involves welldesigned and properly conducted prospective studies. The AOSpine North American MESCC study is one of the largest prospective, multicenter, cohort studies to evaluate surgical outcomes in patients with MESCC in terms both of clinicianassessed criteria and in patient-centered HRQoL. Patient-reported HRQoL outcome measures convey information that can be critical in clinical decision making. Among other HRQoL-measuring instruments, the EQ-5D questionnaire was used. The Global Spine Tumor Study Group recommends the EQ-5D to assess patient-centered HRQoL outcomes in patients with metastatic spinal disease.30 This study shows that surgery improves pain, neurologic and functional status, as well as EQ-5D–measured health utilities and HRQoL for symptomatic patients with a single MESCC lesion that is compressing the spinal cord. Compared with preoperative scores, patient pain severity, pain interference, and the bodily pain scale from the SF-36 v2 were lower at 6-week and 3-, 6-, and 12-month follow-ups. Similar to many studies, spinal surgery for MESCC is associated with rapid, substantial, and sustained pain relief.5-7,11,17-20,31-33 Overall, the proportion of patients with no neurologic impairment (AIS grade E) was higher at the 6-week follow-up than preoperatively. Patients with milder or no neurologic deficits were able to attend the postoperative follow-up appointments more often and over a longer period of time. Of the 87 patients who had at least a 6-week follow-up, six patients suffered a neurologic deterioration, possibly as a result of surgery or primary disease progression. In two of these six patients, primary disease progression is the most-likely cause because deterioration corresponded to the last recorded AIS score. Patients with MESCC represent a frail population with few reserves to deal with additional physical or emotional stress. Consequently, their clinical status is variable from day to day or week to week, which could explain some of the fluctuations between follow-up AIS grades. The impact of different clinical assessors may also account for www.jco.org

minor variations in the AIS assessments. Surgical intervention has a positive impact on neurologic status in patients with MESCC given that surgery, overall, tended to improve ambulatory status, bladder and bowel dysfunction, and motor scores as well as AIS grade. The SF-36 v2 is among the most widely used generic HRQoL measures.30,34 Overall, patients deteriorated at the 6-week followup on the physical component score and on all SF-36 scales related to physical status (physical functioning, role limitations as a result of physical problems, and general health). Because the SF-36 questionnaire requires a 4-week recall, it is likely that immediate postoperative pain and discomfort was a confounding variable. Although MCS in addition to the bodily pain, emotional wellbeing, social functioning, and role limitations as a result of emotional problems scales showed various degrees of improvement, the scores on the general health scale declined for up to 6 months postoperatively—this may be explained by primary disease progression. In addition, postoperative EQ-5D scores were improved, the scoring of which is used as a health utility and HRQoL measure.30,35,36 In their literature review, Street et al35 reported that the Eastern Cooperative Oncology Group (ECOG), SF-36, the pain visual analog scale (VAS), and the assessment of ambulatory status, AIS, and motor scores evaluated factors that are valid for measuring health status in spinal neoplastic disease. Given the overall improvement between pre- and postoperative scores for the MCS and four of the eight scales of the SF-36, EQ-5D, and ODI, our results support the fact that surgery improves function and HRQoL outcomes in patients with MESCC,7,18,20 and that surgery increases health utilities, which attenuates the cost.23,37,38 The main surgical indications were neurologic deficits and intractable pain. Surgical approaches were mostly posterior or a combination of anterior and posterior, totaling 22 and 32 distinct procedural techniques, respectively, 94.4% of which involved reconstruction. Spinal surgeons thus use a variety of interventions for MESCC pathologies and, in the majority of cases, spinal stability is a major concern. The diversity of clinical presentation, including tumor subtype and patient characteristics, as well as surgeon beliefs, expertise, and institutional differences play a major role in the variation of surgical interventions for MESCC. Whereas most patients had an MESCC lesion limited to one vertebral level, surgeries involved medians of five spinal levels and a 272-minute operative time. Consequently, it is likely that most patients underwent an extensive decompressive and reconstructive surgery. Although the surgical approaches and techniques used were recorded, this study was not designed to compare the impact of different methods of stabilization and reconstruction on outcome measures. A majority of patients had at least one other metastasis in addition to their MESCC lesion; therefore, in general, this cohort had a significant overall metastatic burden and underwent extensive spinal surgical intervention. Metastatic burden and surgical intervention, then, may explain, in part, mortality rates of 9%, 45%, and 62% for 30 days, 3 months, and 12 months postoperatively, respectively. Although our 30-day mortality rate corresponds to the 4% to 22% reported in the literature,6,14,18,21,39-42 our 3-month and 12-month mortality rates are higher than the proportions typically cited in the literature—20% to 30%20,32,42 and 40% to 50%,7,14,15,18 respectively. Of note, Crnalic et al42 © 2015 by American Society of Clinical Oncology


