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The Spine Journal 17 (2017) 689–708

Clinical Study

Prognostic factors in patients with spinal metastasis: a systematic review


and meta-analysis
Panya Luksanapruksa, MDa, Jacob M. Buchowski, MD, MSb,*, William Hotchkiss, MDb,
Sasima Tongsai, PhDc, Sirichai Wilartratsami, MDa, Areesak Chotivichit, MDa
a
Department of Orthopedic Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Rd Bangkoknoi, Bangkok 10700, Thailand
b
Department of Orthopedic Surgery, Barnes-Jewish Institute of Health, Washington University in St. Louis, 425 S. Euclid Ave, Campus Box 8233, St. Louis,
MO 63110, USA
c
Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road Bangkoknoi, Bangkok 10700, Thailand
Received 5 May 2016; revised 10 November 2016; accepted 9 December 2016

Abstract BACKGROUND CONTEXT: Incidence of symptomatic spinal metastasis has increased owing
to improvement in treatment of the disease. One of the key factors that influences decision-making
is expected patient survival. To our knowledge, no systematic reviews or meta-analysis have been
conducted that review independent prognostic factors in spinal metastases.
PURPOSE: This study aimed to determine independent prognostic factors that affect outcome in
patients with metastatic spine disease.
STUDY DESIGN: This is a systematic literature review and meta-analysis of publications for prog-
nostic factors in spinal metastatic disease.
PATIENT SAMPLE: Pooled patient results from cohort and observational studies.
OUTCOME MEASUREMENT: Meta-analysis for poor prognostic factors as determined by hazard
ratio (HR) and 95% confidential interval (95% CI).
METHODS: We systematically searched relevant publications in PubMed and Embase. The
following search terms were used: (“‘spinal metastases’” OR “‘vertebral metastases’” OR ““spinal
metastasis” OR ‘vertebral metastases’) AND (‘“prognostic factors”’ OR “‘survival’”). Inclusion
criteria were prospective and retrospective cohort series that report HR and 95% CI of independent
prognostic factors from multivariate analysis. Two reviewers independently assessed all papers.
The quality of included papers was assessed by using Newcastle-Ottawa Scale for cohort studies
and publication bias was assessed by using funnel plot, Begg test, and Egger test. The prognostic
factors that were mentioned in at least three publications were pooled. Meta-analysis was
performed using HR and 95% CI as the primary outcomes of interest. Heterogeneity was assessed
using the I2 method.

FDA device/drug status: Not applicable. No funds were received in support of this work.
Author disclosures: PL: Nothing to disclose. JMB: Royalties: Wolters There are no relevant financial activities outside the submitted work.
Kluwer Health, Inc. (A), Globus Medical, Inc. (E), K2M, Inc. (C); Con- The disclosure key can be found on the Table of Contents and at
sulting: CoreLink, Inc. (B), Globus Medical, Inc. (B), K2M, Inc. (B), www.TheSpineJournalOnline.com.
Medtronic, Inc. (C), Stryker, Inc. (B); Speaking and/or Teaching Arrange- * Corresponding author. Department of Orthopedic Surgery, Barnes-
ments: Broadwater/Vertical Health (Spine Surgery LIVE) (B), DePuy Synthes Jewish Institute of Health, Washington University in St. Louis, 425 S. Euclid
(C), Globus Medical, Inc. (C), Orthofix (C), Stryker, Inc. (C); Fellowship Ave, Campus Box 8233, St. Louis, MO 63110, USA. Tel.: +1 (314) 747 4950;
Support: OMeGA (D, Paid directly to institution/employer), AO North America fax: +1 (314) 747 2599.
(F, Paid directly to institution/employer), OREF (D, Paid directly to institution/ E-mail address: buchowskij@wustl.edu (J.M. Buchowski)
employer), outside the submitted work. WH: Nothing to disclose. ST: Nothing
to disclose. SW: Nothing to disclose. AC: Nothing to disclose.

http://dx.doi.org/10.1016/j.spinee.2016.12.003
1529-9430/© 2016 Elsevier Inc. All rights reserved.
690 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

RESULTS: A total of 3,959 abstracts (1,382 from PubMed and 2,577 from Embase) were
identified through database search and 40 publications were identified through review of cited
publications. The reviewers selected a total of 51 studies for qualitative synthesis and 43 studies for
meta-analysis. Seventeen poor prognostic factors were identified. These included presence of a
neurologic deficit before surgery, non-ambulatory status before radiotherapy (RT), non-ambulatory
status before surgery, presence of bone metastases, presence of multiple bone metastases (>2 sites),
presence of multiple spinal metastases (>3 sites), development of motor deficit in <7 days before
initiating RT, development of motor deficit in <14 days before initiating RT, time interval from
cancer diagnosis to RT <15 months, Karnofsky Performance Score (KPS) 10–40, KPS 50–70,
KPS<70, Eastern Cooperative Oncology Group (ECOG) grade 3–4, male gender, presence of
visceral metastases, moderate growth tumor on Tomita score (TS) classification, and rapid growth
tumor on TS classification.
CONCLUSIONS: Seventeen independent poor prognostic factors were identified in this study. These
can be categorized into cancer-specific and nonspecific prognostic factors. A tumor-based prognos-
tic scoring system that combines all specific and general factors may enhance the accuracy of survival
prediction in patients with metastatic spine disease. © 2016 Elsevier Inc. All rights reserved.

Keywords: Systematic review; meta-analysis; survival; prognostic factors; spinal metastases; prognostic score

Introduction Materials and methods


The spine is one of the most common sites of metastatic This systematic review and meta-analysis was con-
disease. The prevalence of symptomatic spinal metastasis has ducted according to the Preferred Reporting Items for
increased owing to treatment improvements and longer patient Systematic Reviews and Meta-Analyses protocol [7].
survival. The current treatments for spinal metastasis are ra-
diotherapy (RT), systemic chemotherapy, and surgery. One
of the key factors that could assist in decision-making is ex- Data source and search strategy
pected survival of the patient.
We searched Embase and PubMed for all studies before
Four scoring systems provide survival estimates for pa-
May of 2015 involving survival factors for patients with spinal
tients with spinal metastasis. The revised Tokuhashi [1], Tomita
metastasis. The following search terms were used: (“‘spinal
[2], van der Linden [3], and Bauer [4] scoring systems use dif-
metastases’” OR “‘vertebral metastases’” OR ““spinal me-
ferent factors and weigh these factors to calculate expected
tastasis” OR ‘vertebral metastases’) AND (‘“prognostic
survival. The revised Tokuhashi scoring system uses six factors
factors”’ OR “‘survival’”). The search limits were English
on a 15-point scale: a general condition or performance score,
language, studies conducted in humans, and full text avail-
number of extraspinal bone metastases, number of vertebral
able. The inclusion criteria were prospective and retrospective
body metastases, presence or removability of metastases to major
cohort series that reported survival factors (hazard ratio [HR]
internal organs, primary cancer site, and Frankel neurologic
and 95% confidential interval [95% CI]) in adult patients with
condition. The Tomita scoring system uses three factors on a
spinal metastases. Exclusion criteria were no survival factor
10-point scale: growth rate of primary tumor, presence or treat-
report, mixed report with other bone metastases, duplicated
ability of visceral metastases, and the number of bone metastases.
report, no multivariate analysis, fewer than 30 patients, and
The van der Linden scoring system uses three factors on a 6-point
another type of publication including case report, review article,
scale: Karnofsky Performance Score (KPS), primary tumor, and
or technical report. Additional articles were identified from
presence or absence of visceral metastases. Using different
the reference lists of the retrieved studies that were relevant
scoring systems for the same patient can result in different ex-
to survival in spinal metastases. Both reviewers (PL, SW) in-
pected survival periods that lead to different treatment strategies.
dependently screened abstracts and titles after removing
In addition, additional other survival factors were not in-
duplicated publications. Then, full-paper readings were per-
cluded in the previous scoring systems, which could offer help
formed to determine final inclusion. Disagreements were
to decision-makers including postoperative ambulatory status
resolved by discussion for consensus.
[5], albumin level [6], and others.
To our knowledge, no systematic review or meta-analysis
that reviews survival factors for patients with spinal metasta-
Quality assessment
ses has been conducted. The purpose of this study is to review
independent survival factors in spinal metastases from cohort Quality assessment of included studies was performed
studies. independently by two reviewers (PL, SW) using the
P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708 691

