Volume 74, No.10: 2022 Siriraj Medical Journal

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Nitiwut Saenmanot, M.D.*, Monchai Ruangchainikom, M.D.*, anase Ariyawatkul, M.D.*, Ekkapoj Korwutthikulrangsri,

M.D.*, Soraya Saenmanot, Ph.D.**, Panya Luksanapruksa, M.D.*, Werasak Sutipornpalangkul, M.D.*, Sirichai

Wilartratsami, M.D.*, Chatupon Chotigavanichaya, M.D.*

*Department of Orthopedic Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ailand, **Faculty of Public Health,

Mahidol University Amnatcharoen Campus, Amnatcharoen, ailand.

Survival Analysis of and Prognostic Factors for

Metastatic Epidural Spinal Cord Compression

Compared between Preoperative Known and

Unknown Primary Tumors

ABSTRACT

Objective: To analyze the median survival time of and prognostic factors for metastatic epidural spinal cord

compression (MESCC) secondary to preoperative unknown primary tumor (pre-op UPT) compared to MESCC

secondary to preoperative known primary tumor (pre-op KPT).

Materials and Methods: is retrospective cohort study reviewed all consecutive MESCC patients who underwent

surgical decompression with or without stabilization within 72 hours of admission during 2010 to 2016. Survival

was compared between the pre-op UPT and pre-op KPT groups, and preoperative and postoperative prognostic

factors for survival were analyzed.

Results: A total of 169 patients (pre-op UPT: 51, and pre-op KPT: 118) were enrolled. e survival rate at 3, 6, and

12 months was 84.3%, 58.8%, and 47.1% in the pre-op UPT group, and 72.0%, 48.3%, and 34.7% in the pre-op KPT

group, respectively. e median survival time secondary to lung cancer was signicantly longer in the pre-op UPT

group (6.0±1.4 months) than in the pre-op KPT group (3.6±0.2 months) (p=0.031). Multivariate analysis revealed

survival time to be inuenced by preoperative known or unknown primary tumor status, revised Tokuhashi score,

the adjuvant therapy, and postoperative complications, including myocardial infarction, gastrointestinal bleeding,

and urinary tract infection.

Conclusion: MESCC secondary to preoperative unknown primary tumor patients who had the clinical presentation

with acute progressive neurological decits who need urgency spine surgery has comparable survival to MESCC

secondary to preoperative known primary tumors.

Keywords: Metastasis; spinal cord compression; unknown primary tumor; survival time; prognosis; urgency

decompression (Siriraj Med J 2022; 74: 684-692)

Corresponding author: Monchai Ruangchainikom

E-mail: monchai.ortho@gmail.com

Received 30 April 2022 Revised 12 September 2022 Accepted 13 September 2022

ORCID ID:http://orcid.org/0000-0003-0525-6390

http://dx.doi.org/10.33192/Smj.2022.80

All material is licensed under terms of

the Creative Commons Attribution 4.0

International (CC-BY-NC-ND 4.0)

license unless otherwise stated.

INTRODUCTION

Cancer is one of the leading causes of death.

Spinal

metastasis was found in seventy percent of cancer death

undergoing autopsy, and 10% of spinal metastasis patients

developed neurological decits.

2,3

Metastatic epidural spinal cord compression (MESCC)

patients who can realize potential benet from surgical

decompression should be urgently treated to improve

patient functional status, mental status and to prevent

persistent loss of motor and/or sensory function.

4,5

Surgical

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management is usually considered in patients who have

a life expectancy of greater than 3 months.

Survival time prediction has important clinical

implications, including decision-making relative to the

potential benet of surgical treatment or palliative cancer

therapies. ere are many scales/scoring systems for

predicting the prognosis of MESCC patients, especially

Tomita

and revised Tokuhashi

, which are the most

widely accepted scoring systems. ese assessment tools

are useful when standard diagnostic strategy is complete,

to include tumor marker, Tc-99m bone scan, positron

emission tomography (PET) scan, chest-abdomen-pelvis

computed tomography (CT) scan, magnetic resonance

imaging (MRI) of the spine with contrast, and tissue

biopsy. However, these investigations take time that may

delay proper management of spinal metastasis patients

who have acute neurological decit as the rst clinical

presentation. ese patients whose primary tumor was

initially not denitively known were described as MESCC

with preoperative unknown primary tumor (MESCC

with pre-op UPT).

