Clinical presentation, management and outcomes of sacral metastases: a multicenter, retrospective cohort study
Original Article

Clinical presentation, management and outcomes of sacral metastases: a multicenter, retrospective cohort study

Raphaële Charest-Morin1, Charles G. Fisher1, Ann L. Versteeg2, Arjun Sahgal3, Peter Pal Varga4, Daniel M. Sciubba5, James M. Schuster6, Michael H. Weber7, Michelle J. Clarke8, Laurence D. Rhines9, Stefano Boriani10, Chetan Bettegowda5, Michael G. Fehlings11, Paul M. Arnold12, Ziya L. Gokaslan13, Nicolas Dea1

1Department of Orthopaedics, Division of Spine, University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada; 2Department of Orthopaedic Surgery, University Medical Center Utrecht, Utrecht, Netherlands; 3Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada; 4National Center for Spinal Disorders and Buda Health Center, Budapest, Hungary; 5Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; 7Department of Orthopaedic Surgery, McGill University, Montreal, Qc, Canada; 8Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA; 9Department of Neurosurgery, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA; 10IRCCS Galeazzi Orthopedic Inst, Milan, Italy; 11Department of Surgery, Division of Neurosurgery and Spinal Program, University of Toronto and Toronto Western Hospital, Toronto, ON, Canada; 12Department of Neurosurgery, University of Kansas Medical Center, Kansas City, KS, USA; 13Department of Neurosurgery, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA

Contributions: (I) Conception and design: N Dea, CG Fisher, AL Versteeg, R Charest-Morin; (II) Administrative support: AL Versteeg; (III) Provision of study materials or patients: A Sahgal, CG Fisher, PP Varga, DM Sciubba, LD Rhines, S Boriani, C Bettegowda, MG Fehlings, PM Arnold, JM Schuster, MH Weber, MJ Clarke, ZL Gokaslan; (IV) Collection and assembly of data: A Sahgal, CG Fisher, PP Varga, DM Sciubba, LD Rhines, S Boriani, C Bettegowda, MG Fehlings, PM Arnold, JM Schuster, MH Weber, MJ Clarke, ZL Gokaslan; (V) Data analysis and interpretation: AL Versteeg, R Charest-Morin; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Raphaële Charest-Morin, MD. Department of Orthopaedics, Division of Spine, University of British Columbia and Vancouver General Hospital, 818 west 10th avenue, Blusson Spinal Cord Centre, 6th floor, Vancouver, British Columbia, V5Z 1M9, Canada. Email: raphaele.charestmorin@vch.ca.

Background: Sacral metastases are rare and literature regarding their management is sparse. This multicenter, prospective, observational study aimed to determine health related-quality of life (HRQOL) and pain in patients treated for sacral metastases with surgery and/or radiation therapy (RT). The secondary objectives were to describe the adverse event (AE) profile and change in neurologic function in this population.

Methods: Twenty-three patients presenting with symptomatic sacral metastases were identified from the Epidemiology, Process and Outcomes of Spine Oncology (EPOSO) dataset, a prospective multicenter study on spinal metastases. Patients requiring surgery and/or RT between August 2013 and February 2017 were prospectively enrolled. HRQOL, assessed by the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQv2.0), the Short Form-36 version 2 (SF-36v2), and the EuroQol-5Dimension (EQ-5D) was documented at baseline, 6 weeks, 3 and 6 months post-treatment. Pain numeric rating scale (NRS), AEs, lower extremities motor score (ASIA), and bowel and bladder function were also recorded.

Results: Eight patients underwent surgery ± RT and 15 patients underwent RT alone. Mean age was 59.3 (SD 11.7) years and 13 patients were female. At 6 months, 3 (37.5%) surgical patients and 2 (13.3%) RT patients were deceased. There was a trend showing that surgical patients had worse baseline HRQOL and pain. Pain NRS, EQ-5D, SOSGOQv2.0, and the mental component of the SF-36v2 showed improvement, irrespective of treatment (P>0.05). Ten AEs occurred in the surgical cohort, dominated by wound complications (n=3). Bowel and bladder function improved at 6 weeks in both groups.

Conclusions: Surgical treatment and RT are both valid treatment options for symptomatic sacral metastases. Improvement in HRQOL can be expected with an acceptable AE rate.