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Fehlings et al

reported a mortality rate of 59% at 12 months in 54 patients with MESCC with prostate cancer. The WHO defines perioperative death as death occurring within 30 days of surgery. Given that our 30-day mortality rate is similar to other studies, our higher mortality rates at 3 and 12 months postoperatively are more likely the result of the significant metastatic burden in our cohort rather than a direct consequence of surgery. This study has several limitations. First, this is an observational study of a relatively restricted patient population: those with a single solitary MESCC. Generalization of our findings to patient populations with multiple spine metastases requires caution. Second, our inclusion criteria required the presence of epidural spinal cord compression. Patients with spinal metastases without epidural compression may have different results after surgical treatment. Third, population censoring was high as a result of significant mortality. Furthermore, some patients withdrew or were lost to follow-up and could have worse outcomes than those subjects who remained in the study. Finally, we performed a large number of statistical evaluations in an exploratory manner. This increases the possibility of random significant findings through inflation of type I error as a result of multiplicity. This is a common issue in observational studies; however, the emerging pattern of improvements associated with surgical treatment across different outcome measures is unlikely to result from multiplicity, which would be expected to have a random pattern. Although this is a large prospective, multicenter study, it is limited by its small sample size and lack of controls. Nonetheless, this study provides strong evidence that surgical intervention, including spinal reconstruction, is beneficial to patients with

REFERENCES 1. Cole JS, Patchell RA: Metastatic epidural spinal cord compression. Lancet Neurol 7:459-466, 2008 2. Prasad D, Schiff D: Malignant spinal-cord compression. Lancet Oncol 6:15-24, 2005 3. Mak KS, Lee LK, Mak RH, et al: Incidence and treatment patterns in hospitalizations for malignant spinal cord compression in the United States, 19982006. Int J Radiat Oncol Biol Phys 80:824-831, 2011 4. Loblaw DA, Laperriere NJ, Mackillop WJ: A population-based study of malignant spinal cord compression in Ontario. Clin Oncol (R Coll Radiol) 15: 211-217, 2003 5. Tokuhashi Y, Ajiro Y, Umezawa N: Outcome of treatment for spinal metastases using scoring system for preoperative evaluation of prognosis. Spine 34:69-73, 2009 6. Jansson KA, Bauer HC: Survival, complications and outcome in 282 patients operated for neurological deficit due to thoracic or lumbar spinal metastases. Eur Spine J 15:196-202, 2006 7. Ibrahim A, Crockard A, Antonietti P, et al: Does spinal surgery improve the quality of life for those with extradural (spinal) osseous metastases? An international multicenter prospective observational study of 223 patients—Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2007. J Neurosurg Spine 8: 271-278, 2008 8. Sundaresan N, Digiacinto GV, Hughes JE, et al: Treatment of neoplastic spinal cord compression:

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MESCC—even for those with important disease burden—for achieving prompt and sustained pain relief and improved neurologic, functional, health utilities, and HRQoL outcomes. Given the overall low incidence, clinical heterogeneity, and rapid emergence of efficient medical therapies for the treatment of MESCC, we support current efforts to collect prospective longitudinal data on spine oncology patients.43,44 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org

