Does Duration of Symptoms in Metastatic Spine Disease Affect Recovery and Outcomes? A Systematic Review and Meta-Analysis

Abstract

Study Design

Systematic review and meta-analysis.

Objectives

We sought to evaluate the association between pre-treatment symptom duration and outcomes in patients undergoing radiotherapy (RT)/surgery for metastatic epidural spinal cord compression (MESCC).

Methods

A systematic review included publications evaluating the association between pre-treatment symptom duration and outcomes after RT/surgery in adults with MESCC. Primary exposure was pre-treatment symptom duration. Outcomes were motor-recovery, ambulation, survival and local control. Pooled-effect-estimates were calculated.

Results

Of 4639 studies, 37 met the inclusion criteria (26-RT,11-surgery). RT: All studies defined symptom duration as time from motor-weakness onset to RT. Longer symptom duration was associated with improved motor-recovery (Pooled-effect-estimate=2.08, 95%CI:1.68-2.58,p<0.001) and decreased mortality-risk (improved-survival)((Pooled-effect-estimate=0.72, 95%CI:0.69-0.76,p<0.001). Although longer symptom duration was consistently associated with better ambulation and lower local recurrence, few studies precluded meta-analysis. Surgery: Symptom duration was defined as time from neurological-deficit onset to surgery in 7/11 studies; three-studies used ambulatory status, and one-study used both. Longer symptom duration was associated with increased risk-of-death (worse-survival)(Pooled-effect-estimate=1.28, 95%CI:0.54-3.03,p=0.575), though statistically insignificantly. Meta-analysis for motor-recovery wasn’t feasible, but most studies found longer symptom duration worsened motor-recovery, while ambulation findings were inconsistent.

Conclusion

Symptom duration was associated with differing outcome patterns by treatment modality. In RT cohorts, longer symptom duration was associated with improved survival and motor recovery. In surgical cohorts, it trended toward worse survival, though this did not reach statistical significance. Most surgical studies suggested an inverse association between symptom duration and motor recovery. These findings are exploratory, and should be interpreted in context of treatment selection-bias and between-cohort heterogeneity.

Introduction

Metastatic spine disease affects up to 30% patients with advanced systemic malignancies.^1,2 Spinal cord compression is a common and devastating complication, causing pain, neurologic deficits, and functional decline.^2,3 Radiotherapy (RT) and surgical decompression are the mainstays of treatment, aimed at preserving neurologic function, spinal stability, and oncologic control.^2,4,5

A critical factor influencing outcomes in patients with spinal metastases is the pre-treatment symptom duration, particularly motor deficits.^4,6,7 Delays in diagnosis or intervention may allow progressive cord compromise, limiting the reversibility of neurologic dysfunction and reducing treatment efficacy.^6,7 Consequently, timely recognition and prompt treatment are considered key principles in managing metastatic spinal cord compression. ⁶ However, the strength and consistency of evidence supporting a direct relationship between symptom duration and clinical outcomes remain uncertain. Prior studies have suggested that shorter intervals between symptom onset and treatment are associated with improved neurologic recovery and functional independence.^6,7 Yet, the heterogeneity in study designs, outcome definitions, and reporting standards has limited the generalizability of these findings. ⁸ Moreover, no comprehensive meta-analysis has systematically examined the association between symptom duration and RT or surgical outcomes in this population.

Despite broad recognition that earlier intervention may improve outcomes in metastatic spinal cord compression, the specific association between symptom duration and post-treatment recovery remains unclear. In this study, we performed a systematic review and meta-analysis to evaluate the association between the pre-treatment symptom duration (motor function) and clinical outcomes (motor recovery and survival) in patients undergoing RT or surgery for metastatic spine disease.

Methods

Data Search and Study Selection

The systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. ⁹ Institutional review board approval was waived. The review was not registered on PROSPERO. A comprehensive literature search was performed in PubMed and Embase databases, from 01/01/1990 to 03/03/2025, using a combination of keywords and MeSH terms (Supplemental Digital Content 1).

Studies were included in the systematic review if they:1) included adult patients with metastatic spinal cord compression, 2) reported pre-treatment symptom duration, 3) studied the correlation between the symptom duration and postoperative outcomes. Exclusion criteria were:1) studies evaluating primary spine tumors, 2) conference abstracts, 3) dissertations, 4) reviews, editorials, or non-primary research, 7) non-English articles, and 8) articles without fully accessible text.