fixed-effects model was used when the effects were assumed


to be homogenous. In the presence of heterogeneity, we
used a random-effect model. Sensitivity analysis was per-
formed by omitting each study at a time to investigate its
Context effect on the overall meta-analysis result. We rejected the
The authors performed a systematic review to determine studies that caused higher statistical heterogeneity (I2>90).
negative prognostic factors in patients with spinal A p-value <.05 was considered statistically significant.
metastases. Publication bias was assessed using a funnel plot, Begg
Contribution test, and Egger test. A trim-and-fill method was used to
They found 17 independent negative prognostic factors. estimate pooled HR after adjusting for funnel plot asymme-
try arising from publication bias. The interobserver reliability
Implications between two reviewers was assessed by kappa statistic.
While many of the factors are known and several are in- Meta-analysis was performed using meta package (R Devel-
corporated into existing classification systems (Tokuhashi, opment Core Team, 2015, Vienna, Austria) version 3.2.2.
Tomita, etc.), this study provides pooled information that
should be quite helpful for patient education/discussion of
prognosis. The tables specifically might prove quite Results
beneficial. Included studies
A total of 3,959 abstracts were identified through data-
base searching (1,382 from PubMed and 2,577 from Embase),
and 40 additional publications were identified through review
Newcastle-Ottawa Scale for cohort studies with total score of cited publications. There were 642 duplicate publica-
ranges of 0–9 calculated from three major categories includ- tions, and thus a total of 3,357 unique abstracts were screened.
ing selection, comparability, and outcome [8]. Of these abstracts, 135 were selected for full paper review.
A total of 84 articles were excluded for the following reasons:
Data extraction and outcome assessment 38 had no survival factor reported, 23 had no multivariate anal-
ysis, 2 had duplicate reports, 4 had results mixed with other
This review focused on prognostic factors for overall sur- bone metastases, 2 had no significant factor after multivari-
vival in patients with spinal metastasis. Both reviewers ate analysis, 1 had fewer than 30 patients, six were other types
independently extracted data including first author, name of of publications (case report, review article, or technical report),
journal, year of publication, data collection year, treatment, and 8 did not report HR or a 95% CI. The reviewers se-
number of patients, type of study (prospective or retrospec- lected a total of 51 studies for qualitative synthesis and 43
tive), mean or median age of the sample, type of tumor, studies for meta-analysis. The flow diagram of the literature
independent survival factors, HR, and 95% CI from multi- search is shown in Fig. 1. The kappa statistics of article screen-
variable analyses only. Disagreements were discussed until ing, data extraction, and quality assessment were 0.98 (95%
consensus was achieved. CI, 0.96–1.00), 1.00, and 0.90 (95% CI, 0.80–1.00)
respectively.
Data analysis and statistical analysis
Characteristics and quality of the included studies
Hazard ratio was used as the primary effect estimate in
the meta-analysis. However, only HRs and 95% CI of the A total of 13,666 patients were enrolled from 51 in-
variables reported as significant predictors in at least three cluded studies. Most of the included studies were retrospective
papers were pooled in meta-analysis. Poor prognostic factors (48 of 51) [5,6,9–53], conducted in a single institute (31 of
were the factors that had negative effect to the survival of 51), and published between 2005 and 2015. Three studies were
patients with spinal metastasis. The outcome was defined as prospective cohort studies [3,54–56]. The number of en-
the risk of a poor prognostic factor. Risk of favorable rolled patients ranged from 30 to 2,029 patients. The age of
prognostic factor was recalculated to the risk of poor enrolled patients ranged from 23.15 to 72.3 years, and median
prognostic factor. In case the reference category for the survival ranged from 4.5 to 22 months. Forty-nine percent
exposed category differed between studies, the HRs were of included patients (25 of 51) reported mixed primary site
recalculated, specifying the lowest risk category as the of tumors. Additionally, the percentage of studies that re-
reference. Statistical heterogeneity was assessed using Co- ported patients who underwent only RT, only surgery, or who
chrane Q test, with a p-value set at .1 for significance. received unclear treatment were 45.09%, 43.13%, and 11.76%,
Heterogeneity between trials was evaluated based on respectively. The average Newcastle-Ottawa Scale score was
inconsistency (I2) index, and substantial heterogeneity 6.98 (range 6–8). Characteristics of the included studies are
was represented by an I2 value greater than 50%. The shown in Table 1.
692 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

small cell lung cancer included non-adenocarcinoma pathology


[51], and renal cell carcinoma included no zoledronic acid
treatment [45] and Fuhrman grade 4 [58]. Detail of specific
factors is shown in Table 2.
The nonspecific poor prognostic factors included age, sys-
temic disease, non-ambulatory status before RT, preoperative
non-ambulatory status, American Society of Anesthesiolo-
gists (ASA) status, extraspinal bone metastases
[19,20,23,29,30,32,33,36,37,39,44,50,51,53,55], number of
spinal metastases, abnormal blood test, comorbidities, pre-
vious chemotherapy, primary tumor site, interval from
diagnosis to spinal metastases [19,29,30,41], time develop-
ing motor deficits before RT, interval from diagnosis to RT,
preoperative neurologic deficit, severe pain, KPS, Eastern Co-
operative Oncology Group (ECOG) grade, no adjuvant therapy,
RT course, revised Tokuhashi score (RTS), Tomita score (TS),
gender, and visceral metastases. However, each group had their
own variables. The details of nonspecific factors are shown
in Table 3, and prognostic factors comparing each primary
tumor site are shown in Table 4.
There were nine poor prognostic factors reported from
single studies, including admission through emergency room
[11], increased time from diagnosis of cancer to surgery [11],
time from primary diagnosis to operation <6 months [55],
pelvis metastases compared with lower limb metastases
[55], local disease progression after stereotactic radiosur-
gery [41], progression of systemic disease at time of
stereotactic radiosurgery [41], preoperative RT [56], opera-
tive strategy other than en bloc resection [55], and postoperative
non-ambulatory status [27].
There were multiple independent prognostic factors in the
eight studies that were excluded because of no reported HR
or 95% CI. Demirci et al. reported on nasopharyngeal cancer
metastases including age, American Joint Committee on
Cancer T classification, and tumor response [59]. Drzymalski
et al. reported on prostate cancer metastases including pres-
ence of additional metastasis at the diagnosis of spinal
metastasis, longer duration between the diagnosis of pros-
tate cancer to spinal metastasis, and higher prostate-specific
antigen level at the diagnosis [60]. Ogihara et al. reported on
Fig. 1. The Preferred Reporting Items for Systematic Reviews and Meta- non–small cell lung cancer metastases including serum albumin
Analyses flow diagram of literature search. level below 3 g/dL, serum calcium more than 10.5, and ECOG
Performance Status 3–4 [61]. Rades et al. reported on unknown
primary cancer metastases including non-ambulatory status
Prognostic factors before RT, other bone metastases at the time of RT, time to
develop motor deficit before RT more than 7 days, and vis-
There were poor prognostic factors specific to each type ceral metastases at the time of RT [62]. There were four studies
of tumor. Breast cancer included negative estrogen receptor that reported on mixed tumor metastases including KPS, vis-
[40,43], negative progesterone receptor [43], negative hor- ceral involvement, systemic treatment, rapid primary tumor
monal receptor [43], poorly or undifferentiated pathology [11], and visceral metastases, increasing age, and an RTS below
and shorter course RT (1×8 Gy or 5×4 Gy) [50]. Hepatocel- 7 [3,52,63,64].
lular carcinoma included biologically effective dose Gy10<38
and uncontrolled primary hepatocellular carcinoma [13]. Lung Meta-analysis result
cancer included biologically effective dose <40 Gy, tissue other
than adenocarcinoma, and no use of epidermal growth factor As noted above, 17 poor prognostic factors were
receptor-targeted treatment in adenocarcinoma [20]. Non– identified. These included the presence of a neurologic
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Table 1
Characteristics of the included studies
Mean
Publication Collection No. age Median survival Tumor
Author Nos. year year of pts. (y) (95% CI) (mo) type Treatment Type Prognostic factors HR 95% CI
Arrigo 7 2011 1999–2009 200 58.9 8 (6.9–10.3) Mixed Surgery R Non-ambulatory 2.355 1.517–3.658
et al. Charlson comorbidity 2.955 1.341–6.512
[9] index ≥2
Radio-resistant tumor 2.557 1.3672–9.912
Bollen 7 2013 2001–2010 106 59 10.7 (0.2–107.5) Mixed Surgery R KPS 10–40 2.7 1.1–6.6
et al. Tomita fast-growing 3.1 1.6–6.2
[10] tumors
Visceral metastases 1.7 1.0–2.9
Cahill 8 2011 1986–2005 379 72 15.7 (11.9–18.5) Breast Surgery R Admission via 1.53 1.20–1.97
et al. emergency room
[11] Time cancer diagnosis to 0.97 0.95–0.99
surgery (per 1 y)
Poorly or 1.49 1.14–1.95
undifferentiated
histology
Chen 8 2010 2001–2007 41 23.15 10.36 (8.22-2.49) HCC Mixed R Serum albumin>37 g/dL 0.295 0.106–0.819
et al. LDH>200 U/L 5.626 1.562–20.265
[12]
Choi 8 2014 1992–2012 192 56 4.5 (3.7–5.3) HCC RT R No extrahepatic 0.571 0.391–0.835
and metastases other than
Seong bone
[13] ECOG status 3–4 1.895 1.302–2.757
Biologically effective 0.536 0.393–0.751
dose Gy10>53
Uncontrolled primary 3.585 0.383–0.751
HCC
Chong 7 2012 2002–2010 105 58.3 6 (0–45) Mixed Surgery R No postoperative 3.23 1.80–5.77
et al. adjuvant therapy
[14] Number of spinal 1.94 1.10–3.43
metastases≥3 levels
Crnalic 8 2012 2003–2010 68 72.3 5 (0.3–59) Prostate Surgery R KPS 50–70 3.97 1.57–10.04
et al.
[15]
Dardic 6 2014 2005–2010 196 66 7 (0.16–70) Mixed Mixed R KPS 50–70 2.07 1.44–2.96
et al. KPS 10–40 2.7 1.70–4.30
[16] Multiple spinal 1.49 1.04–2.14
metastases
Tomita fast growth tumor 2.05 1.44–2.92
Treatable visceral 1.93 1.31–2.85
metastases
Untreatable visceral 4.77 2.98–7.63
metastases
Han 8 2015 2003–2012 30 52.2 17 (N/A) RCC Surgery R Revised Tokuhashi score 0.225 0.063–0.796
et al. (>10)
[17]
Hosono 6 2005 1985–2001 165 N/A N/A Mixed Surgery R Present paresis 1.79 1.11–2.96
et al. Present pain 2.53 1.12–7.26
[18] Poor primary tumor site 2.36 1.67–3.35
Kataoka 6 2012 1990–2008 143 61 22 (1–127) Mixed Mixed R Extraspinal bone 1.75 1.04–2.79
et al. metastases
[19] Disease free before 1.77 1.02–2.34
metastases<12 mo
Tomita: mod. growth 1.797 1.12–3.39
tumor
Tomita: rapid growth 6.802 3.62–11.5
tumor
Major organ metastases 2.01 1.09–2.34
Komatsu 8 2012 2004–2009 132 63 4.8 (N/A) Lung RT R Multiple bone metastasis 1.66 1.03–2.68
et al. No EGFR-targeted 2.935 1.61–5.45
[20] treatment in
adenocarcinoma
ECOG >2 1.86 1.19–2.89
Biological effective 2.148 1.3–3.54
dose<40 Gy
Other tissue than 1.74 1.12–2.70
adenocarcinoma
Kumar 7 2014 2007–2011 87 52 14 (1–120) Nasopharynx Mixed R KPS 80–100 0.07 0.03–0.18
et al. No major internal organ 0.25 0.11–0.54
[21] One vertebral metastasis 0.23 0.09–0.64
Leithner 7 2008 1998–2006 69 20 14 (N/A) Mixed Surgery R Rapid growth tumor 9.32 3.87–22.5
et al. Visceral metastases 2.17 1.15–4.09
[22]
(Continued)
694 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

