The spine is a frequent site for metastases.1 Metastatic epidural spinal cord compression (MESCC) is a dreaded complication of cancer and has a major detrimental impact on quality of life. First described by Spiller2 in 1925, MESCC is characterized by an extradural mass associated with radiological evidence of compression of the spinal cord or cauda equina, causing clinical features such as: pain, motor, sensory, or sphincter dysfunction.3
Although up to 90% of patients with cancer have spinal metastases at autopsy,4 approximately 2.5% to 10% develop a symptomatic spinal metastasis.4–7 A recent population-based study revealed that 3.4% of American patients with cancer develop MESCC per year.8 The median age at diagnosis is 40 to 65 years and there is an equal sex distribution. Although survival varies widely, the median survival is about 6 months.4,5,7 If left untreated, MESCC usually leads to severe pain and progressive neurological impairment.1,4–7 Consequently, MESCC is considered a condition that requires early diagnosis and expeditious treatment.
Once cancer has become metastatic, it is rarely curable and treatments aim at maintaining function and quality of life, stabilizing the progression of disease, and minimizing complications. Therapeutic modalities in MESCC include various operative (open and minimally invasive procedures, kyphoplasty, and vertebroplasty) and nonoperative (corticosteroids, radiotherapy, and chemotherapy) alternatives. Although laminectomy followed by radiotherapy was once considered the mainstay of treatment,9 it fell into disfavor in the early 1980s when a number of retrospective studies10–12 and 1 small randomized clinical trial (RCT)13 suggested that radiotherapy alone was as effective in relieving pain, and improving ability to walk and sphincter control. Also, Findlay14 reported that 51% of patients with MESCC treated with laminectomy showed evidence of vertebral collapse and more than 75% of patients experienced a major neurological deterioration postoperatively.
With the advances in surgical decompressive and reconstructive techniques, surgery has regained a prominent role in the treatment of patients with MESCC. This shift in treatment approach has been propelled by a landmark RCT in which Patchell et al15 compared de novo circumferential decompressive and reconstructive surgery followed by radiotherapy to radiotherapy alone. The study demonstrated that surgery was associated with a higher rate of ability to walk (84% vs. 57%), promoted greater retention of ability to walk (median, 122 vs. 13 d), and enabled patients with paraplegia to recover the ability to walk more frequently (63% vs. 19%). Narcotics and steroids were also used less in the surgical group. In addition, patients who underwent surgery tended to survive longer (126 d vs. 100 d). Surgery did not increase the hospital stay and 30-day morbidity was worse in the radiotherapy only group. Moreover, recent meta-analyses have concluded that decompressive surgery followed by radiotherapy is associated with improved walking status16,17 and survival17 in comparison with radiotherapy alone in selected patients with MESCC.
With an aging population as well as advances in diagnostic tools and treatment options, the incidence of MESCC is rising.18 MESCC is not only associated with significant physical and psychological consequences on patients and their family/caregivers, but also comes with a heavy socioeconomic burden. Indeed, among patients with cancer in their last year of life, those with MESCC are hospitalized about twice longer.19 Furthermore, MESCC treated with surgery is the most expensive skeletal-related event in patients with cancer, costing nearly $83,000.20
With this background, we performed a systematic review of the literature to compare the cost-effectiveness of surgery with nonoperative management in MESCC. To accomplish this goal, we sought to answer the following key questions in adult patients with MESCC:
- Is there evidence to suggest that surgery combined with pre- or postoperative radiotherapy is cost-effective compared with radiotherapy alone?
- Is there evidence to suggest that surgery combined with chemotherapy and radiotherapy is cost-effective compared with radiotherapy and chemotherapy?
- Is there evidence to suggest that surgical intervention for spinal instability, resulting from spinal metastasis itself or its treatment, is cost-effective compared with nonoperative treatment?
MATERIALS AND METHODS
A detailed description of our methodology is provided in the Supplemental Digital Content, Appendix A available at http://links.lww.com/BRS/A894.
Electronic Literature Search
A systematic search of PubMed, EMBASE, the Cochrane Collaboration database, University of York, Centre for Reviews and Dissemination (NHS-EED and HTA), and the Tufts CEA Registry was performed to identify studies examining the cost-effectiveness of surgery in the management of MESCC compared with nonoperative treatment. We searched the literature through January 18, 2014 and selected articles based on inclusion criteria outlined a priori in the PICO (Population, Intervention, Comparison, Outcome) table (Table 1). Our search included the use of both controlled vocabulary and key words to identify terms specific to MESCC, surgical decompression, radiotherapy, and economic evaluations. The formal search strategy is provided in the Supplemental Digital Content, Appendix B available at http://links.lww.com/BRS/A894. Studies published in any language in peer-reviewed journals that examined, compared, and synthesized the costs and consequences of alternative treatment options were considered for inclusion.
Study Selection and Data Abstraction
One reviewer screened the electronic search results and excluded nonrelevant studies. Then, 2 reviewers screened the remaining titles and abstracts, retrieved the full texts of potentially relevant studies, and independently evaluated the studies against inclusion and exclusion criteria. Discrepancies were discussed and consensus was reached regarding final inclusion of studies. Data on type of economic evaluation, country, currency, model type, analytic perspective, clinical effectiveness data, costs included in the analyses, and results were abstracted into standardized abstraction tables.
The Quality of Health Economic Studies (QHES) instrument developed by Ofman et al21 was used to provide an initial basis for critical appraisal of the methodological quality of included economic studies21 and is described in detail in the Supplemental Digital Content available at http://links.lww.com/BRS/A894. Factors important in critical appraisal of studies from an epidemiological perspective were also considered. Two reviewers independently applied the QHES instrument to included studies. Discrepancies in ratings were discussed, consensus was reached, and a final score was obtained.