For the meta-analysis, only studies reporting multivariable regressions with risk ratios and 95%CIs were included in the analysis. The studies were grouped based on the intervention, and the outcome evaluated for the analysis. More than 3 studies were required to proceed with the meta-analysis.

Data Extraction and Quality Assessment

Two independent reviewers screened titles, abstracts, and full texts. Extracted data included study characteristics, primary tumor site, symptom type/duration, treatment modality, outcomes, and effect estimates from multivariable analysis. Symptom duration was categorized as defined by each study, and thresholds varied across studies. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS) for observational studies, evaluating selection, comparability, and outcome ascertainment. ¹⁰ The level of evidence for each study was also classified using the Oxford Centre for Evidence-Based Medicine criteria, with prospective observational studies classified as Level II and retrospective studies as Level III evidence. ¹¹

Exposure Variables

The primary exposure was pre-treatment symptom duration, most commonly the interval from onset of motor deficits to initiation of RT or surgery. In some surgical cohorts, ambulatory status or combined neurological definitions were used. When available, we also extracted covariates such as age, sex, visceral metastases, and vertebral involvement, and assessed their association with outcomes.

Treatment Variables

Interventions included RT or surgery for metastatic spinal cord compression. Studies were grouped according to intervention for analysis. No differentiation was made between type of RT. Moreover, all surgical procedures and approaches were grouped in a single category, without subdividing based on surgical decision-making.

Outcome Variables

The primary outcome was motor function after treatment. Motor function was often referred to as motor recovery and was also measured with ambulation. Secondary outcomes included overall survival and local tumor control, reflecting the broader clinical impact of treatment timing.

Statistical Analysis

All analyses were performed using IBM SPSS v29. Random-effects meta-analysis was conducted to account for between-study variability, with between-study variance estimated using the restricted maximum likelihood (REML) method. Only studies reporting adjusted effect estimates from multivariable regression models with risk ratios (or hazard ratios treated as approximations of risk ratios) and corresponding 95% confidence intervals were included in quantitative pooling. Effect estimates were log-transformed for pooling and back-transformed for presentation. Where studies reported odds ratios or hazard ratios, these were treated as approximations of risk ratios given the clinical context; no formal conversion was applied. Pooled effect estimates and corresponding 95%CIs were calculated and stratified by intervention and outcome. Owing to limited eligible studies, meta-analyses were confined to RT with motor recovery and survival, and surgery with survival; remaining outcomes were synthesized qualitatively. Heterogeneity was evaluated using the I² statistic, with thresholds of 25%, 50%, and 75% representing low, moderate, and substantial heterogeneity, respectively.

Results

The search criteria yielded 4,639 studies from PubMed/Embase databases, of which 3,935 were screened. After exclusions, 235 full-texts were assessed for eligibility, and 37 were included in the final review—26 evaluating RT and 11 surgery (Figure 1). Of the included studies, 4 (10.8%) were prospective and classified as Level II evidence, while 33 (89.2%) were retrospective and classified as Level III evidence. The level of evidence for each study is summarized in the corresponding tables. Methodological quality assessment using the NOS is summarized in Table 1.

Figure 1.

PRISMA diagram for the systematic review

Table 1.