Keywords: Sacral metastases; surgery; radiation therapy (RT); health related-quality-of-life (HRQOL); adverse events (AEs)


Submitted Sep 05, 2018. Accepted for publication Apr 23, 2019.

doi: 10.21037/atm.2019.04.88


Introduction

Symptomatic spinal metastases occur in approximately 10–20% of the cancer population with the minority occurring in the sacrum (1,2). Preservation of neurological and physical function as well as addressing mechanical instability is primary objectives in the treatment of spinal metastases. For sacral metastases, a paucity of literature, unfamiliarity to most surgeons, and a historically high rate of adverse events (AEs) have led surgeons to shy away from operating on this population (3).

With the evolution of better surgical implants, less invasive procedures, intraoperative navigation, better blood salvage options and novel methods of radiation therapy (RT), the spinal surgeon is better equipped to effectively treat these patients. The impact of surgery and/or RT for sacral metastases on health related-quality of life (HRQOL) remains largely unknown. The primary objective of this study is to determine HRQOL and pain for patients with sacral metastases treated with surgery and/or RT. Secondary objectives were to describe the AE profile following RT or surgery and to observe how treatment affects neurologic function (lower extremity motor score, bowel and bladder function) in this population.


Methods

Design

Data were obtained from the Epidemiology, Process and Outcomes of Spine Oncology (EPOSO) [ClinicalTrials.gov (NCT01825161)], a prospective multicenter observational study on Spinal Metastases. This study was developed and funded by the AOSpine Knowledge Forum Tumor (AOSKFT) and by an Orthopedic Research and Education Foundation grant. Patients were recruited across 10 participating centers (North America and Europe) selected for their experience in handling patients with metastatic spine tumors. Patient enrollment began in August 2013 and ended in February 2017. Research ethics board approval was obtained at each center. Patients between 18 and 75 years old, treated for sacral metastases (S1 to S5) with surgery and/or radiotherapy were included. Patients were excluded if the primary site of cancer was the central nervous system or spine.

Demographic data, initial Spine Instability Neoplastic Score (SINS), information regarding the oncologic status and treatment data were collected at baseline.

For this study, patients included had at least 12 weeks follow up data completed with data collected at 6 weeks, 3 months and 6 months. A patient was lost to follow-up if he/she did not come for the scheduled study visit. Prior to declared lost to follow-up, three phone calls with at least 2 days in between each call were executed by the study personnel.

Outcomes measures

The baseline status of all patients was assessed using a variety of HRQOL outcome measures including the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQv2.0), the Short Form-36 version 2 (SF-36v2) and the EuroQol-5Dimension (EQ-5D). SOSGOQv2.0 was developed specifically for the metastatic spine population (4). It encompasses 6 domains: physical function, neural function, pain, mental health, social function and post therapy questions. SOSGOQ scores were calculated according to the revised scoring system of the SOSGOQ2.0. A higher score corresponds with a higher level of functioning for the physical function and social function and a lower level of neurological symptoms, pain and symptoms for the mental health domain. The SF-36v2 and EQ-5D are generic measures of patient health status (5,6).

In addition, AEs were followed prospectively using a predefined list of common AEs. Neurologic examination with the ASIA (American Spinal Injury Association) motor score and bowel and bladder function were recorded at baseline and at follow up. Pain was assessed with the numeric rating scale (NRS) (7).

Statistical analysis

Standard descriptive statistics were used to represent demographic data. Differences in baseline parameters were tested by using Fisher’s exact test for categorical variables and t-test or Wilcoxon rank sum test for continuous variables. A mixed effect model was used to test for differences in patient reported outcome compared to baseline and between both treatments. P values were adjusted due to multiple testing by Tukey-Kramer. AE data was analyzed per patient and per AE time by using AEs which occurred up to 6 months after treatment. Confidence intervals for AE percentage were calculated using the exact binomial method.

All statistical analyses were performed using SAS (version 9.4, SAS Institute Inc., Cary, NC, USA). Significance was defined as P<0.05.


Results

Study population

A total of 40 patients with sacral metastases were screened for inclusion, of which 23 satisfied study inclusion and exclusion criteria (Figure 1). Eight patients underwent surgery ± RT and 15 patients underwent RT alone. At 6 months follow up, 3 (37.5%) surgical patients and 2 (13.3%) RT patients were deceased. Table 1 gives a comparative breakdown of the demographic and tumor characteristics of the population.