Table 1
(Continued)
Mean
Publication Collection No. age Median survival Tumor
Author Nos. year year of pts. (y) (95% CI) (mo) type Treatment Type Prognostic factors HR 95% CI
Mizumoto 7 2008 2002–2006 544 63 5.9 (4.9–6.8) Mixed RT R Age >70 1.433 1.14–1.80
et al. Multiple bone metastasis 1.647 1.17–2.32
[23] Elevated serum calcium 2.57 1.87–3.54
Previous CMT 1.826 1.47–2.27
ECOG 3–4 2.191 1.79–2.68
Unfavorable primary 3.326 2.62–4.22
tumor
Visceral metastases 1.694 1.36–2.11
Moon 7 2011 1987–2008 182 56 8 (6–10) Mixed Surgery R Preoperative ECOG 4 4.984 1.955–12.707
et al. Preoperative ECOG 3 3.206 1.647–6.244
[24] Tomita score 8–10 7.842 2.862–21.485
Tomita score 6–7 3.164 1.242–8.061
Nemelc 7 2014 2000–2010 81 59 9.5 (6.875–12.125) Mixed Surgery R ASIA-C versus ASIA A 13.03 4.57–37.16
et al. Multiple myeloma versus 0.22 0.05–0.95
[25] breast
Lung cancer versus 4.52 1.73–11.78
breast
Colorectal versus breast 5.53 1.60–5.53
Oh et al. 6 2012 1996–2008 52 60.6 N/A Mixed Surgery R Preoperative albumin 1.93 1.073–6.504
[26] level<3.5 g/dL
Rapid growth primary 3.15 1.276–7.081
site
Park 7 2011 2001–2008 103 54.6 10 (8.21–11.80) Mixed Surgery R No postoperative 1.586 1.021–2.645
et al. ambulation
[27] Tokuhashi score (9–11) 0.524 0.335–0.820
versus 0–8
Good prognostic cancer 0.627 0.479–0.899
Pointillart 7 2011 2005–2007 142 61.8 5 (N/A) Mixed Surgery R ASA score >3 2.273 1.049–4.927
et al. Vascular disease as a 2.461 1.347–4.497
[28] comorbidity
Preoperative 2.471 1.377–4.437
chemotherapy
Subjective pain score>6 1.988 1.153–3.428
KPS 80–100 0.978 0.964–0.992
Primary lung tumor 4.44 1.35–14.62
Weight loss 2.608 1.286–5.289
Rades 6 2006 1992–2005 1852 N/A N/A Mixed RT R Ambulator status before 0.47 0.39–0.56
et al. RT
[29] Other bone metastases at 1.29 1.04–1.59
time of RT
Interval tumor diagnosis 0.8 0.75–0.85
to MSCC >15 mo
Motor deficits time 0.72 0.68–0.77
before RT>14 d
Lung cancer 1.23 1.18–1.29
Visceral metastases at the 4.89 4.26–5.60
time of RT
Rades 6 2013 1992–2011 2029 N/A N/A Mixed RT R Non-ambulatory before 1.94 1.65–2.29
et al. RT
[30] Further bone metastases 1.34 1.12–1.61
Interval from diagnosis 1.22 1.14–1.29
to MSCC<15 mo
Time to development of 1.73 1.53–1.95
motor deficits <7 d
ECOG 3–4 1.46 1.2–1.74
Male 1.15 1.01–1.30
Lung cancer 1.18 1.03–1.23
Visceral metastases 4.46 3.92–5.08
Rades 7 2015 N/A 58 N/A N/A Head-and- RT R Non-ambulatory before 4.31 1.85–10.20
et al. Neck RT
[31] Visceral metastases 7.2 3.17–17.58
Rades 7 2012 1992–2010 171 N/A N/A Breast RT R Other bone metastases 1.93 1.18–3.13
et al. Time developing motor 1.55 1.30–1.86
[33] deficits<14 d
Non-ambulatory before 1.75 1.23–2.50
RT
Number of involved 1.27 1.01–1.60
vertebrae≥3
Visceral metastases 7.6 5.39–10.84
(Continued)
P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708 695