Newcastle–Ottawa Scale (NOS) Assessment

Study	Rep. cohort	Non-exposed	Exposure	Outcome absent	Comparability	Outcome assessment	Follow-up length	Follow-up adequacy	Total
Iida et al., 2024	★	☆	★	★	☆	★	★	★	6
Park et al., 2024	★	☆	★	★	★	★	★	★	7
Rades et al., 2022	★	☆	★	★	★★	★	★	★	8
Rades et al., 2022	★	☆	★	★	★★	★	★	★	8
Cui et al., 2021	★	☆	★	★	☆	★	☆	☆	4
Lun et al., 2019	★	☆	★	★	★★	★	★	★	8
Rades et al., 2019	★	☆	★	★	★★	★	★	★	8
Rades et al., 2018	★	☆	★	★	☆	★	★	★	6
Ohashi et al., 2017	★	☆	★	★	★★	★	★	★	8
Park et al., 2016	★	☆	★	★	★★	★	★	★	8
Lei et al., 2015	★	☆	★	★	★★	★	★	★	8
Rades et al., 2015	★	☆	★	★	★★	★	★	★	8
Rades et al., 2015	★	☆	★	★	★★	★	★	★	8
Rades et al., 2015	★	☆	★	★	★	★	★	★	7
Huttenlocher et al., 2014	★	☆	★	★	★★	★	★	★	8
Rades et al., 2014	★	☆	★	★	★★	★	★	★	8
Rades et al., 2014	★	☆	★	★	★★	★	★	★	8
Rades et al., 2014	★	☆	★	★	★★	★	★	★	8
Quraishi et al., 2013	★	☆	★	★	★	★	★	★	7
Rades et al., 2013	★	☆	★	★	★★	★	★	★	9
Zhang et al., 2013	★	☆	★	★	★★	★	★	★	8
Douglas et al., 2012	★	☆	★	★	★★	★	★	★	8
Douglas et al., 2012	★	★	★	★	★★	★	★	★	9
Douglas et al., 2012	★	★	★	★	★★	★	★	★	9
Rades et al., 2012	★	☆	★	★	★★	★	★	★	8
Rades et al., 2012	★	☆	★	★	★★	★	★	★	8
Rades et al., 2012	★	☆	★	★	★★	★	★	★	8
Rades et al., 2012	★	☆	★	★	★★	★	★	★	8
Rades et al., 2012	★	☆	★	★	★★	★	★	★	8
Kim et al., 2011	★	☆	★	★	★	★	★	★	7
Hessler et al., 2009	★	☆	★	★	★	★	★	★	7
Rades et al., 2006	★	☆	★	★	★★	★	★	★	8
Rades et al., 2006	★	☆	★	★	★★	★	★	★	8
Rades et al., 2002	★	☆	★	★	★★	★	★	★	8
Rades et al., 2001	★	☆	★	★	★	★	★	★	7
Rades et al., 2000	★	☆	★	★	★	★	★	★	7
Rades et al., 1999	★	☆	★	★	★	★	★	★	7

All RT studies used a consistent definition of symptom duration, defining it as the interval from motor-weakness onset to initiation of RT (100%). In contrast, the surgery studies demonstrated greater heterogeneity in symptom-duration definitions: 7/11 studies (63.6%) defined it as the time from neurological-deficit onset to surgery, three studies (27.3%) used ambulatory status–based definitions, and one study (9.1%) incorporated both approaches. This heterogeneity limits meaningful comparative analysis across studies, and the findings should therefore be interpreted with caution.

Outcome: Motor Recovery

RT

Ten studies assessed the relationship between motor deficit duration and postoperative motor recovery following RT (Table 2).^12-21 Longer symptom duration was consistently associated with improved motor recovery. Among the four studies included in the pooled analysis,^12,17,18,20 longer symptom duration was associated with improved motor recovery (Pooled effect estimate:2.08, 95%CI:1.68-2.58, p<0.001) (Figure 2), with moderate heterogeneity (I ² =0.29).

Table 2.

Studies Evaluating the Relationship Between Duration of Symptoms and Neurological Function

Authors	Country	Study design	Level of evidence	Primary tumor	Symptom evaluated	Duration of symptoms- groups	Relationship between duration and outcome
Surgery
Cui et al., 2021	China	Retrospective cohort	III	All metastatic spine tumors	Ambulation	A: <3 days B: 4-7 days C: >7 days	Shorter duration of symptoms associated with better motor outcome
Quraishi et al., 2013	UK	Retrospective cohort	III	All metastatic spine tumors	Neurological Deficit	A: <24hours B: 24-48 hours C: >48 hours	Shorter duration of symptoms associated with better motor outcome
Hessler et al., 2009	Germany	Retrospective cohort	III	All metastatic spine tumors	Neurological Deficit	A: <1 day B: 1-3 days C: 3-5 days D: 5-10 days E: 10-15 days F: >15 days	Shorter duration associated with better neurologic outcome
Radiotherapy
Rades et al., 2012	Germany	Retrospective cohort	III	Colorectal	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better motor outcome.
Douglas et al., 2012	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: <7 days B: >7 days	Slower development of symptoms associated with better motor outcome.
Rades et al., 2012	Germany	Retrospective cohort	III	Non-Small Cell Lung Cancer	Motor Deficits	A: <7 days B: >7 days	Slower development of symptoms associated with better motor outcome.
Rades et al., 2012	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better motor outcome.
Rades et al., 2006	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better motor outcome.
Rades et al., 2002	Germany	Prospective cohort	II	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better motor outcome.
Rades et al., 2001	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better motor outcome
Rades et al., 2000	Germany	Prospective cohort	II	All metastatic spine tumors	Motor Deficits	A: 1-14 days B: >14 days; A: ≤48 hours >48 hours	Slower development of symptoms associated with better motor outcome
Huttenlocher et al., 2014	Germany	Retrospective cohort	III	Melanoma	Motor Deficits	A: <7 days B: >7 days	Slower development of symptoms associated with better motor outcome
Rades et al., 1999	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: 1-14 days B: >14 days and A: ≤48 hours B:>48 hours	Slower development of symptoms associated with better motor outcome

Figure 2.