Figure 1 Patient eligibility/screening, treatment, and follow-up.
Table 1
Table 1 Cohorts characteristic
Full table

Surgery ± RT

All patients underwent a single posterior procedure. Table 2 summarizes surgical details. Four patients had tumor in S1 extending lower in the sacrum (S2–S5), two had tumor confined to S1 only, and two patients had tumor located from S2–S5. Preoperative embolization was performed in three patients. One patient required a flap for closure. Two patients had postoperative adjuvant therapy and three had surgery after prior history of radiotherapy (more than 2 months before). Adjuvant RT was given at two months postoperatively (one received conventional RT and the other, SBRT). No patients died during the surgical admission.

Table 2
Table 2 Surgical details
Full table

RT

In the RT group, 7 (46.7%) received stereotactic body radiotherapy (SBRT) and 8 (53.3%) conventional radiotherapy. For SBRT, the mean dose was 27.4 (SD 3.2) Gy with a mean number of fraction of 3.3 (range: 2–5). For patients who underwent conventional RT, the mean dose was 17.5 (SD 10.9) Gy with a mean number of fraction of 5 (range: 1–12). No heavy particle radiation was used.

HRQOL

SOSGOQv2.0

The postoperative SOSGOQv2.0 scores were better than the preoperative score at any time points for the surgical cohort. The baseline score for the RT group was higher than the surgical cohort and improved at 6 weeks and 6 months. The results of each domain at every follow up time are presented in Table 3.

Table 3
Table 3 Descriptive SOSGOQv2.0 domains per sacral treatment
Full table

SF-36v2

As expected, the baseline values for the SF-36v2 PCS for both cohorts were lower than the general population. The PCS value for the surgical cohort improved slightly initially and then decreased at longer follow-up. Conversely, the RT group scores decreased at early follow-up and improved thereafter (Table 4). The differences from baseline at different time points and between the 2 cohorts did not reach statistical significance either for the SF-36v2 PCS.

Table 4
Table 4 Mixed effect models derived estimates of the differences in mean scores of efficacy endpoints (Pain NRS, EQ-5D, SF-36v2 and SOSGOQv2.0) by time measurement and treatment group
Full table

Worse SF-36v2 MCS score were observed at baseline for the surgical group (P=0.044). Both groups achieved values close to the normative population at 3 and 6 months with higher improvement in the surgical group (Table 4).

EQ-5D

For the entire cohort, the observed mean pre-treatment EQ-5D score was 0.60 (SD 0.28). It improved post treatment gradually to 0.73 (SD 0.24) at 6 months. The surgical cohort started with worse preoperative scores compared to the RT group (P=0.255) (Table 4).

Pain

Pain at baseline was different between groups. Pain in the surgical cohort was experienced by 7 of the 8 patients and clearly showed a predominance of mechanical pain: 57.1% of the axial pain was mechanical alone, 28.6% was both mechanical and biological. In the RT group, in the 10/15 patients who experienced pain, axial and radicular pain was predominantly biological (70% and 71.4%).

The overall NRS pain improved from the pre-treatment level in the whole population. A worse pain score was observed at baseline in the surgical group but did not reach statistical significance. Both groups improved at 6 weeks and at 6 months although this was not statistically significant (P>0.05) (Table 4). In the surgical group, six patients experienced axial mechanical pain pre-operatively with a median NRS pain score of 7.5 (IQR: 5–8). The median pain improved progressively at 6 weeks, 3 and 6 months. In the RT group, 3 patients had mechanical axial pain which showed improvement over time (Figure 2).

Figure 2 Box plots of descriptive data showing numeric rating scale (NRS) for (A) overall pain, (B) mechanical pain, and (C) biological pain for each treatment over 6 months. The symbol in each box represents the mean while any symbol outside the whiskers represents an outlier (more than 1.5 interquartile from the median value).

Neurologic function

None of the 23 patients had complete loss of bowel and bladder function. Pre-treatment, 2 patients in the surgical group and 1 patient in the RT group experienced partial bowel and bladder loss. Two of these patients recovered normal function at 6 weeks and 1 patient in the surgical group was lost to follow up (Table 5). Using the SOSGOQv2.0 specific question regarding bladder and bowel function, the impact on HRQOL of the deficits appeared to be mild and stable in both cohorts.