Table 1
(Continued)
Mean
Publication Collection No. age Median survival Tumor
Author Nos. year year of pts. (y) (95% CI) (mo) type Treatment Type Prognostic factors HR 95% CI
Rades 6 2014 N/A 552 N/A N/A Mixed RT R Non-ambulatory before 2.17 1.72–2.72
et al. RT
[32] Extraspinal organs≥2 1.61 1.47–1.77
sites
Interval from diagnosis 1.26 1.13–1.42
to RT<15 mo
Time developing motor 1.34 1.16–1.55
deficits<14 d
ECOG 3–4 2.41 1.98–2.92
Male 1.32 1.05–1.67
Lung and other tumor 1.09 1.04–1.13
(vs. breast and
prostate)
Rades 7 2012 N/A 121 N/A N/A Colorectal RT R Non-ambulatory before 2.8 1.78–4.37
et al. cancer RT
[34] The time of developing 1.33 1.01–1.77
motor deficits<14 d
ECOG 3–4 2.96 1.84–4.74
Visceral metastases 3.19 1.94–5.47
Rades 6 2011 N/A 382 N/A N/A Mixed RT R Non-ambulatory before 2.47 1.46–4.05
et al. RT
[35] ECOG 3–4 2.37 1.48–3.73
Low-dose RT (30 Gy/10 1.64 1.11–2.44
fractions)
Lung and other tumor 3.93 2.11–7.18
(vs. breast and
prostate)
Visceral metastases 5.4 2.83–9.88
Rades 7 2012 1992–2010 356 N/A N/A Lung RT R Ambulatory before RT 0.58 0.42–0.79
et al. Bone metastases 1.38 1.08–1.76
[36] Cancer diagnosis interval 0.84 0.70–0.99
to RT >15 mo
Time developing motor 0.78 0.69–0.88
deficits>7 d
ECOG performance 1.45 1.03–2.03
score 3–4
Male 1.32 1.01–1.75
Visceral metastases 2.87 2.17–3.85
Rades 7 2012 1992–2010 436 N/A N/A Prostate RT R Non-ambulatory before 3.17 2.16–4.69
et al. RT
[37] Other bone metastases 1.53 1.04–2.28
Interval from diagnosis 1.27 1.05–1.53
MSCC to RT <15 mo
ECOG 3–4 2.67 1.76–4.12
Visceral metastases 4.15 2.76–6.15
Rades 7 2014 1998–2011 69 N/A N/A Renal cell RT R Non-ambulatory before 3.03 1.51–6.13
et al. carcinoma RT
[38] Number of involved 2.65 1.64–4.52
extraspinal organs≥2
Interval from diagnosis 1.46 1.08–1.99
of MSCC to RT <15
mo
Rades 7 2008 1995–2007 164 N/A 7 (N/A) Mixed RT R Non-ambulatory before 3.25 1.80–5.85
et al. recurrence RT
[57] Time to develop motor 1.54 1.02–2.20
deficits<14 d
ECOG 3–4 4.75 2.59–8.78
Visceral metastases 15.44 7.59–39.73
Rades 6 2011 2006–2007 265 N/A N/A Mixed RT P No bisphosphonates after 2.86 1.82–4.79
et al. radiotherapy
[54] ECOG 3–4 2.09 1.47–2.99
Number of involved 111 1.01–1.23
vertebrae≥4
Visceral metastases 1.66 1.23–2.24
Non-ambulatory before 1.14 1.02–1.92
RT
Rief 8 2014 200–2012 303 64.1 9.8 (N/A) NSCL RT R Bone metastases>1 site 1.09 1.03–1.15
et al.
[39]
Sciubba 8 2007 1993–2001 87 53 21 (12–27) Breast Surgery R Estrogen receptor 3.7 1.7–8.1
et al. negative
[40]
(Continued)
696 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

Table 1
(Continued)
Mean
Publication Collection No. age Median survival Tumor
Author Nos. year year of pts. (y) (95% CI) (mo) type Treatment Type Prognostic factors HR 95% CI
Sellin 7 2015 2005–2013 37 62.2 16.3 (7.4–25.3) RCC RT R Metastasis<12 mo after 2.57 1.12–5.90
et al. primary diagnosis
[41] Local progression 3.69 1.64–8.29
KPS score <70 4 1.67–10.0
Progression of systemic 13.15 4.3–40.19
disease
Switlyk 7 2015 2007–2008 317 65 8.2 (0.4–80) Mixed RT R Albumin <30 g/L 2.9 1.5–5.6
et al. Strong opioids use 2.7 1.4–3.7
[6] KPS 50–70 2.3 1.5–3.5
KPS 10–40 2.6 1.0–6.4
Prostate versus breast 2.2 1.2–3.9
Other versus breast 6.2 3.6–10.7
Visceral metastases 2 or 1.6 1.0–2.6
more locations
Tabouret 7 2015 2004–2010 148 60 8.9 (4.8–13) Mixed Surgery R ASA 3–4 3.07 1.78–5.31
et al. Extra-bone multiple 2.41 1.48–3.94
[42] systemic metastases
KPS>70 0.5 0.3–0.84
Tatsui 8 2014 1993–2007 267 59.2 11 (9.5–13) RCC Surgery R Progressing systemic 4.1 2.9–5.8
et al. disease at spine
[58] surgery
Preoperative neurologic 1.8 1.2–2.7
deficit
Fuhrman grade 4 1.8 1.2–2.6
Wang 8 2014 1992–2011 151 58.7 21.2 (15.9–25.1) Breast Surgery R Estrogen receptor 0.52 0.329–0.92
et al. positive
[43] Progesterone receptor 0.41 0.19–0.88
positive
Hormonal receptor 0.48 0.27–0.84
positive
Ratasvuori 8 2014 1999–2009 307 62 12.9 (N/A) Breast Surgery P Age over 65 1.398 1.083–1.804
et al. Multiple skeletal 2.331 1.449–3.751
[55] metastases
146 73 6.1 (N/A) Prostate Surgery P Time from primary 2.107 1.227–3.617
diagnosis to
operation>6 mo
122 65 12.1 (N/A) RCC Surgery P Operation other than en 1.833 1.032–3.255
bloc resection
Pelvis metastases (vs. 0.4 0.178–0.899
lower limb
metastases)
307 62 12.9 (N/A) BREAST SURGERY P KPS<70 1.506 1.171–1.936
97 64 3.6 (N/A) LUNG SURGERY P KPS<70 1.715 1.119–2.628
122 65 12.1 (N/A) RCC SURGERY P KPS<70 2.955 1.894–4.61
97 64 3.6 (N/A) Lung SURGERY P Presence of organ 2.049 1.299–3.233
metastases
146 73 3.1 (N/A) Prostate SURGERY P Presence of organ 1.911 1.216–3.002
metastases
Weber 7 2013 N/A 95 N/A N/A Prostate RT R Non-ambulatory before 2.7 1.46–5.24
et al. RT
[44] Number of involved 1.88 1.09–3.14
extraspinal organs>1
Cancer diagnosis to RT 1.64 1.24–2.19
interval <15 mo
ECOG 3–4 4.69 2.04–12.28
Yamashita 6 2011 2006–2008 85 60.3 11.6 (6–17.3) Mixed Mixed P KPS 50–70 2.92 1.55–5.48
et al. Preoperative EBRT 2.14 1.12–4.10
[56] Lung cancer (vs. thyroid, 4.25 2.06–8.78
breast, etc.)
Renal cell cancer (vs. 2.6 1.13–5398
thyroid, breast, etc.)
Unremovable major 4.44 2.35–8.41
organ metastases
Yang 7 2012 2001–2009 217 55.5 6 (4.9–7.1) Mixed Surgery R Non-ambulatory status 5.397 3.56–8.181
et al. Preoperative Tomita 1.439 1.003–2.065
[5] score>6 points
Rapid growth tumor 1.607 1.046–2.469
Yasuda 8 2013 1978–2010 45 N/A 27.2 (N/A) RCC Surgery R No zoledronic acid 1.89 1.27–2.96
et al. treatment
[45] Calcium (>10 mg/dL) 2.58 1.31–4.69
(Continued)
P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708 697

Table 1
(Continued)
Mean
Publication Collection No. age Median survival Tumor
Author Nos. year year of pts. (y) (95% CI) (mo) type Treatment Type Prognostic factors HR 95% CI
Yeung 6 2014 2001–2011 128 60.2 3.1 (N/A) Mixed Mixed R KPS 10–40 6.89 3.07–15.46
et al. KPS 50–70 2.62 1.41–4.86
[46] Lung, bladder, stomach 1.86 1.06–3.26
versus breast, prostate
Liver, unidentified versus 2.49 1.23–5.01
breast, prostate
Kidney, uterus 2.76 1.15–6.65
Unremovable visceral 1.73 1.15–2.62
metastasis
Removable visceral 4.82 1.11–20.99
metastasis
Zhang 8 2013 2003–2011 36 49.9 26.3 HCC Surgery R Tomita score of 8 or 3.549 1.374–9.168
et al. more
[47]
Bollen 6 2014 2001–2010 1043 64.8 8.9 (7.4–10.3) Mixed Mixed R KPS 10–70 1.9 1.6–2.2
et al. Rapid growth tumor 3.5 2.9–4.4
[48] Moderate growth tumor 1.6 1.3–2.1
Visceral metastases 1.5 1.3–1.7
Rades 6 2015 N/A 142 N/A N/A Mixed RT R ECOG 3–4 2.76 1.69–4.39
et al. Non-ambulatory before 2.49 1.36–4.26
[49] RT
Visceral metastases at the 4.47 2.44–7.70
time of RT
Rades 7 2013 1995–2011 510 N/A N/A Breast RT R Non-ambulatory before 2.13 1.44–3.13
et al. RT
[50] Other bone metastases 2.51 1.19–5.26
Cancer diagnosis interval 1.29 1.03–1.61
to RT<15 mo
Time of developing 1.45 1.14–1.85
motor deficits<7 d
ECOG 3–4 2 1.34–3.00
Shorter-course 1.25 1.03–1.51
radiotherapy (1×8 or
5×4 Gy)
Visceral metastases 11.04 6.81–18.43
Rades 7 2014 N/A 131 N/A N/A Non–small RT R Non-ambulatory before 2.07 1.32–3.26
et al. cell lung RT
[51] cancer Number of involved 1.6 1.28–2.00
extraspinal organs >1
Time to developing 1.31 1.01–1.72
motor deficits<14 d
ECOG 3–4 2.36 1.39–4.11
Female 1.67 1.06–2.73
Non-adenocarcinoma 1.37 1.07–1.76
histology
Weber 7 2014 N/A 145 N/A N/A Breast RT R Non-ambulatory before 2.32 1.34–5.32
et al. RT
[53] Number of involved 2.19 1.61–3.00
extraspinal organs>1
Time to developing 1.5 1.05–2.17
motor deficits<7 d
ECOG 3–4 4.09 2.17–8.14
KPS, Karnofsky Performance Score; LDH, lactate dehydrogenase; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; RT, radiotherapy; RCC, renal
cell carcinoma; EGFR, epidermal growth factor receptor; CMT, chemotherapy; ASIA, American Spinal Injury Association; ASA, American Society of Anesthesiologists; MSCC,
metastatic spinal cord compression tumor; NSCL, non–small cell lung cancer.