Forest plot for studies evaluating the effect of duration of symptoms on motor recovery for patients undergoing radiotherapy

Surgery

Three retrospective studies evaluated symptom duration and motor recovery in surgical cohorts (Table 2).^7,22,23 Although all reported that shorter symptom duration was associated with better postoperative neurologic recovery, a meta-analysis was not feasible due to the limited number of studies reporting multivariable regression. Hessler et al. found that a shorter duration of neurological deficits was associated with better postoperative neurologic improvement, ⁷ with patients undergoing surgery within 7 days of symptom onset demonstrating significantly greater improvement in the American Spinal Injury Association Impairment Scale (AIS), particularly among those with more severe deficits (AIS B/C), compared with those treated after 7 days. ²² Similarly, Quraishi et al. demonstrated that surgery performed within 24–48 hours resulted in greater neurological recovery than surgery delayed beyond 48 hours. ²³

Outcome: Ambulation

RT

Among 8 studies assessing the association between symptom duration and ambulatory function in RT cohorts, only one included multivariable analysis.^{14,15,19,21,24-27} The study found that longer symptom duration (trichotomized as ≤7, 8-14, or >14 days) was associated with better ambulatory function (OR:5.18, 95%CI:1.9-13.9, p=0.004). ²⁴ Six additional studies also arrived at this same conclusion,^{14,15,21,25-27} although without multivariable analyses. In contrast, one study found no significant association between symptom duration (<7 vs. >7 days) and ambulatory recovery following RT. ¹⁹

Surgery

Among the 6 studies evaluating the association between symptom duration and ambulatory outcomes in surgical cohorts, no consistent association was seen (Table 3).^22,28-32 Three studies found no association,^22,29,30 two found shorter duration was associated with better ambulatory function,^31,32 and one reported longer duration was associated with better ambulatory function. ²⁸ Although Park et al ³⁰ did not find a significant association between symptom duration and ambulation outcomes, shorter duration of symptoms led to better recovery in a subgroup analysis of patients with poor preoperative motor strength (MRC Grade:0-2). Only two studies included multivariable analyses, both showing that shorter symptom duration was associated with improved ambulatory function.^31,32 Lack of adequate studies with multivariable regression precluded meta-analyses.

Table 3.

Studies Evaluating the Relationship Between Duration of Symptoms and Ambulatory Function

Authors	Country	Study design	Level of evidence	Primary tumor	Symptom evaluated	Duration of symptoms- groups	Relationship between duration and outcome
Surgery
Iida et al., 2024	Japan	Retrospective cohort	III	All metastatic spine tumors	Ambulation	A: <7 days B: >7 days	Slower development of symptoms associated with better ambulatory function
Park et al., 2024	South Korea	Retrospective cohort	III	All metastatic spine tumors	Motor Deficit, Ambulation	Absolute numbers	No significant association
Cui et al., 2021	China	Retrospective cohort	III	All metastatic spine tumors	Weakness or Numbness	A: <3 days B: 4-7 days C: >7 days	No significant association
Ohashi et al., 2017	Japan	Retrospective cohort	III	All metastatic spine tumors	Ambulation	A: <3days B: 3-7 days C: 8-30 days D: >30 days	No significant association
Kim et al., 2011	South Korea	Retrospective cohort	III	Small Cell Lung Cancer	Ambulation	A: ≤3 days B: >3 days	Shorter duration of symptoms associated with better ambulation function
Park et al., 2015	South Korea	Prospective Longitudinal observational	II	Non-Small Cell Lung Cancer	Neurologic deficit	A: <72 hours B: >72 hours	Shorter duration of symptoms associated with better ambulatory function
Radiotherapy
Rades et al., 2022	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better ambulatory function
Rades et al., 2019	Germany	Retrospective cohort	III	Small Cell Lung Cancer	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better ambulatory function
Rades et al., 2018	Germany	Retrospective cohort	III	Head and neck	Motor Deficits	A: <7 days B: >7 days	Slower development of symptoms associated with better ambulatory function
Rades et al., 2014	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better ambulatory function
Rades et al., 2002	Germany	Prospective cohort	II	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better ambulatory function
Rades et al., 2001	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better ambulatory function
Rades et al., 2000	Germany	Prospective cohort	II	All metastatic spine tumors	Motor Deficits	A: 1-14 days B: >14 days A: ≤48 hours B: >48 hours	Slower development of symptoms associated with better ambulatory function
Huttenlocher et al., 2014	Germany	Retrospective cohort	III	Melanoma	Motor Deficits	A: <7 days B: >7 days	No significant association