Urgent surgical decompression is quite common

in MESCC patients with pre-op UPT. To the best of

our knowledge, there is no study that has compared

survival time between MESCC with pre-op UPT and

MESCC with the preoperative known primary tumor

(MESCC with pre-op KPT) in this urgent neurological

compromise setting.

us, survival analysis of all consecutive MESCC

with pre-op UPT or pre-op KPT who underwent surgical

decompression was the main objective of this study. e

secondly aim was to identify prognostic factors associated

with median survival time in both groups.

MATERIALS AND METHODS

is retrospective cohort study reviewed all 193

consecutive MESCC patients who underwent surgical

decompression with or without stabilization within 72

hours of admission to Siriraj Hospital during 2010 to

2016. is study was approved by Siriraj Institutional

Review Board (SIRB) of the Faculty of Medicine Siriraj

Hospital, Mahidol University, Bangkok, ailand (Si

013/2016).

To be eligible for inclusion, MESCC patients who

underwent surgical decompression must have had all of

the following components of preoperative management:

1) complete medical history and physical examination; 2)

standard laboratory analysis, including tumor markers;

3) plain radiography of involved bone and chest X-ray;

and, 4) MRI spine with contrast medium, with imaging

of the whole spine the sagittal view. MESCC patients with

incomplete data or who died from a non-cancer-related

cause were excluded.

Patient survival time was investigated by telephone

call and a review of medical records. Preoperative and

postoperative assessment parameters were reviewed and

recorded, as follows: general demographic data, smoking

or nonsmoking, American Spinal Injury Association

(ASIA) impairment scale score, site of pathologic spinal

level, number of spinal metastases, pre-op KPT, pre-

op UPT, nal identied primary tumor site, revised

Tokuhashi score aer complete investigation, adjuvant

therapy, operative time and operative complications.

Statistical analysis

Chi-square test was used to compare categorical

variables (results shown as number and percentage),

and Student’s t-test was used for continuous variables

(results shown as mean plus/minus standard deviation).

Survival analyses were performed by Kaplan-Meier

method, with subsequent group comparison by log-rank

test. Prognostic factors associated with survival time

were identied by Cox proportional hazards model.

A p-value of < 0.05 was considered statistically signicant.

SPSS for Windows version 18.0 was used for all statistical

analyses.

RESULTS

Participants

Of the 193 MESCC patients that were evaluated for

eligibility, 24 were excluded. Of those, 19 were excluded

for having incomplete patient data or because we could

not determine their postoperative status. Another 5

cases were excluded because they died of a non-cancer-

related cause (3 suicides, 1 trauma, and 1 murder). e

remaining 169 MESCC patients were included in our

nal analysis (Fig 1).

Descriptive data

e baseline characteristics of the 169 enrolled

MESCC patients (101 males, 68 females) were evaluated

and compared between the pre-op UPT and pre-op KPT

groups. e mean age of study patients was 54.9±12.8

years. Fiy-one cases (30.2%) with preoperative unknown

primary tumor site were identied. All MESCC patients

presented with incomplete spinal cord lesion, and most

(59.2%) had ASIA impairment scale grade D. Almost

three-quarters (69.2%) of MESCC patients who underwent

urgent spinal decompression presented with more than

one level of spinal metastasis, and the most commonly

aected spinal region was thoracic spine (50.3%). Regarding

the postoperative revised Tokuhashi score aer complete

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686

Fig 1. Flow chart describing the patient enrollment process.

investigation according to the standard diagnostic strategy,

most patients (55.6%) had a score that fell into the 0-8

group.

e distribution of identied primary tumor site

in the pre-op UPT and pre-op KPT groups is shown in

Table 2. e most common identied primary tumor

site was the lung in both groups. From histological study,

eight of nine cases in the cancer of unknown primary

site (CUP) patients were adenocarcinoma, and the other

was undierentiated carcinoma.