deficit before surgery, non-ambulatory status before RT, The 17 poor prognostic factors with similar variables that
non-ambulatory status before surgery, presence of bone were mentioned in at least three studies were pooled in the
metastases, presence of multiple bone metastases (>2 sites), meta-analysis. The details of meta-analysis results are shown
presence of multiple spinal metastases (>3 sites), develop- in Table 5.
ment of motor deficit in <7 days before initiating RT, The pooled HR of all factors showed statistical signifi-
development of motor deficit in <14 days before initiating cance except preoperative non-ambulatory status (p=.377). The
RT, time interval from cancer diagnosis to RT <15 months, sensitivity analysis of all factors demonstrated that exclu-
KPS 10–40, KPS 50–70, KPS<70, ECOG grade 3–4, male sion of each study did not affect the conclusion of pooled HRs
gender, presence of visceral metastases, moderate growth except the preoperative neurologic deficit. The pooled HR of
tumor on TS classification, and rapid growth tumor on TS preoperative neurologic deficit resulted in no statistical sig-
classification. nificance if Hosono et al. (p=.128) [18] or Tatsui et al. (p=.125)
698 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

Table 2
Present specific and general poor prognostic factors of each primary tumor site

Tumor Specific factors General factors


Breast cancer • Negative estrogen receptor [40,43] • Age more than 65 years [55]
• Negative progesterone receptor [43] • Non-ambulatory status before radiotherapy [33,50,53]
• Negative hormonal receptor [43] • Multiple extraspinal bone metastases [33,50,53,55]
• Poorly or undifferentiated pathology [11] • Admission through emergency room [11]
• shorter course radiotherapy (1×8 Gy or • Increasing time from diagnosis of cancer to surgery (per 1 y) [11]
5×4 Gy) [50] • Interval from cancer diagnosis to radiotherapy of MSCC<15 mo [50]
• Time of developing motor deficits
o <7 days [50]
o <14 days [33,53]
• KPS<70 [55]
• ECOG performance status 3–4 [50,53]
• Number of involved vertebrae≥3 [33]
• Visceral metastases [33,50]
Colorectal cancer • Non-ambulatory before RT [34]
• Time of developing motor deficits<14 d [34]
• ECOG performance status 3–4 [34]
• Visceral metastases [34]
Hepatocellular carcinoma • Biologically effective dose Gy10<38 [13] • Albumin<37 g/dL [12]
(HCC) • Uncontrolled primary HCC [13] • Extrahepatic metastases other than bone [13]
• LDH>200 U/L [12]
• ECOG performance status 3–4 [13]
• Tomita score of 8 or more [47]
Head and neck cancer • Non-ambulatory status before radiotherapy [31]
• Visceral metastases [31]
Nasopharyngeal cancer • Poor KPS [21]
• Major internal organ metastases [21]
• Multiple vertebral metastases [21]
Lung cancer • biological effective dose<40 Gy [20] • Non-ambulatory before RT [36]
• other tissue than adenocarcinoma [20] • Multiple bone metastasis [20]
• No use of EGFR-targeted treatment in • Other bone metastases [36]
adenocarcinoma [20] • Interval from cancer diagnosis to RT<15 mo [36]
• Time developing motor deficits<7 d [36]
• ECOG ≥2 [20]
• ECOG 3–4 [36]
• KPS<70 [55]
• Male [36]
• Visceral metastases [36,55]
Non–small cell lung cancer Non-adenocarcinoma pathology [51] • Non-ambulatory status before RT [51]
• Multiple bone metastases [39,51]
• Time to developing motor deficits <14 d [51]
• Male [51]
Prostate cancer • Non-ambulatory before RT [37] [44]
• Other bone metastases [37]
• Multiple extraspinal metastases [44]
• Interval from cancer diagnosis MSCC to RT<15 mo [37]
• Time from primary diagnosis to operation<6 mo [55]
• Interval from cancer diagnosis to RT<15 mo [44]
• ECOG performance score 3–4 [37,44]
• Visceral metastases [37,55]
• KPS 50–70 [15]
(Continued)
P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708 699

Table 2
(Continued)
Tumor Specific factors General factors
Renal cell carcinoma • No zoledronic acid treatment [45] • Non-ambulatory before RT [38]
• Fuhrman grade 4 [58] • Number of involved extraspinal organs ≥2 [38]
• Serum calcium >10 mg/dL [45]
• Progressing systemic disease at spine surgery [58]
• Interval from cancer diagnosis to RT ≤15 mo [38]
• Diagnosis of metastasis less than 12 mo after primary diagnosis [41]
• Local disease progression after spinal SRS [41]
• Preoperative neurologic deficit [58]
• Operation strategy other than en bloc resection [55]
• Pelvis metastases compared with lower limb metastases [55]
• KPS <70 [41,55]
• Progression of systemic disease at time of spinal SRS [41]
• Revised Tokuhashi score 4–9 compared with 10–12 [17]
Recurrence of tumor in the • Non-ambulatory before RT [57]
previously irradiated part • Time to development of motor deficits before RT<14 d [57]
of spine • ECOG performance score 3–4 [57]
• Visceral metastases [57]
ECOG, Eastern Cooperative Oncology Group; RT, radiotherapy; MSCC, metastatic spinal cord compression tumor; LDH, lactate dehydrogenase; EGFR,
epidermal growth factor receptor; KPS, Karnofsky Performance Score; CMT, chemotherapy; HCC, hepatocellular carcinoma; SRS, stereotactic radiosurgery.

Table 3
Present poor prognostic factors from studies that are reported in various primary tumor sites
Factor Variables
Age Age >70 [23]
Systemic disease Progression of systemic disease at time of spinal SRS [6]
multiple systemic metastases [42], weight loss [28]
Non-ambulatory before RT Non-ambulatory before RT [30,32,35,49,54]
Preoperative non-ambulatory Preoperative non-ambulatory [5,9]
Postoperative non-ambulatory Postoperative non-ambulatory [27]
ASA status ASA score 3–4 [28,42]
Extraspinal bone metastases Presence of extraspinal bone metastases [19,29,30]
Multiple extraspinal bone metastases (≥2 sites) [23,32]
Number of spinal metastases Multiple spinal metastases ≥2 [16], ≥3 [14], ≥4 [54]
Abnormal blood test Elevated serum calcium [23], preoperative albumin level<3.5 g/dL [26]
Comorbidities Charlson comorbidity index ≥2 [9], vascular disease as comorbidity [28]
Previous chemotherapy Previous chemotherapy before RT [23], preoperative chemotherapy [28]
Preoperative radiotherapy Preoperative EBRT [56]
Interval from diagnosis to spinal metastases Disease free before developing spinal metastases<12 mo [19]
Interval from diagnosis to MSCC<15 mo [29,30]
Time developing motor deficits before RT Time developing motor deficits before RT<7 d [30]
Time developing motor deficits before RT<14 d [29,32]
Interval from diagnosis to RT Interval from cancer diagnosis to RT≤15 mo [32]
Preoperative neurologic deficit Preoperative paresis [18], ASIA-C compared with ASIA-E [25]
Severe pain Strong opioids use [6], present pain [18], subjective pain score>6 [28]
Karnofsky Performance Score (KPS) [3] KPS 10–40 [6,10,16,46], KPS 50–70 [6,16,46,56], KPS<70 [28,42,48]
Eastern Cooperative Oncology Group (ECOG) ECOG 3–4 [23,30,32,35,54], preoperative ECOG status 3–4 [24]
No adjuvant therapy No postoperative adjuvant therapy [14], no administration of bisphosphonates
after radiotherapy [54]
Radiotherapy course Low-dose RT (30 Gy/10 fractions) [35]
Revised Tokuhashi score RTS 9–11 [27]
Tomita score Preoperative Tomita score>6 [5]
Tomita score 6–7 compared with Tomita score 2–3 [24]
Tomita score 8–10 compared with Tomita score 2–3 [24]
Gender Male [30,32]
Visceral metastases [3,10,19,22,23,29,30,35,48,49,52,54] Treatable visceral metastases [16,46]
Non-treatable visceral metastases [16,46,56]
Visceral metastases≥2 locations [6]
ECOG, Eastern Cooperative Oncology Group; RT, radiotherapy; KPS, Karnofsky Performance Score; ASIA, American Spinal Injury Association; SRS,
stereotactic radiosurgery; RTS, revised Tokuhashi score; EBRT, external beam radiotherapy; MSCC, metastatic spinal cord compression tumor; ASA, Amer-
ican Society of Anesthesiologists.
700 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