Outcome: Survival

RT

For patients undergoing RT, 18 studies largely demonstrated that longer symptom duration was associated with better survival,^{8,12,16,17,19,20,25,33-43} with most studies dichotomizing duration as 1-7 or >7 days,^{17,35,37,39-41} or trichotomizing as ≤7, 8-14, or >14 days.^{12,20,25,33,34,36} Among sixteen studies included in the meta-analysis (Figure 3), twelve (75.0%) found that longer symptom duration was associated with better survival, while four (25.0%) found no significant association between them. Overall, longer symptom duration was associated with significantly decreased risk of mortality (improved survival) (Pooled effect estimate=0.72, 95%CI: 0.69-0.76, p<0.001), with low heterogeneity (I²=0.00).

Figure 3.

Forest plot for studies evaluating the effect of duration of symptoms on survival for patients undergoing radiotherapy

Surgery

The 6 studies examining the relationship between symptom duration and survival after surgery demonstrated variable results, with marked heterogeneity in the definition of symptom duration (Table 4).^{23,31,32,44-46} Lun et al. found that longer symptom duration (≥5 days) was associated with worse prognosis, ⁴⁶ while Lei et al. found that longer duration (>14 days) was associated with better survival. ⁴⁵ Zhang et al. found no significant association between symptom duration and prognosis when duration was binarized at 3 months or 6 months, after adjustment. ⁴⁴ In contrast, Park et al. found that shorter time to surgery, defined as <72 hours, was associated with better survival. ³² Although longer symptom duration was generally associated with worse survival, this association was not statistically significant (Pooled effect estimate:1.28, 95%CI:0.54–3.03, p=0.575) (Figure 4), with substantial heterogeneity across studies (I²=0.83).

Table 4.

Studies Evaluating the Relationship Between Duration of Symptoms and Survival

Authors	Country	Study design	Level of evidence	Primary tumor	Symptom evaluated	Duration of symptom groups	Relationship between duration and outcome
Surgery
Lun et al., 2019	China	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: ≤5 days B: >5 days	Shorter duration of symptoms associated with better survival
Lei et al., 2015	China	Retrospective cohort	III	Non-Small Cell Lung Cancer	Motor Deficits	A: <14 days B: >14 days	Longer duration of symptoms is associated with better survival
Quraishi et al., 2013	United Kingdom	Retrospective cohort	III	All metastatic spine tumors	Neurological Deficit	A: <24h B: 24-48h C: >48h	No significant association
Kim et al., 2011	South Korea	Retrospective cohort	III	All metastatic spine tumors	Ambulation	A: ≤3 days B: >3 days	No significant association
Zhang et al., 2013	China	Retrospective case series	III	Hepatocellular	Neurologic Deficit and Pain	A: ≤3 months B: >3 months and A: ≤6 months B: >6 months	No significant association
Park et al., 2015	South Korea	Prospective Longitudinal observational	II	Non-Small Cell Lung Cancer	Neurologic Deficit	A: <72 hours B: >72 hours	Shorter duration of symptoms associated with better survival
Radiotherapy
Rades et al., 2022	Germany	Prospective Cohort	II	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	No significant association
Rades et al., 2019	Germany	Retrospective cohort	III	Small Cell Lung Cancer	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	No significant association
Rades et al., 2015	Germany	Retrospective cohort	III	Prostate	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better survival
Rades et al., 2015	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better survival
Rades et al., 2015	Germany	Retrospective cohort	III	Head and Neck	Motor Deficits	A: 1-7 days B: >7 days	No significant association
Rades et al., 2014	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better survival
Rades et al., 2014	Germany	Retrospective cohort	III	Renal	Motor Deficits	A: 1-7 days B: >7 days	No significant association
Rades et al., 2013	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: 1-7 days B: >7 days	Slower development of symptoms associated with better survival
Rades et al., 2012	Germany	Retrospective cohort	III	Colorectal	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better survival
Douglas et al., 2012	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: 1-7 days B: >7 days	Slower development of symptoms associated with better survival
Rades et al., 2012	Germany	Retrospective Cohort	III	Non-Small Cell Lung Cancer	Motor Deficits	A: 1-7 days B: >7 days	Slower development of symptoms associated with better survival
Rades et al., 2012	Germany	Retrospective Cohort	III	Prostate Cancer	Motor Deficits	A: 1-7 days B: >7 days	No significant association
Rades et al., 2012	Germany	Retrospective cohort	III	Non-Small Cell Lung Cancer	Motor Deficits	A: 1-7 days B: >7 days	Slower development of symptoms associated with better survival
Rades et al., 2012	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better survival
Rades et al., 2005	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: 1-14 days B: >14 days	Slower development of symptoms associated with better survival
Rades et al., 2006	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	Slower development of symptoms associated with better survival
Huttenlocher et al., 2014	Germany	Retrospective cohort	III	Melanoma	Motor Deficits	A: <7 days B: >7 days	No significant association
Douglas et al., 2012	Germany	Retrospective cohort	III	Multiple myeloma	Motor Deficits	A: 1-14 days B: >14 days	No significant association