Table 5
Table 5 Bowel and bladder function per sacral treatment
Full table

At baseline, the mean lower extremity motor score was 48.4 (range: 29–50) for the overall cohort and was similar at 3-month follow-up (48.7). Interestingly, neurologic deficit tended to be stable over time in the RT cohort. In the surgical cohort, one patient showed neurologic improvement at 6 weeks and the other patient was lost to follow up (Table 6). At baseline, the neurologic function domain of the SOSGOQv2.0 was worse in the surgical group compared to the RT group: mean 71.9 (18.9) vs. 83.7 (19.5). The scores in both groups tended to remain nearly stable over time. The lower extremity motor function domain of the SOSGOG however remained stable at 12 weeks in the RT group and slightly improved in the surgical cohort.

Table 6
Table 6 Neurologic function per sacral treatment
Full table

AEs

A total of 10 AEs occurred in 3 patients of the surgical cohort. Wound infection (n=3) was the most common postoperative AEs. Two patients experienced thromboembolic events and 1 patient presented with a systemic infection. Only one intra-operative AE was reported (massive blood loss) (Table 7).

Table 7
Table 7 Summary of operative adverse events on patient level
Full table

AEs related to chemotherapy and/or RT occurred 10 times in four (66.7%) patients in the surgical cohort and 24 times in 7 (46.7%) patients in the RT cohort (Table 8). An L5–S1 neuritis was observed in one patient following surgery combined with RT. Pain flare was reported in 2 cases following RT.

Table 8
Table 8 Summary of radiation and chemotherapy adverse events
Full table

Discussion

This is the first study to assess HRQOL outcomes, a key outcome measure, in patients with symptomatic sacral metastases. Moreover, this paper represents the largest retrospective study of a prospective cohort of sacral metastases treated with either surgery and/or RT. This analysis demonstrated that these patients improved their pain and their quality of life with treatment. Using a generic (EQ-5D) tool, HRQOL increased maximally at 3 months in the surgical cohort and then declined, likely secondary to progression of systemic disease. On the other hand, early and sustained modest improvement in HRQOL was found when using a disease specific tool (SOSGOQv2.0). Improvement in HRQOL was less dramatic in the radiation cohort but is likely due to a ceiling effect as their baseline HRQOL was substantially better.

Interestingly, looking at surgery in other metastatic spinal locations, the improvement in the EQ-5D compares favourably (8). de Ruiter et al. reported an improvement of 0.15 at 3 months following surgical intervention for tumors predominantly located in the thoracic and lumbar spine, compared to a 0.22 improvement at 3 months in our study (9). Although the minimum clinically important difference (MCID) thresholds for EQ-5D has not been determined in the metastatic spine population, and a definition of MCID thresholds is inconsistent throughout the literature, it has been fixed at 0.1 by Wilson in patients with chronic pain (10). As pain palliation is the main surgical indication in this population, we believe that the improvement in EQ-5D is clinically significant although our results should be interpreted with caution due to low numbers.

The main objective of this study was not to compare different treatment modalities for sacral metastases, but to describe this population and provide a better understanding of treatment outcomes. Nevertheless, interesting findings emerged. Surgical patients consistently had worse baseline pain and HRQOL. The nature of the pain was also different: surgical patients had a predominance of mechanical pain resulting from instability whereas radiation patients suffered from biological pain resulting from tumor invasion. Mechanical pain is related to instability and typically is exacerbated with movement and relieved with recumbency. Biological or tumoral pain is a pain that is constant and not modified by movement. Pain improved significantly in both groups. This could be explained by the instantaneous stability conferred by surgical stabilisation, which was the driving surgical indication observed in our cohort. Although it would be expected that patients with mechanical pain improved with surgery, it was interesting that patients with mechanical pain who underwent RT alone also showed improvement. This limits the generalization that mechanical pain equals surgery, but the samples size is too small to make any conclusions. As neurological compression in sacral metastases may be secondary to tumors extending into the foramen and ventrally to the sacrum, surgery may not provide an appropriate decompression and may thus be futile to restore neurologic function. Nonetheless, surgical decompression remains a valid treatment when progressive neurological deficits are seen secondary to focal spinal canal involvement.