Table 4
Present prognostic factor comparing primary tumor site
Poor prognosis Good prognosis
Primary tumor Radio-resistant tumor [9] Radiosensitive tumor
site [3,52] Moderate growth tumor of Tomita classification [19,48] Slow growth tumor of Tomita classification
Fast growth tumor of Tomita classification [5,10,16,19,22,48] Slow growth tumor of Tomita classification
Lung, bladder, stomach [46] Breast, prostate, thyroid
Liver, unidentified [46] Breast, prostate, thyroid
Renal cell, uterus [46] Breast, prostate, thyroid
Renal cell [56] Breast, prostate, thyroid
Poor prognosis tumor (other than good prognosis group) [18,23,26,27,35] Myeloma, thyroid, renal cell, breast, prostate, lymphoma
Renal cell [56] Thyroid
Prostate [6], lung, colorectal cancer [25], other tumor except breast [6] Breast
Lung [28–30] Other tumor except lung
Lung [32] Breast, prostate
Lung [56] Breast, prostate, thyroid
Slow growth=breast, prostate, etc.; moderate growth=renal cell, uterus, etc.; and rapid growth=lung, stomach, etc.

Fig. 2. Forest plot showing pooled hazard ratio and funnel plot showing publication bias for Karnofsky Performance Score.
Table 5
Show results of meta-analysis including pooled HR, 95% CI, sensitivity analysis, and publication bias

Pooled Heterogeneity Sensitivity Affected Publication bias


Prognostic factors N Total pts. HR range Pooled HR 95% CI (I2) Model p analysis study Begg Egger
Non-ambulatory status before RT 17 7,478 1.14–4.31 2.15 1.89–2.44 48.4% Random <.0001 No effect None 0.021 0.086
[29–38,44,49–51,53,54,57]

P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708


Preoperative non-ambulatory [5,9,14,15,18] 5 755 0.90–2.36 1.20 0.80–1.82 63.6% Random .377 No effect None 1 0.618
Presence of bone metastases 10 5,879 0.95–2.51 1.41 1.27–1.56 0% Fixed <.0001 No effect None 0.245 0.154
[13,19,22,29,30,33,34,36,37,50]
Multiple bone metastases (>2 sites) 10 2,426 1.09–2.65 1.78 1.43–2.20 90.7% Random <.0001 No effect None 0.929 0.011
[20,32,36,38,39,42,44,53,55] 9 2,123 1.60–2.65 1.70 1.57–1.83 26.7% Fixed <.0001 No effect None 0.061 0.019
Spinal metastases ≥3 sites [14,29,32,33,36,38,44] 8 3,710 0.99–1.94 1.13 1.02–1.24 54% Random .014 No effect None 0.026 0.002
Time developing motor deficits before RT<7 d 6 3,167 1.22–1.90 1.48 1.26–1.74 60.9% Random <.0001 No effect None 0.573 0.993
[30,31,36,38,51,53]
Time developing motor deficits before RT <14 d 7 3,086 1.31–1.55 1.39 1.32–1.47 0% Fixed <.0001 No effect None 0.453 0.739
[29,32–34,44,51,57]
Interval from cancer diagnosis to RT <15 mo 9 6,030 1.19–1.64 1.25 1.20–1.30 0% Fixed <.0001 No effect None 0.012 0.055
[29,30,32,36–38,44,50,51]
Preoperative neurologic deficit [18,25,58] 3 513 1.79–13.03 2.97 1.28–6.91 84.2% Random .012 Effect Hosono et al. 0.117 0.153
[18], Tatsui
et al. [58]
KPS 10–40 [6,10,16,46] 4 747 2.60–6.89 3.17 2.26–4.47 30.3% Fixed <.0001 No effect None 1 0.666
KPS 50–70 [10,15,16,22,46,56] 7 922 1.30–3.97 2.09 1.66–2.63 30.6% Fixed <.0001 No effect None 0.348 0.451
KPS<70 [12,14,21,28,41,42,48,55] 8 2,129 0.75–14.39 1.89 1.33–2.67 93.7% Random .0003 No effect None 0.788 0.011
[12,14,21,28,41,42,48,55] 7 1,987 0.75–14.39 2.05 1.49–2.82 79.1% Random <.0001 No effect None 0.532 0.580
ECOG 3–4 [13,20,23,29–32,34–38,44,49–51,53,54,57] 19 8,175 1.18–4.75 2.14 1.83–2.50 67.7% Random <.0001 No effect None 0.152 0.087
Male [5,24,29,30,32,36,39,46,51] 9 5,750 1.17–1.67 1.19 1.10–1.27 0% Fixed <.0001 No effect None 0.144 0.013
Presence of visceral metastases 21 9,026 1.09–15.44 3.10 2.35–4.07 94.2% Random <.0001 No effect None 0.272 0.922
[9,10,14,19,21–23,29–31,33–37,48–50,54,55,57]
Moderate growth tumor of Tomita [5,10,16,19,22,48] 6 1,644 1.07–1.80 1.55 1.30–1.85 29.9% Fixed <.0001 No effect None 0.851 0.944
Fast growth tumor of Tomita [5,10,16,19,22] 5 731 1.70–9.32 3.06 1.65–5.68 85% Random .0004 No effect None 0.327 0.246
RT, radiotherapy; KPS, Karnofsky Performance Score; ECOG, Eastern Cooperative Oncology Group.

701
702 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

Fig. 3. Forest plot showing pooled hazard ratio and funnel plot showing publication bias for bone and spinal metastases.

[58] was omitted. Additionally, omitting the study of Rief et al. and 25 poor prognostic factors that applied to all groups. The
[39] for multiple bone metastases and the study of Pointillart HRs of 17 factors mentioned in at least three publications were
et al. [28] for KPN<70 decreased I2 to less than 90%. There pooled. The sensitivity analysis of all factors revealed that
was no significant publication bias. The forest plot and funnel pooled estimate of effect did not change when each study was
plot are shown in Figs. 2–7. omitted. The homogeneity analysis showed large homoge-
neity. Most of the included studies were single-center,
retrospective studies.
Discussion
The RTS was the most popular prognostic scoring system.
This systematic review included 51 publications for qual- However, this system had overall predictive value of 66% [65].
itative study and 43 publications for meta-analysis. There were Lee et al. reported that the RTS was slightly more accurate
13 poor prognostic factors specific to each primary cancer than TS, but both showed low accuracy in predicting 6 months’
P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708 703

Fig. 4. Forest plot showing pooled hazard ratio and funnel plot showing publication bias for interval from cancer diagnosis and time developed motor deficit
before radiotherapy.

residual survival [66]. Yu et al. reported that only 8.6% of general prognostic factor had great variance between primary
patients with lung cancer spinal metastasis actually fol- tumor sites. For example, the HRs of positive visceral me-
lowed the RTS. Furthermore, RTS could predict survival tastases in prostate, breast, and lung cancer were 1.91–4.15,
accurately only in those patients with visceral tumors and 7.6–11.04, and 2.04–2.87, respectively. The HR of studies that
disease progression after first-time chemotherapy, simulta- report with mixed primary tumor ranged from 1.08 to 4.89.
neously. They suggested that both factors should be added We hypothesized that if RTS added and accurately weighted
into the RTS system to increase validity and accuracy [67]. these significant factors, the accuracy of RTS could in-
However, our study found new factors that were not men- crease significantly.
tioned in RTS, including gender, ambulatory status, hormonal Moreover, each metastatic cancer had specific prognos-
receptor, age, interval between cancer diagnosis and RT, ab- tic factors that may be related to the response rate of
normal blood test (calcium, albumin, and lactate adjuvant therapy. Specific prognostic factors for metastatic
dehydrogenase), time to development of motor deficit, ASA breast cancer included hormonal receptor, poorly differenti-
score, comorbidities, disease-free interval, severe pain, ad- ated pathology, and a course of RT. Specific prognostic
juvant therapy, and RT course. Additionally, the effect of each factors for metastatic lung cancer were non-adenocarcinoma
704 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