AUTHOR CONTRIBUTIONS Conception and design: Michael G. Fehlings, Branko Kopjar, Mark Dekutoski, John France, Ziya Gokaslan, Eric Massicotte, Laurence Rhines, Alexander Vaccaro Administrative support: Branko Kopjar Provision of study materials or patients: Michael G. Fehlings, Mark Dekutoski, Peter Rose, Alexander Vaccaro Collection and assembly of data: Paul Arnold, Joel Finkelstein, Charles Fisher, Ziya Gokaslan, Eric Massicotte, Laurence Rhines, Peter Rose, Arjun Sahgal, James Schuster, Alexander Vaccaro Data analysis and interpretation: Anick Nater, Lindsay Tetreault, Branko Kopjar, Paul Arnold, Joel Finkelstein, Eric Massicotte, Arjun Sahgal Manuscript writing: All authors Final approval of manuscript: All authors

Results of a prospective study. Neurosurgery 29: 645-650, 1991 9. Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 366:643-648, 2005 10. Bollen L, de Ruiter GC, Pondaag W, et al: Risk factors for survival of 106 surgically treated patients with symptomatic spinal epidural metastases. Eur Spine J 22:1408-1416, 2013 11. Tomita K, Kawahara N, Kobayashi T, et al: Surgical strategy for spinal metastases. Spine 26: 298-306, 2001 12. Hammerberg KW: Surgical treatment of metastatic spine disease. Spine 17:1148-1153, 1992 13. Hatrick NC, Lucas JD, Timothy AR, et al: The surgical treatment of metastatic disease of the spine. Radiother Oncol 56:335-339, 2000 14. Hirabayashi H, Ebara S, Kinoshita T, et al: Clinical outcome and survival after palliative surgery for spinal metastases: Palliative surgery in spinal metastases. Cancer 97:476-484, 2003 15. Weigel B, Maghsudi M, Neumann C, et al: Surgical management of symptomatic spinal metastases: Postoperative outcome and quality of life. Spine 24:2240-2246, 1999 16. Wibmer C, Leithner A, Hofmann G, et al: Survival analysis of 254 patients after manifestation of spinal metastases: Evaluation of seven preoperative scoring systems. Spine 36:1977-1986, 2011 17. Pointillart V, Vital J-M, Salmi R, et al: Survival prognostic factors and clinical outcomes in patients with spinal metastases. J Cancer Res Clin Oncol 137: 849-856, 2011

18. Quan GM, Vital JM, Aurouer N, et al: Surgery improves pain, function and quality of life in patients with spinal metastases: A prospective study on 118 patients. Eur Spine J 20:1970-1978, 2011 19. Falicov A, Fisher CG, Sparkes J, et al: Impact of surgical intervention on quality of life in patients with spinal metastases. Spine 31:2849-2856, 2006 20. Wai EK, Finkelstein JA, Tangente RP, et al: Quality of life in surgical treatment of metastatic spine disease. Spine 28:508-512, 2003 21. Klimo P Jr., Thompson CJ, Kestle JR, et al: A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease. Neuro-oncol 7:64-76, 2005 22. Lee CH, Kwon J, Lee J, et al: Direct decompressive surgery followed by radiotherapy versus radiotherapy alone for metastatic epidural spinal cord compression: A meta-analysis. Spine (Phila Pa 1976) 39:E587-E592, 2014 23. Fehlings MG, Nater A, Holmer H: Costeffectiveness of surgery in the management of metastatic epidural spinal cord compression: A systematic review. Spine 39:S99-S105, 2014 24. Moulding HD, Elder JB, Lis E, et al: Local disease control after decompressive surgery and adjuvant high-dose single-fraction radiosurgery for spine metastases. J Neurosurg Spine 13:87-93, 2010 25. Moussazadeh N, Laufer I, Yamada Y, et al: Separation surgery for spinal metastases: Effect of spinal radiosurgery on surgical treatment goals. Cancer Contr 21:168-174, 2014 26. Laufer I, Iorgulescu JB, Chapman T, et al: Local disease control for spinal metastases following “separation surgery” and adjuvant hypofractionated