A systematic review on the management of metastatic sacral tumors published in 2012 revealed two prospective case-series that addressed these tumors: Gerszten et al. (11) reported on local control rate for 103 sacral tumors treated with radiosurgery and Akasu et al. (3) described survival and local control for abdominal sacral resection for rectal cancer (12). The other studies included were retrospective or case reports (13-23). More recently, Feiz-Erfan et al. (24) retrospectively reported that patients with sacral metastases showed significant and sustained pain improvement following surgery. Similarly to Feiz-Erfan et al. (24), we showed that surgical treatment is associated with marginal improvement in motor score and preservation of sphincter function. Du et al. (25) were the first to report HRQOL for this population using the QLQ-C30, a cancer specific outcome tool. In their retrospective study of 154 patients, QLQ-C30 improvement at 3 months post-operatively was observed. However, no information regarding loss to follow up and missing data were reported, limiting generalizability. Finally, our surgical related AE rate of 37.5% compares favourably to other contemporary case-series on sacral metastases (24,25).

This study adds to the literature by showing that select patients should be considered for surgery, especially when there is a stability issue or localized neurologic compromise in a radio-resistant tumor. Many tools are available to overcome the inherent difficulties associated with these cases. Multidisciplinary management is paramount. Pre-operative embolization is useful in avoiding transfusions and significant blood loss (26,27). The cell saver is a promising adjunct. Recent evidence supports the use of cell saver in surgery for spinal metastases. The absence of viable tumor cells in the salvaged blood has been demonstrated (28-31). Kumar et al. have shown that tumor cells that passed through the cell saver device, with or without the leucocyte depletion filter, are morphologically altered and have lost the ability to form new metastatic deposits (32). A recent systematic review on the safety and efficacy of lysine analogues in cancer patients did not show an increased risk of venous thromboembolism while being effective in reducing blood loss (33). Percutaneous sacroplasty is increasingly popular with a low rate of complication (34). Alternatively, neuropathic and neoplastic pain can effectively be controlled with neuromodulation options. Finally, good local control can be achieved with SBRT (35). This was observed in our study with only one patient showing progression at 6 months.

Limitations of this study are derived from the type of population studied and the relative rarity of sacral metastases. To overcome the rarity, this study was designed to be multicenter. Still, due to the small sample size, the ability to perform a detailed multivariate analysis was impossible. Furthermore, due to the nature of the population studied, follow up data were difficult to capture, even though a systematic approach was used. Finally, this study was performed in experienced centers, limiting generalization. However, this study is a representative sample of an underreported population. It may stimulate interest within the spinal community and lead to larger studies in the future.


Conclusions

Modern management of sacral metastases encompasses surgery and/or RT. Both alternatives appear to be reasonable therapeutic options. Based on patient symptomatology, more aggressive treatment, including surgery, may be beneficial. This cohort study described improvements in HRQOL and pain following both treatments. Furthermore, an acceptable AE rate and stabilisation of the neurologic deficits can be anticipated with either surgery and/or RT.


Acknowledgments

We are grateful to the collaborating centers local clinical research personnel and support staff for their active participation. This study was organized and funded by AOSpine International, through the AOSpine Knowledge Forum Tumor, a pathology-focused working group of up to ten international spine experts acting on behalf of AOSpine in the domain of scientific expertise. A research grant for this study was received from the Orthopedic Research and Education Foundation (OREF). Study support was provided directly through AOSpine’s Research department and AO’s Clinical Investigation and Documentation unit. This work was supported by the AOSpine Knowledge Forum Tumor (AOSKFT) and by an Orthopedic Research and Education Foundation grant.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: Research ethics board approval was obtained at each center (No. NCT01825161) and written informed consent was obtained from all patients.


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Cite this article as: Charest-Morin R, Fisher CG, Versteeg AL, Sahgal A, Varga PP, Sciubba DM, Schuster JM, Weber MH, Clarke MJ, Rhines LD, Boriani S, Bettegowda C, Fehlings MG, Arnold PM, Gokaslan ZL, Dea N. Clinical presentation, management and outcomes of sacral metastases: a multicenter, retrospective cohort study. Ann Transl Med 2019;7(10):214. doi: 10.21037/atm.2019.04.88