Fig. 5. Forest plot showing pooled hazard ratio and funnel plot showing publication bias for non-ambulatory status and neurologic deficit.

type and no epidermal growth factor receptor-targeted therapy ic considerations. Laufer et al.’s study mentions that “systemic
in adenocarcinoma type. Higher prostate-specific antigen disease assessment determines what a patient can tolerate
level was the only specific factor in prostate metastatic physiologically and is dependent on extent of tumor dissem-
cancer. Unfortunately, current prognostic scores did not add ination, medical comorbidities and tumor histology” [68].
any specific factors in their systems. Currently, there are However, there are no clearly identified specific medical
some new prognostic scores that are specific to primary morbidities. Our study found many systemic factors that
tumor including prostate cancer [15] and nasopharyngeal may be used for determining prognosis and that may guide
cancer [21]. However, these new scoring systems do not the treatment in NOMS approach including ASA status,
include all potential nonspecific prognostic factors and lack Charlson comorbidity index >2, vascular disease, elevated
external validity studies. serum calcium, preoperative albumin level<3.5 g/dL, severe
Laufer et al. reported a new approach to spinal meta- pain, and weight loss.
static tumors termed the “NOMS” approach. This approach There are several limitations to this study. First, most of
consists of neurologic, oncologic, mechanical, and system- the included studies were retrospective studies that did not
P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708 705

Fig. 6. Forest plot showing pooled hazard ratio and funnel plot showing publication bias for primary tumor and visceral metastases.
706 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

Fig. 7. Forest plot showing pooled hazard ratio and funnel plot showing publication bias for male and Eastern Cooperative Oncology Group grade.

have a specific survival period (eg 5-year or 10-year overall References


survival). Second, there were many studies reported by
[1] Tokuhashi Y, Matsuzaki H, Oda H, Oshima M, Ryu J. A revised scoring
Rades et al. that did not clearly define the source of system for preoperative evaluation of metastatic spine tumor prognosis.
enrolled patients, median survival, and were conducted Spine 2005;30:2186–91.
only on radiated patients. Third, 75% (38 of 51) of included [2] Tomita K, Kawahara N, Kobayashi T, Yoshida A, Murakami H,
studies had a Newcastle-Ottawa Scale score of 6–7, which Akamaru T. Surgical strategy for spinal metastases. Spine 2001;26:298–
indicates only moderate quality. Finally, we selected only 306.
[3] van der Linden YM, Dijkstra SP, Vonk EJ, Marijnen CA, Leer JW;
English publications, which may have some selection bias. Dutch Bone Metastasis Study Group. Prediction of survival in patients
A multicenter prospective cohort study is needed to prove with metastases in the spinal column: results based on a randomized
the effect of these independent prognostic factors. trial of radiotherapy. Cancer 2005;103:320–8.
[4] Bauer HC, Wedin R. Survival after surgery for spinal and extremity
metastases. Prognostication in 241 patients. Acta Orthop Scand
Conclusion 1995;66:143–6.
[5] Yang SB, Cho W, Chang UK. Analysis of prognostic factors relating
This systematic review and meta-analysis showed that in- to postoperative survival in spinal metastases. J Korean Neurosurg Soc
dependent poor prognostic factors can be categorized into 2012;51:127–34.
tumor-specific and nonspecific factors. The current prognos- [6] Switlyk MD, Kongsgaard U, Skjeldal S, et al. Prognostic factors in
patients with symptomatic spinal metastases and normal neurological
tic scoring system has moderate accuracy. A tumor-based
function. Clin Oncol 2015;27:213–21.
prognostic scoring system that combines all specific and [7] Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred
general factors of each primary tumor may enhance the ac- reporting items for systematic reviews and meta-analyses: the PRISMA
curacy of survival prediction. statement. Int J Surg 2010;8:336–41.
P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708 707

[8] Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale [28] Pointillart V, Vital JM, Salmi R, Diallo A, Quan GM. Survival
(NOS) for assessing the quality of nonrandomised studies in meta- prognostic factors and clinical outcomes in patients with spinal
analyses. Available at: http://www.ohri.ca/programs/clinical metastases. J Cancer Res Clin Oncol 2011;137:849–56.
_epidemiology/oxford.asp. Accessed December 30, 2015. [29] Rades D, Fehlauer F, Schulte R, et al. Prognostic factors for local control
[9] Arrigo RT, Kalanithi P, Cheng I, et al. Predictors of survival after and survival after radiotherapy of metastatic spinal cord compression.
surgical treatment of spinal metastasis. Neurosurgery 2011;68:674–81 J Clin Oncol 2006;24:3388–93.
discussion 81. [30] Rades D, Hueppe M, Schild SE. A score to identify patients with
[10] Bollen L, de Ruiter GC, Pondaag W, et al. Risk factors for survival metastatic spinal cord compression who may be candidates for best
of 106 surgically treated patients with symptomatic spinal epidural supportive care. Cancer 2013;119:897–903.
metastases. Eur Spine J 2013;22:1408–16. [31] Rades D, Schild SE, Karstens JH, Hakim SG. Predicting survival of
[11] Cahill KS, Chi JH, Day AL, Claus EB. Trends in survival after surgery patients with metastatic epidural spinal cord compression from cancer
for breast cancer metastatic to the brain and spinal column in medicare of the head-and-neck. Anticancer Res 2015;35:385–8.
patients: a population-based analysis. Neurosurgery 2011;68:705–13 [32] Rades D, Weber A, Karstens JH, Schild SE, Bartscht T. Prognostic role
discussion 13. of the number of involved extraspinal organs in patients with metastatic
[12] Chen H, Xiao J, Yang X, Zhang F, Yuan W. Preoperative scoring spinal cord compression. Clin Neurol Neurosurg 2014;118:12–15.
systems and prognostic factors for patients with spinal metastases from [33] Rades D, Douglas S, Veninga T, et al. Prognostic factors in a series
hepatocellular carcinoma. Spine 2010;35:E1339–46. of 504 breast cancer patients with metastatic spinal cord compression.
[13] Choi C, Seong J. Predictive factors of palliative radiotherapy response Strahlenther Onkol 2012;188:340–5.
and survival in patients with spinal metastases from hepatocellular [34] Rades D, Douglas S, Huttenlocher S, et al. Prognostic factors and a
carcinoma. Gut Liver 2015;9:94–102. survival score for patients with metastatic spinal cord compression from
[14] Chong S, Shin SH, Yoo H, et al. Single-stage posterior decompression colorectal cancer. Strahlenther Onkol 2012;188:1114–18.
and stabilization for metastasis of the thoracic spine: prognostic factors [35] Rades D, Panzner A, Rudat V, Karstens JH, Schild SE. Dose escalation
for functional outcome and patients’ survival. Spine J 2012;12:1083–92. of radiotherapy for metastatic spinal cord compression (MSCC) in
[15] Crnalic S, Lofvenberg R, Bergh A, Widmark A, Hildingsson C. patients with relatively favorable survival prognosis. Strahlenther Onkol
Predicting survival for surgery of metastatic spinal cord compression 2011;187:729–35.
in prostate cancer: a new score. Spine 2012;37:2168–76. [36] Rades D, Douglas S, Veninga T, et al. Metastatic spinal cord
[16] Dardic M, Wibmer C, Berghold A, Stadlmueller L, Froehlich EV, compression in non-small cell lung cancer patients. Prognostic factors
Leithner A. Evaluation of prognostic scoring systems for spinal in a series of 356 patients. Strahlenther Onkol 2012;188:472–6.
metastases in 196 patients treated during 2005–2010. Eur Spine J [37] Rades D, Douglas S, Veninga T, et al. A survival score for patients
2015;24:2133–41. with metastatic spinal cord compression from prostate cancer.
[17] Han S, Wang T, Jiang D, et al. Surgery and survival outcomes of 30 Strahlenther Onkol 2012;188:802–6.
patients with neurological deficit due to clear cell renal cell carcinoma [38] Rades D, Weber A, Bartscht T, Bajrovic A, Karstens JH, Schild SE.
spinal metastases. Eur Spine J 2015;24:1786–91. A new prognostic factor for the survival of patients with renal cell
[18] Hosono N, Ueda T, Tamura D, Aoki Y, Yoshikawa H. Prognostic carcinoma developing metastatic spinal cord compression. Strahlenther
relevance of clinical symptoms in patients with spinal metastases. Clin Onkol 2014;190:667–70.
Orthop Relat Res 2005;436:196–201. [39] Rief H, Muley T, Bruckner T, et al. Survival and prognostic factors
[19] Kataoka M, Kunisada T, Tanaka M, et al. Statistical analysis of in non-small cell lung cancer patients with spinal bone metastases: a
prognostic factors for survival in patients with spinal metastasis. Acta retrospective analysis of 303 patients. Strahlenther Onkol 2014;190:59–
Med Okayama 2012;66:213–19. 63.
[20] Komatsu T, Kunieda E, Oizumi Y, Tamai Y, Akiba T. An analysis of [40] Sciubba DM, Gokaslan ZL, Suk I, et al. Positive and negative prognostic
the survival rate after radiotherapy in lung cancer patients with bone variables for patients undergoing spine surgery for metastatic breast
metastasis: is there an optimal subgroup to be treated with high-dose disease. Eur Spine J 2007;16:1659–67.
radiation therapy? Neoplasma 2012;59:650–7. [41] Sellin JN, Reichardt W, Bishop AJ, et al. Factors affecting survival
[21] Kumar N, Tan JJ, Zaw AS, et al. Evaluation of scoring systems and in 37 consecutive patients undergoing de novo stereotactic radiosurgery
prognostic factors in patients with spinal metastases from for contiguous sites of vertebral body metastasis from renal cell
nasopharyngeal carcinoma. Spine J 2014;14:2946–53. carcinoma. J Neurosurg Spine 2015;22:52–9.
[22] Leithner A, Radl R, Gruber G, et al. Predictive value of seven [42] Tabouret E, Cauvin C, Fuentes S, et al. Reassessment of scoring systems
preoperative prognostic scoring systems for spinal metastases. Eur Spine and prognostic factors for metastatic spinal cord compression. Spine
J 2008;17:1488–95. J 2015;15:944–50.
[23] Mizumoto M, Harada H, Asakura H, et al. Prognostic factors and a [43] Wang M, Jensen AB, Morgen SS, et al. Survival analysis of breast
scoring system for survival after radiotherapy for metastases to the spinal cancer subtypes in patients with spinal metastases. Spine 2014;39:1620–
column: a review of 544 patients at Shizuoka Cancer Center Hospital. 7.
Cancer 2008;113:2816–22. [44] Weber A, Bartscht T, Karstens JH, Schild SE, Rades D. Survival in
[24] Moon KY, Chung CK, Jahng TA, Kim HJ, Kim CH. Postoperative patients with metastatic spinal cord compression from prostate cancer
survival and ambulatory outcome in metastatic spinal tumors: prognostic is associated with the number of extra-spinal organs involved. Anticancer
factor analysis. J Korean Neurosurg Soc 2011;50:216–23. Res 2013;33:4505–7.
[25] Nemelc RM, Stadhouder A, van Royen BJ, Jiya TU. The outcome and [45] Yasuda Y, Fujii Y, Yuasa T, et al. Possible improvement of survival
survival of palliative surgery in thoraco-lumbar spinal metastases: with use of zoledronic acid in patients with bone metastases from renal
contemporary retrospective cohort study. Eur Spine J 2014;23: cell carcinoma. Int J Clin Oncol 2013;18:877–83.
2272–8. [46] Yeung Y-N, Cheung K-K, Lam T-C, Cheng H-O, Chow Y-Y. A study
[26] Oh I-S, Kim S-I, Ha K-Y. Significant predictive values for the life of the predictive value of the modified Tokuhashi score in metastatic
expectancy in patients with spinal metastasis following surgical spinal tumour causing cord compression in a Southern Chinese
treatment. Eur J Orthop Surg Traumatol 2012;22:17–24. population. J Orthop Trauma Rehabil 2014;18:15–21.
[27] Park JH, Rhim SC, Jeon SR. Efficacy of decompression and fixation [47] Zhang D, Xu W, Liu T, et al. Surgery and prognostic factors of patients
for metastatic spinal cord compression: analysis of factors prognostic with epidural spinal cord compression caused by hepatocellular
for survival and postoperative ambulation. J Korean Neurosurg Soc carcinoma metastases: retrospective study of 36 patients in a single
2011;50:434–40. center. Spine 2013;38:E1090–5.
708 P. Luksanapruksa et al. / The Spine Journal 17 (2017) 689–708