Figure 4.

Forest plot for studies evaluating the effect of duration of symptoms on survival for patients undergoing surgery

Outcome: Local Control

RT

Six-studies assessed the relationship between symptom duration and local control in RT cohorts (Table 5).^{12,16,18,20,25,47} Among these, one defined duration as 1-7 vs. >7 days, ¹⁸ another defined duration of 1-14 days vs. >14 days, ⁴⁷ and remaining studies trichotomized duration into ≤7, 8-14, and >14 days.^12,16,20,25 No study found a significant association between duration of symptoms and local control. Lack of multivariable regression precluded meta-analyses.

Table 5.

Studies Evaluating the Relationship Between Duration of Symptoms and Local Control

Authors	Year	Country	Study design	Level of evidence	Primary tumor	Symptom evaluated	Duration of symptoms- groups	Relationship between duration and outcome
Radiotherapy
Rades et al.	2019	Germany	Retrospective cohort	III	Small Cell Lung Cancer	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	No significant association
Rades et al.	2012	Germany	Retrospective cohort	III	Colorectal	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	No significant association
Douglas et al.	2012	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: 1-7 days B: >7 days	No significant association
Rades et al.	2012	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	No significant association
Rades et al.	2005	Germany	Retrospective cohort	III	All metastatic spine tumors	Motor Deficits	A: 1-14 B: >14 days	No significant association
Rades et al.	2006	Germany	Retrospective cohort	III	Breast	Motor Deficits	A: ≤7 days B: 8-14 days C:>14 days	No significant association

Surgery

No studies assessed the relationship between duration of symptoms and local control in patients undergoing surgery.

Analysis of Covariates

The following covariates were descriptively tabulated across studies to characterize the study populations and explore potential patterns of association with the outcomes of interest (motor function and survival). These data represent pooled descriptive summaries and should not be interpreted as adjusted analyses, given the heterogeneity in outcome definitions, treatment settings, and covariate reporting across studies. The covariates examined were: age, sex, visceral metastases, and vertebral involvement. Across 6,926 patients, 2,919 (42.1%) were in the older age group, which was often defined as above 65-years-old. The overall favorable outcome rate was 55.2%; among older patients it was 53.9%. In the surgery group, 271 older patients (41.7%) had a favorable outcome rate of 27.4% compared with 28.4% overall. For sex, in the RT group, 245 of 356 patients (68.8%) were male, with favorable outcomes in 40.0% versus 36.5% overall. In the surgical group, 2,166 of 3,301 patients (65.6%) were male with favorable outcomes in 31.8% versus 33.0% overall. For visceral metastases, across 6,607 patients, 2,872 (43.4%) had visceral disease; favorable outcome rates were 11.8% in RT and 33.2% in surgery, compared with 55.2% overall. For vertebral involvement, among 6,926 patients, 3,118 (45.0%) had higher vertebral involvement; favorable outcome rates were 55.7% in surgery compared with 55.2% overall, with inconsistent results in RT.