or high-dose single-fraction stereotactic radiosurgery: Outcome analysis in 186 patients. J Neurosurg Spine 18:207-214, 2013 27. Al-Omair A, Masucci L, Masson-Cote L, et al: Surgical resection of epidural disease improves local control following postoperative spine stereotactic body radiotherapy. Neuro-oncol 15:1413-1419, 2013 28. Bate BG, Khan NR, Kimball BY, et al: Stereotactic radiosurgery for spinal metastases with or without separation surgery. J Neurosurg Spine 22: 409-415, 2015 29. Massicotte E, Foote M, Reddy R, et al: Minimal access spine surgery (MASS) for decompression and stabilization performed as an outpatient procedure for metastatic spinal tumours followed by spine stereotactic body radiotherapy (SBRT): First report of technique and preliminary outcomes. Technol Cancer Res Treat 11:15-25, 2012 30. Choi D, Morris S, Crockard A, et al: Assessment of quality of life after surgery for spinal metastases: Position statement of the Global Spine Tumour Study Group. World Neurosurg 80:e175-e179, 2013 31. Holman PJ, Suki D, McCutcheon I, et al: Surgical management of metastatic disease of the lumbar spine: Experience with 139 patients. J Neurosurg Spine 2:550-563, 2005

32. Bauer HC, Wedin R: Survival after surgery for spinal and extremity metastases: Prognostication in 241 patients. Acta Orthop Scand 66:143-146, 1995 33. Ju DG, Zadnik PL, Groves ML, et al: Factors associated with improved outcomes following decompressive surgery for prostate cancer metastatic to the spine. Neurosurgery 73:657-666, discussion 666, 2013 34. Garratt A, Schmidt L, Mackintosh A, et al: Quality of life measurement: Bibliographic study of patient assessed health outcome measures. BMJ 324:1417, 2002 35. Street J, Berven S, Fisher C, et al: Health related quality of life assessment in metastatic disease of the spine: A systematic review. Spine 34:S128-S134, 2009 36. EuroQol Group: EuroQol: A new facility for the measurement of health-related quality of life. Health Policy 16:199-208, 1990 37. Thomas KC, Nosyk B, Fisher CG, et al: Costeffectiveness of surgery plus radiotherapy versus radiotherapy alone for metastatic epidural spinal cord compression. Int J Radiat Oncol Biol Phys 66: 1212-1218, 2006 38. Furlan JC, Chan KK, Sandoval GA, et al: The combined use of surgery and radiotherapy to treat patients with epidural cord compression due to metastatic disease: A cost-utility analysis. Neurooncol 14:631-640, 2012

39. Patil CG, Lad SP, Santarelli J, et al: National inpatient complications and outcomes after surgery for spinal metastasis from 1993-2002. Cancer 110: 625-630, 2007 40. Finkelstein JA, Zaveri G, Wai E, et al: A population-based study of surgery for spinal metastases: Survival rates and complications. J Bone Joint Surg Br 85:1045-1050, 2003 41. Kim JM, Losina E, Bono CM, et al: Clinical outcome of metastatic spinal cord compression treated with surgical excision 6 radiation versus radiation therapy alone: A systematic review of literature. Spine 37:78-84, 2012 ¨ P, et al: 42. Crnalic S, Hildingsson C, Wikstrom Outcome after surgery for metastatic spinal cord compression in 54 patients with prostate cancer. Acta Orthop 83:80-86, 2012 43. Choi D, Crockard A, Bunger C, et al: Global Spine Tumor Study Group: Review of metastatic spine tumour classification and indications for surgery: The consensus statement of the Global Spine Tumour Study Group. Eur Spine J 19: 215-222, 2010 44. Clinical Trials.gov: The Epidemiology, Process and Outcomes of Spine Oncology (EPOSO). https://www.clinicaltrials.gov/ct2/show/ NCT01825161

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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Survival and Clinical Outcomes in Surgically Treated Patients With Metastatic Epidural Spinal Cord Compression: Results of the Prospective Multicenter AOSpine Study The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Michael G. Fehlings Leadership: AOSpine North America, AOSPine International Spinal Cord Injury Knowledge Forum

Research Funding: AOSpine North America

Anick Nater Travel, Accommodations, Expenses: AOSpine North America, Global Spine Tumour Study Group

Eric Massicotte Consulting or Advisory Role: Watermark Consulting Research Funding: Medtronic (Inst), DePuy Companies (Inst), Zimmer (Inst) Travel, Accommodations, Expenses: AOSpine North America