[48] Bollen L, van der Linden YM, Pondaag W, et al. Prognostic factors for in-field recurrences of metastatic spinal cord compression. Cancer
associated with survival in patients with symptomatic spinal bone 2008;113:1090–6.
metastases: a retrospective cohort study of 1,043 patients. Neuro Oncol [58] Tatsui CE, Suki D, Rao G, et al. Factors affecting survival in 267
2014;16:991–8. consecutive patients undergoing surgery for spinal metastasis from renal
[49] Rades D, Huttenlocher S, Veninga T, et al. A matched-pair analysis cell carcinoma. J Neurosurg Spine 2014;20:108–16.
comparing 5x4 Gy and 10x3 Gy for metastatic spinal cord compression [59] Demirci S, Kamer S, Kara G, Yildirim O, Esassolak M. Does the
(MSCC) in patients with favorable survival prognoses. Radiat Oncol prognosis of nasopharyngeal cancer differ among endemic and non-
2015;10:90. endemic regions? Acta Otolaryngol 2011;131:852–60.
[50] Rades D, Douglas S, Schild SE. A validated survival score for breast [60] Drzymalski DM, Oh WK, Werner L, Regan MM, Kantoff P, Tuli S.
cancer patients with metastatic spinal cord compression. Strahlenther Predictors of survival in patients with prostate cancer and spinal
Onkol 2013;189:41–6. metastasis. Presented at the 2009 Joint Spine Section Meeting. Clinical
[51] Rades D, Weber A, Karstens JH, Schild SE, Bartscht T. Number of article. J Neurosurg Spine 2010;13:789–94.
extraspinal organs with metastases: a prognostic factor of survival in [61] Ogihara S, Seichi A, Hozumi T, et al. Prognostic factors for patients
patients with metastatic spinal cord compression (MSCC) from with spinal metastases from lung cancer. Spine 2006;31:1585–90.
non-small cell lung cancer (NSCLC). Anticancer Res 2014;34:2503–7. [62] Rades D, Fehlauer F, Veninga T, et al. Functional outcome and survival
[52] Tancioni F, Navarria P, Pessina F, et al. Assessment of prognostic factors after radiotherapy of metastatic spinal cord compression in patients with
in patients with metastatic epidural spinal cord compression (MESCC) cancer of unknown primary. Int J Radiat Oncol Biol Phys 2007;67:532–
from solid tumor after surgery plus radiotherapy: a single institution 7.
experience. Eur Spine J 2012;21(Suppl. 1):S146–8. [63] Wibmer C, Leithner A, Hofmann G, et al. Survival analysis of 254
[53] Weber A, Bartscht T, Karstens JH, Schild SE, Rades D. Breast cancer patients after manifestation of spinal metastases: evaluation of seven
patients with metastatic spinal cord compression. Number of extraspinal preoperative scoring systems. Spine 2011;36:1977–86.
organs involved by metastases influences survival. Strahlenther Onkol [64] Castel E, Lazennec JY, Chiras J, Enkaoua E, Saillant G. Acute spinal
2014;190:283–6. cord compression due to intraspinal bleeding from a vertebral
[54] Rades D, Lange M, Veninga T, et al. Final results of a prospective study hemangioma: two case-reports. Eur Spine J 1999;8:244–8.
comparing the local control of short-course and long-course radiotherapy [65] Quraishi NA, Manoharan SR, Arealis G, et al. Accuracy of the revised
for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys Tokuhashi score in predicting survival in patients with metastatic spinal
2011;79:524–30. cord compression (MSCC). Eur Spine J 2013;22(Suppl. 1):S21–6.
[55] Ratasvuori M, Wedin R, Hansen BH, et al. Prognostic role of en-bloc [66] Lee CH, Chung CK, Jahng TA, et al. Which one is a valuable surrogate
resection and late onset of bone metastasis in patients with bone-seeking for predicting survival between Tomita and Tokuhashi scores in patients
carcinomas of the kidney, breast, lung, and prostate: SSG study on 672 with spinal metastases? A meta-analysis for diagnostic test accuracy
operated skeletal metastases. J Surg Oncol 2014;110:360–5. and individual participant data analysis. J Neurooncol 2015;123:267–75.
[56] Yamashita T, Siemionow KB, Mroz TE, Podichetty V, Lieberman IH. [67] Yu W, Tang L, Lin F, Yao Y, Shen Z. Accuracy of Tokuhashi score
A prospective analysis of prognostic factors in patients with spinal system in predicting survival of lung cancer patients with vertebral
metastases: use of the revised Tokuhashi score. Spine 2011;36:910–17. metastasis. J Neurooncol 2015;125:427–33.
[57] Rades D, Rudat V, Veninga T, Stalpers LJ, Hoskin PJ, Schild SE. [68] Laufer I, Rubin DG, Lis E, et al. The NOMS framework: approach to
Prognostic factors for functional outcome and survival after reirradiation the treatment of spinal metastatic tumors. Oncologist 2013;18:744–51.