Survival aer surgery

e median survival time between groups was not

signicantly dierent, but there was a trend towards longer

survival time in the pre-op UPT group (8.4 months, 95%

CI: 0.8-16.1) than in the pre-op KPT group (5.1 months,

95% CI: 3.5-6.8) (p=0.127). Kaplan-Meier survival method

and log-rank test were used to estimate survival and

compare the results between groups (Fig 2). e survival

rate at 3, 6, and 12 months was 84.3%, 58.8%, and 47.1%

in the pre-op UPT group, and 72.0%, 48.3%, and 34.7%

in the pre-op KPT group, respectively.

Concerning the lung being the most common primary

tumor site in both groups, the median survival time

secondary to lung cancer was 3.6 months (95% CI: 3.2-

4.0) in the pre-op KPT group, and 6.0 months (95% CI:

3.3-8.7) in the pre-op UPT group (p=0.031) (Fig 3).

Prognostic factors associated with survival time

Univariate analysis (Table 3) showed the following

prognostic factors to be signicantly associated with

survival time: American Spinal Injury Association (ASIA)

Impairment Scale at presentation, patient smoking status,

number of levels of spinal involvement, revised Tokuhashi

score aer inclusion of all standard diagnostic data

(especially identication of the type of metastatic tumor

from histologic nding), adjuvant treatment aer surgical

intervention, and postoperative complications, including

cerebral infarction (stroke), myocardial infarction (MI),

gastrointestinal bleeding (GI bleeding), urinary tract

infection (UTI), and pressure ulcer.

Multivariate analysis (Table 4) revealed preoperative

primary tumor of known or unknown status, adjuvant

therapy, revised Tokuhashi score aer collection of all

standard diagnostic data, and the postoperative complications

MI, GI bleeding, and UTI to be independent prognostic

factors associated with survival.

DISCUSSION

Interest in the predicted survival time of MESCC

patients has increased over the last few years because it is

one of the most important factors for guiding decision-

making in MESCC patients relative to whether patients

with neurological decit that require urgent care should

be given palliative care or operative management. In this

study, the prevalence of MESCC patients who presented

with acute progressive neurological decit that indicated

for spinal decompression was common with secondary

to primary unknown tumor. Moreover, we observed a

comparable between median survival time in the pre-op

UPT group and in the pre-op KPT group. Regarding lung

as the primary tumor site, which was the most common

primary tumor site in the pre-op UPT group (37.3%), we

found a signicantly longer median survival time in the

pre-op UPT group than in the pre-op KPT group. is

is an interesting nding, especially since patients with

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TABLE 1. Demographic and clinical characteristics compared between the preoperative unknown primary tumor

site group (Pre-op UPT) and the known primary tumor site group (Pre-op KPT).

Characteristics Pre-op UPT Pre-op KPT

(n=51) (n=118)

P-value

Gender, n (%)

Male 39 (76.5%) 62 (52.5%) 0.003

Female 12 (23.5%) 56 (47.5%)

Age

Mean age (±SD) 54.9±11.5 54.9±13.3 0.986

ASIA impairment scale

B 9 (17.7%) 19 (16.1%) 0.418

C 9 (17.7%) 32 (27.1%)

D 33 (64.7%) 67 (56.8%)

Pathologic spinal level

Cervical spine 7 (13.7%) 14 (11.9%) 0.917

Thoracic spine 27 (52.9%) 58 (49.2%)

T-L junction (T12-L1) 9 (17.7%) 24 (20.3%)

L2-3 or cord level 8 (15.7%) 22 (18.6%)

Revised Tokuhashi score

Score 0-8 28 (54.9%) 66 (55.9%) 0.116

Score 9-11 20 (39.2%) 33 (28.0%)

Score 12-15 3 (5.9%) 19 (16.1%)

Number of levels of spinal metastasis

1 level 19 (37.3%) 33 (28.0%) 0.296

2 levels 15 (29.4%) 31(26.3%)

 ≥3levels 17(33.3%) 54(45.8%)

Adjuvant therapy

None 7 (13.7%) 11 (9.3%) 0.092

Chemotherapy (CMT) 2 (3.9%) 3 (2.5%)

Radiotherapy (RT) 26 (51.0%) 42 (35.6%)

CMT and RT 16 (31.4%) 62 (52.5%)

Abbreviation: ASIA indicated American Spinal Injury Association

the lung as the primary tumor site are given the lowest

score of 0, the poorest prognosis primary tumor origin

category, when using the Tokuhashi scoring system.