Discussion

The current systematic review and meta-analysis of 37 studies evaluated the relationship between pre-treatment symptom duration and outcomes—motor recovery and survival—in patients with metastatic spinal cord compression undergoing RT or surgery. Symptom duration showed differing associations across treatment modalities. In RT cohorts, longer symptom duration was associated with improved survival and motor outcomes. In the surgical cohort, longer duration showed a trend toward worse survival, though this did not reach statistical significance. Most surgical studies suggested an inverse association between duration and motor recovery. Across both groups, the presence of visceral metastases was consistently associated with poorer results. However, these associations must be interpreted cautiously, as they are likely confounded by treatment selection bias and baseline disease severity differences. Patients treated with RT generally have less severe cord compromise, while surgical cohorts tend to include patients with rapidly progressive or high-grade deficits, making direct comparisons between modalities unreliable. While slower progression may reflect more indolent tumor biology and less severe cord compromise—potentially explaining the favorable associations observed in RT cohorts—this cannot be conclusively determined from the existing literature, as prolonged symptom duration may encompass periods of stability, stepwise decline, or late rapid deterioration. These findings are hypothesis-generating and require further investigation to clarify how both symptom duration and trajectory influence outcomes across treatment settings.

Radiation Therapy

In RT cohorts, longer symptom duration was uniformly associated with better outcomes. The series of studies by Rades and colleagues, consistently shows that longer duration of motor deficits before RT was associated with better therapeutic effect and a more favorable outcomes.^{20,34,36,40,47} Similar findings were observed across multiple cancer histologies.^{20,26,33,37,39,40} When considering the less severe cohort treated with radiation, the finding is not surprising, given that slower, more gradual tumor growth often allows biological adaptations and result in more salvageable neural tissue. ⁴⁸ Experimental models support this concept, showing that acute spinal cord compression causes more severe and irreversible injury, whereas gradual compression preserves large motor neurons and results in less severe histopathologic damage.^48,49 Importantly, these patterns are better explained by the pace of neurologic deterioration and capacity for functional preservation than by simplified distinctions of tumor radiosensitivity. Tumor behavior varies widely within histologies, with some traditionally radiosensitive tumors causing rapid cord compromise and some indolent tumors progressing slowly yet responding poorly to acute RT. As such, outcomes are more reflective of tumor response kinetics and neurologic reserve rather than tumor biology alone.^47,50,51 Inherent selection bias must be acknowledged, as patients with less severe symptoms and lower-grade radiographic cord compression are more likely to be treated with RT alone, likely contributing to the more favorable outcomes observed in RT cohorts compared with surgical series.

Surgery

Across the surgical series, prolonged preoperative symptom duration consistently portended worse postoperative outcomes. Patients undergoing urgent surgery for acute cord compression were likely to experience improved motor recovery and survival, whereas longer symptoms of weakness due to a presumed longer duration of cord compression frequently yielded unfavorable outcomes. Survival has been shown to correlate closely with baseline AIS grade, such that limited neurologic recovery often translates into reduced overall survival. ⁵² The association is strongly favored by the pathophysiology of neurological symptoms in metastatic spine disease. Sustained cord compression leads to demyelination, neuronal and oligodendrocyte apoptosis, microvascular ischemia and blood–spinal barrier disruption, ⁵³ triggering inflammatory cascades and glial scar formation, which hinder axonal regeneration. Even after surgical decompression, irreversible cord injury secondary to the long-standing high-grade compression leads to persistent deficits. ⁵³ Clinical selection factors also warrant consideration. Surgical cohorts likely represent patients with rapidly progressive symptoms, profound motor weakness, with aggressive tumors, who often undergo urgent decompressive surgery to restore spinal stability and prevent further deterioration.^3,54,55 Whereas, RT may be favored in patients with more indolent symptoms, where loss of ambulation may be due to loss of proprioception rather than dense motor loss. Consequently, the surgical cohort likely represents patients with more severe and symptomatic spinal cord compression, further explaining the observed poor outcomes when the time between neurologic deficit and surgery is longer. Additionally, surgical delays may reflect the need for preoperative medical optimization in patients with advanced systemic disease burden or limited physiological reserve, factors that independently worsen prognosis and contribute to reduced survival.^56-58