Lindsay Tetreault No relationship to disclose

Laurence Rhines Consulting or Advisory Role: Stryker, Globus

Branko Kopjar Consulting or Advisory Role: Cerapedics, Smith and Nephew

Peter Rose Travel, Accommodations, Expenses: K2M

Paul Arnold Stock or Other Ownership: Z-plasty Honoraria: University of Missouri Consulting or Advisory Role: Medtronic Sofamor Danek, Stryker Spine, FzioMed, LifeSpine, Spinewave, MIEMS, AOSpine North America, Cerapedics, Integra Life Travel, Accommodations, Expenses: AOSpine North America

Arjun Sahgal Honoraria: Elekta, Medtronic, Varian Medical Systems Consulting or Advisory Role: Varian Medical Systems Research Funding: Elekta Travel, Accommodations, Expenses: Elekta, Varian Medical Systems, Medtronic

Mark Dekutoski Speakers’ Bureau: DePuy, Medtronic Patents, Royalties, Other Intellectual Property: Medtronic (Inst), Mayo Clinic (Inst) Joel Finkelstein No relationship to disclose Charles Fisher Consulting or Advisory Role: Medtronic, Nuvasive Research Funding: The Orthopaedic Research and Education Foundation (Inst) Patents, Royalties, Other Intellectual Property: Medtronic Travel, Accommodations, Expenses: Medtronic John France No relationship to disclose Ziya Gokaslan Leadership: AO North America Stock or Other Ownership: Spinal Kinetics Honoraria: AO Foundation


James Schuster No relationship to disclose Alexander Vaccaro Employment: Rothman Institute Leadership: Association of Collaborative Spine Research, Innovative Surgical Design, AOSpine North America Stock or Other Ownership: Replication Medica, Globus, Paradigm Spine, Stout Medical, Progressive Spinal Technologies, Advanced Spinal Intellectual Properties, Spine Medica, Computational Biodynamics, Spinology, Small Bone Innovations, Cross Current, InVivo, Flagship Surgical, Cytonics, Bonovo Orthopaedics, Electrocore, Gamma Spine, Location Based Intelligence, FlowPharma, Reimbursement Strategy Inc., Rothman Institute and Related Properties, Innovative Surgical Design, Avaz Surgical Consulting or Advisory Role: Ellipse, Expert Testimony, Orthobullets, Innovative Surgical Design, Medacorp, Guidepoint Global, Gerson Lehrman Group, Stout Medical, Globus, Stryker Spine, Medtronics, DePuy, Vertex (I) Patents, Royalties, Other Intellectual Property: Thieme, Jaypee, Elsevier, Taylor & Francis, DePuy, Medtronic, Stryker Spine, Globus, Aesculap




Acknowledgment We thank the collaborating centers’ local clinical research personnel and support staff for their active participation. The AOSpine MESCC study involved ten hospitals from nine North American centers: University of Toronto, Toronto, Ontario, Canada; Johns Hopkins University, Baltimore, MD; Mayo Clinic, Rochester, MN;, Thomas Jefferson University Hospital, Philadelphia, PA; University of British Columbia, Vancouver, BC, Canada; University of Pennsylvania, Philadelphia, PA; University of Kansas, Kansas City, KS; MD Anderson Cancer Center, Houston, TX; and West Virginia University, Morgantown, WV. Appendix

This appendix provides information that does not appear in the main article text.

Table A1. AIS at the 6-Week Follow-Up Preoperative AIS Grade A B C D E Overall

No. of Patients Graded (n = 136)

No. of Patient Follow-Ups (% preoperative)

A

B

C

D

E

↓ Postoperative (%)

↔ Postoperative (%)

↑ Postoperative (%)

2 3 17 48 66

0 1 (33.3%) 10 (58.8%) 29 (60.4%) 47 (71.2%)

— — — 1 —

— 1 — — —

— — — 2 —

— — 7 9 3

— — 3 17 44

— — 0 3 (10.3%) 3 (6.4%) 6 (6.9%)

— 1 (100%) 0 9 (31.0%) 44 (93.6%) 54 (62.1%)

— — 10 (100%) 17 (58.7%) N/A 27 (31.0%)

NOTE. ↓ = postoperative deterioration compared with preoperative status, ↔ = postoperative status has not changed compared with preoperative status, and ↑ = postoperative improvement compared with preoperative status. Abbreviation: AIS, American Spinal Injury Association impairment scale.

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