MESCC with preoperative unknown primary tumor

with acute progressive neurological decits presents a

major decision-making challenge for a spine surgeon,

and it makes it dicult for the surgeon to oer the patient

accurate information specic to prognosis, survival,

and management. ese unknowns can lead to surgeon

reluctance to perform urgent spinal decompression and

stabilization, but a failure to do so can lead to adverse

outcomes for the patient compared to those who receive

urgent intervention. e general recommendation is to

perform surgery only in patients with a life expectancy

of greater than 3 months, and the common survival

prediction scoring systems are commonly based on

primary tumor, performance status, number of levels

of spine metastasis, neurological status, and presence

of visceral metastases.

6-9

A recent guideline from the

Netherlands Comprehensive Cancer Organization relative

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688

TABLE 2. Distribution of identied primary tumor sites compared between the pre-op UPT and pre-op KPT groups.

Identied primary tumor site Pre-op KPT Pre-op UPT

(n=118) (n=51)

CA Lung 28 (23.7%) 19 (37.3%)

CA Breast 28 (23.7%) 1 (2.0%)

CA Prostate 10 (8.5%) 5 (9.8%)

Hematologic malignancy 10 (8.5%) 9 (17.6%)

CA Nasopharynx 8 (6.8%) 1 (2.0%)

CA Liver 7 (5.9%) 4 (7.8%)

CA Cervix 7 (5.9%) 0 (0.0%)

CA Colon 6 (5.1%) 0 (0.0%)

CA Thyroid 4 (3.4%) 1 (2.0%)

CA Kidney 2 (1.7%) 0 (0.0%)

CA Bladder 1 (0.8%) 0 (0.0%)

Others 7 (5.9%) 2 (3.9%)

Cancer of unknown primary site (CUP) - 9 (17.6%)

Fig 2. Kaplan-Meier survival graphs compared between pre-op

unknown primary tumor site group (Pre-op UPT, green line) and

the pre-op known primary tumor site group (Pre-op KPT, blue line).

Fig 3. Kaplan-Meier survival graphs compared between those with

pre-op unknown primary tumor site with post-op determination of

primary lung cancer (lung CA) (Pre-op UPT, green line) and those

with pre-op primary tumor site known to be the lung (Pre-op KPT,

blue line).

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TABLE 3. Univariate analysis for prognostic factors that predict survival time in MESCC patients who underwent

surgical decompression within 72 hours of hospital admission.