Clinical Implications

While these findings should not be interpreted as definitive clinical guidance given their observational nature and susceptibility to confounding, they may inform future hypothesis-driven research and clinical reasoning. In RT candidates, a slower course of neurologic decline may be associated with more favorable outcomes—particularly when surgery is not feasible due to comorbidities, tumor characteristics, or patient preference—though this interpretation must remain cautious, as symptom duration alone cannot reliably distinguish slow progression from intermittent or late rapid deterioration. In surgical cohorts, the available data suggest that prolonged preoperative symptom duration may be associated with less favorable neurologic recovery, consistent with the pathophysiologic rationale for timely decompression, although the strength of this evidence is limited. More broadly, these associations highlight that RT and surgical populations are inherently different in baseline severity and disease trajectory; while RT patients generally present with less severe cord compromise, surgical patients often present with severe or rapidly progressive deficits, often in the setting of mechanical instability. Recognizing these inherent selection differences is critical when interpreting modality-specific associations. These observations may warrant consideration in future prospective studies designed to evaluate whether symptom duration can be meaningfully integrated into treatment decision-making.

Limitations

Several limitations warrant consideration. First, the included studies were heterogeneous in definitions of symptom duration, outcomes, and follow-up, complicating pooled analyses. An additional limitation is that the meta-analysis pooled adjusted odds ratios, hazard ratios, and risk ratios as approximate effect measures without formal conversion. Although this approach is commonly used when event rates are low and effect estimates are expected to be similar, it may have influenced the magnitude and interpretation of the pooled effect estimates and should therefore be interpreted with caution. Second, most data were derived from retrospective cohorts, limiting causal inference. Third, all RT studies originated from a single research group, raising concerns about generalizability, potential non-independence of study populations, and the possibility of publication bias, center-specific practices and the same patients being reported in multiple studies. Although we reviewed the published study characteristics, recruitment periods, and participating institutions for evidence of cohort overlap, insufficient reporting prevented definitive assessment. Consequently, potential non-independence between RT cohorts may have resulted in an overestimation of the precision of the pooled effect estimates. Fourth, inherent differences in patient selection between surgical and RT cohorts may account for much of the contrasting associations of symptom duration. Finally, recall bias in reporting symptom onset and unmeasured confounders, such as steroid use or systemic disease burden, could further influence outcomes. A key limitation of the literature is the lack of distinction between symptom duration and rate of neurologic progression. Although this review focused on symptom duration as reported in the included studies, it became apparent that most studies implicitly treated longer duration as equivalent to slower progression and shorter duration as rapid decline. However, these are distinct clinical concepts, and the available literature did not report them separately. Consequently, associations between symptom duration and outcomes—particularly the favorable findings in RT cohorts—should be interpreted cautiously. We hypothesize that the differing associations observed in RT and surgical cohorts may reflect selection bias, with patients experiencing longer, indolent symptom progression preferentially treated with RT and those with rapidly progressive deficits undergoing surgery. Finally, an important limitation of this study is the heterogeneity in the definition of symptom duration across surgical studies, whereas RT studies used a uniform definition. This variability limits the ability to perform meaningful comparative analyses and may affect the interpretation and generalizability of the findings. While unconfirmable with existing data, this represents a plausible explanation for treatment selection and outcomes. Despite these limitations, the modality-specific associations observed, while biologically plausible, should be regarded as hypothesis-generating and interpreted with caution given the limitations outlined above.

Conclusion

This systematic review and meta-analysis identified differing associations between pre-treatment symptom duration and outcomes in MESCC across treatment modalities. In patients receiving radiotherapy, longer symptom duration was associated with better survival and greater motor recovery. In contrast, among those undergoing surgery, longer symptom duration showed a non-significant trend toward worse survival, and most surgical series suggested an inverse association with motor recovery. Across both modalities, visceral metastases were consistently associated with worse outcomes. Importantly, these associations are likely heavily influenced by treatment selection bias and differences in baseline disease severity between RT and surgical cohorts. Accordingly, these findings should be regarded as exploratory and hypothesis-generating rather than practice-defining. Further prospective studies with standardized exposure definitions, formal adjustment for confounders, and clear distinction between symptom duration and rate of neurologic progression are needed to clarify the role of symptom duration in guiding treatment decisions for MESCC.

ORCID iDs

Harsh Jain https://orcid.org/0000-0001-9396-3989

C. Rory Goodwin https://orcid.org/0000-0002-6540-2751

Cordula Netzer https://orcid.org/0000-0001-7381-373X

Laurence D. Rhines https://orcid.org/0000-0002-8474-1521

Scott L. Zuckerman https://orcid.org/0000-0003-2951-2942

Data Availability Statement

All data used in this systematic review are from publicly available published studies. No new data were generated.*