Variables n

Univariate Analysis

HR 95% CI P-value

Preoperative primary tumor

known 118 1.334 0.920 – 1.933 0.129

unknown 51 1

Gender: males/females 101/68 1.088 0.777 – 1.523 0.625

Age

17 – 40 years 26 1.641 0.871 – 3.091 0.125

41 – 50 years 34 1.105 0.595 – 2.054 0.751

51 – 60 years 50 1.206 0.678 – 2.146 0.523

60 – 70 years 39 0.864 0.468 – 1.594 0.640

> 70 years 20 1

ASIA impairment scale

B 28 1.998 1.276 – 3.129 0.002*

C 41 1.108 0.737 – 1.664 0.622

D 100 1

Adjuvant therapy

None 18 2.344 1.345 – 4.086 0.003*

Chemotherapy(CMT) 5 1.186 0.371 – 3.787 0.774

Radiotherapy(RT) 68 1.092 0.763 – 1.563 0.630

Combined CMT and RT 78 1

Smoker (+/-) 43/126 1.471 1.010 – 2.142 0.044*

Pathologic level

Cervical spine 30 1 0.888 – 2.720 0.122

Thoracic spine 21 1.554 0.670 – 2.424 0.460

T-L junction (T12-L1) 85 1.274 0.718 – 2.532 0.353

L2-3 or cord level 33 1.3481

Spinal related symptom period

< 1 week 101 0.992 0.450 – 2.190 0.985

1 – 4 weeks 61 0.812 0.362 – 1.820 0.613

>4 weeks 7 1

Morbidity stage

ASA 1 7 1

ASA 2 85 0.990 0.430 – 2.281 0.982

ASA 3 75 1.233 0.532 – 2.858 0.625

ASA 4 2 2.2461 0.449 – 11.233 0.325

Group Tokuhashi score

Score 0-8 94 5.308 2.909 – 9.686 < 0.001*

Score 9-11 53 1.623 0.862 – 3.053 0.133

Score 12-15 22 1

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TABLE 3. Univariate analysis for prognostic factors that predict survival time in MESCC patients who underwent

surgical decompression within 72 hours of hospital admission. (Continued)

Variables n

Univariate Analysis

HR 95% CI P-value

Number of spinal level involvement

1 level 52 1

2 levels 46 1.652 1.063 – 2.567 0.025*

 ≥3levels 71 1.713 1.141–2.572 0.009*

Group operative time (hours)

< 3 hours 12 1

3 – 4 hours 60 0.758 0.391 – 1.467 0.410

4 – 5 hours 54 1.028 0.531 – 1.992 0.934

5 – 6 hours 26 1.042 0.501 – 2.170 0.912

> 6 hours 17 1.074 0.491 – 2.345 0.859

Post-op complications

Cerebral infarction (+/-) 3/166 3.754 1.172 – 12.028 0.026*

Myocardial infarction (+/-) 11/158 2.307 1.209 – 4.402 0.011*

Pneumonia (+/-) 42/127 2.803 1.925 – 4.081 <0.001*

Gastrointestinal bleeding (+/-) 11/158 3.973 2.108 – 7.489 <0.001*

Urinary tract infection (+/-) 68/101 1.650 1.177 – 2.313 0.004*

Thromboembolism (+/-) 18/151 1.590 0.942 – 2.686 0.083

Pressure ulcer (+/-) 54/115 1.521 1.072 – 2.157 0.019*

Abbreviations: ASIA; indicated American Spinal Injury Association, ASA; American Society of Anesthesiologists grade of physical status

to MESCC secondary to preoperative unknown primary

tumor recommends that, if it is possible, MRI of the

whole spine and PET-CT of the thorax/abdomen should

be performed, and that tissue biopsy should be obtained

within 1 day.

An attempt to complete all recommended

investigations and tissue biopsy would delay the critical

time needed for recovery of injured neural tissue. e

results of our study revealed a survival time of greater

than 3 months in 72.0%-84.3% of MESCC patients.

Yalamanchili, et al. found that rapid progression is

common in patients who present with neurological

decit. ey found that 30% of patients with weakness

could progress to paraplegia within 1 week, and that

the likelihood of regaining neurological function was

very poor when paraplegia was present for more than

24 hours.

Preserving the remaining functional neural

tissue, increasing the chance of neural tissue injury

recovery, and improving ambulatory status all play an

important role in patient survival and quality of life and

mental status.

A meta-analysis of spinal metastasis by

Luksanapruksa, et al. found neurological decits and

ambulatory status to be commonly reported prognostic

factors for survival.

12-15

Cancer of unknown primary site (CUP) was not

uncommon (17.6%) in this study, and the most common

histopathologic nding was adenocarcinoma. is is

similar to previous studies that reported a prevalence

of CUP in patients with MESCC of 13.4%-14.5%, and

the tissue pathology was usually adenocarcinoma.

16,17

CUP is usually associated with more aggressive behavior

and shorter survival time, which are derived from both

biologic condition, such as prior immunoediting and/

or featuring a high degree of immunosuppression, and

lack of a specic guideline for clinical management.

17,18

Our univariate analysis revealed several potential

prognostic factors signicantly associated with survival

time. Subsequent multivariate analysis that included those

factors revealed independent prognostic factors for survival

time. Among those, we found preoperative primary tumor

of known or unknown status to play an important role

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TABLE 4. Multivariate analysis for prognostic factors that predict survival time in MESCC patients who underwent

surgical decompression within 72 hours of hospital admission.

Variables n

Multivariate analysis

HR 95% CI P-value

Pre-op primary tumor

known 118 1.657 1.060 – 2.590 0.027*

unknown 51 1

ASIA impairment scale

B 28 0.992 0.583 – 1.689 0.978

C 41 0.752 0.472 – 1.197 0.229

D 100 1

Adjuvant therapy

None 18 3.359 1.760 – 6.414 <0.001*

Chemotherapy(CMT) 5 2.401 0.691 – 8.346 0.168

Radiotherapy(RT) 68 0.944 0.616 – 1.447 0.792

Combined CMT and RT 78 1

Smoker (+/-) 43/126 1.435 0.930 – 2.214 0.103

Pathologic level

Cervical spine 30 1

Thoracic spine 21 1.855 0.978 – 3.518 0.058

T-L junction (T12-L1) 85 0.892 0.443 – 1.798 0.750

L2-3 or cord level 33 1.987 0.983 – 4.017 0.056

Group Tokuhashi score

Score 0-8 94 6.854 3.351 – 14.016 <0.001*

Score 9-11 53 1.892 0.973 – 3.679 0.060

Score 12-15 22 1

Number of spinal level involvement

1 level 52 1

2 levels 46 1.259 0.731 – 2.169 0.407

 ≥3levels 71 0.937 0.542–1.622 0.817

Post-op complications

Cerebral infarction (+/-) 3/166 1.427 0.354 – 5.752 0.618

Myocardial infarction (+/-) 11/158 3.104 1.450 – 6.648 0.004*

Pneumonia (+/-) 42/127 1.402 0.870 – 2.260 0.165

GI bleeding (+/-) 11/158 3.565 1.702 – 7.465 0.001*

Urinary tract infection (+/-) 68/101 1.519 1.018 – 2.265 0.041*

Thromboembolism (+/-) 18/151 0.960 0.498 – 1.850 0.904

Pressure ulcer (+/-) 54/115 1.262 0.824 – 1.935 0.285

Abbreviation: ASIA indicated American Spinal Injury Association

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in survival time. We also found independent association

between the revised Tokuhashi score and survival. Similar

to other studies

16,17

, adjuvant therapy was identied as

an important prognostic factor for survival; however,

dierences in survival were reported among dierent

adjuvant treatments and dierent types of tumors.

19-21

Lastly, we also found postoperative complications, including

myocardial infarction, gastrointestinal bleeding, and

urinary tract infection, to be independent prognostic

factors to decreased life expectancy. A systematic review

by Bakar, et al. found a high prevalence of various types

of postoperative complications in MESCC patients that

ranged in prevalence from 5% to 42.6%.

Limitations

is study has some mentionable limitations. First,

our study’s retrospective design suggests the potential for

missing or incomplete data. However, we endeavored to

exclude all cases with incomplete data. Second, the small

number of each identied primary tumor type except for

lung cancer means that Kaplan-Meier survival analysis

could only be performed for MESCC secondary to lung

cancer. ird and last, the ndings of this study could

not analyze the decision making for adjuvant treatments

in various types of primary tumor and ununiformed

optimal chemotherapy in the period of this study with

rapid development of chemotherapy.

CONCLUSION

Survival time of MESCC patients who had the

clinical presentation with acute progressive neurological

decits depends on multiple prognostic factors, however;

the preoperative unknown primary tumor origin is not

negative factor for survival in palliative spine surgery.

ACKNOWLEDGEMENTS

We thank the personnel from the Siriraj Hospital

record and research section for their assistance, the

Department of Orthopedic Surgery, Faculty of Medicine

Siriraj Hospital, Mahidol University, Bangkok, ailand

for their support, and Miss Nhathita Panatreswas for

assisting in journal submission process.

Conict of interest: e authors declare that there is

no conict of interest.

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