Our systematic search identified 38 articles. After excluding irrelevant studies based on title or abstract, 5 studies were retrieved for full text review, three22–24 of which did not meet inclusion criteria for our target population, study design, or intervention/comparison, respectively. Two articles25,26 met the inclusion criteria. An overview of the included studies, results, and limitations are provided in Tables 2 and 3, and summarized below. QHES scores are provided in the Supplemental Digital Content, Appendix C available at http://links.lww.com/BRS/A894; and detailed study characteristics and results are provided in the data abstraction tables in the Supplemental Digital Content, Appendix D available at http://links.lww.com/BRS/A894.
One included study25 was a cost-utility analysis (CUA) whereas the other26 was a cost-effectiveness analysis (CEA). Both studies scored highly on the QHES instrument, with scores of 88 and 86 points, respectively. Both studies took place in Canada, but employed different analytic perspectives (publicly funded health care system25 and societal26), and used different currencies (2010 US dollar ($)25 and 2003 Canadian dollar (Can$).26) Both analyses used clinical data from the same RCT: Patchell et al.15
One study from the senior author's group25 used a decision tree and Markov model, and included placement (home or institution), ability to walk, continence, and survival as outcome measures in their model. The other study26 used a Weibull model and used the outcome of ability to walk for the baseline measure of effectiveness and survival time until death for the sensitivity analysis. This study26 reported that outcomes were measured every 4 weeks until death while the other one25 did not report the time frame of effectiveness outcomes included. Both studies conducted 1-way and 2-way sensitivity analyses to test the robustness of their models, and also used Monte Carlo simulations to perform probabilistic sensitivity analyses.
Both studies found that surgery plus radiotherapy was not only more expensive but also more effective than radiotherapy alone (Table 3). For the surgery plus radiotherapy group, the cost-utility study25 reported an incremental cost-effectiveness ratio (ICER) of $250,307 per quality-adjusted life year (QALY) gained ($685 per quality-adjusted life day gained), and the cost-effectiveness study26 reported ICERs of Can$60 per additional day of walking, and Can$30,940 per life year gained.
Both studies reported that the ICER fell into the dominant (southeastern) quadrant in 18% of the Monte Carlo simulations (18.11% in one study25 and 18.0% in the other study26), representing the probability that surgery plus radiotherapy would be more effective and less costly than radiotherapy alone. The study by Furlan et al25 also reported that the ICER fell into the dominated (northwestern) quadrant in 30.15% of the simulations, representing the probability that the surgery plus radiotherapy treatment would be less effective and more costly. This same study25 also found that surgery plus radiotherapy was more cost-effective in 24% of simulations at a willingness to pay of $50,000, and that there was a 91.11% probability of surgery plus radiotherapy being cost-effective over radiotherapy only at a willingness-to-pay of $1,683,000 per QALY gained. The other study from the Vancouver team26 found that 50% of all generated ICERs were lower than Can$57 and 95% were lower than Can$242 per additional day of walking (95% CI, −$72.74–$309.44), meaning that this intervention was in the range from a financial savings of about Can$73 to a cost of Can$310 per additional day of walking. In other words, when surgery plus radiotherapy was not cost saving, 95% of the time an additional day of walking cost less than Can$242 (Table 3).
Despite their highly sensitive nature, health budget constraints are an undeniable reality and represent a major limitation to achieving advances in health outcomes in all societies. Therefore, cost-effective health care interventions are the cornerstones to maximizing societal health. To optimally allocate scarce resources, it is essential to define the cost per unit of enhanced health.
Only 2 articles addressed our first key question regarding the potential additive value of surgery to radiotherapy alone in the management of MESCC. Our search did not yield any study related to our other 2 key questions: cost-effectiveness of (1) adding surgery to a regimen of chemotherapy and radiation or (2) spinal instrumentation to patients with MESCC and actual or relative oncological spinal instability. Given that chemotherapy is often added as a third line treatment after surgery and radiation is administered, it is reasonable to infer that surgery would continue to add value to the management of a patient with MESCC even when chemotherapy is instituted. However, the paucity of data comparing the effectiveness of surgery versus nonoperative management in patients with MESCC with spinal instability is reflected in the lack of cost-effectiveness studies with regard to the role of surgical intervention in the setting of oncological spinal instability; this is a key knowledge gap that represents an opportunity for future research.
By achieving pain relief as well as maintaining or improving neurological functions, both decompressive spinal surgery followed by radiotherapy and radiotherapy alone have shown effectiveness.27,28 Consequently, from the health care system or societal perspectives, the rationale for proceeding with economic evaluations is well justified.
Furlan et al25 and Thomas et al26 attempted to answer a technical efficiency question: which alternative provides the best clinical outcome and at what cost, where CEA26 and CUA25 are appropriate economic methodologies. CEA examines the differences between the 2 alternatives in terms of costs and effectiveness, and measures (in natural units) their primary goal(s). CEA is useful in this setting because the 2 therapeutic modalities are compared within a single targeted population. However, it is difficult to compare results of various cost-effectiveness analyses when the effectiveness measures are different. Such comparison is possible with CUA because the value of health outcomes is made by using utilities (e.g., QALY), which are more generic outcomes and measured from patients directly. CUA is the preferred full economic evaluation when (1) an intervention has multiple objectives, (2) quality of life and/or quantity of life are considered important outcomes.29 Quality of life is indisputably an aspect of outermost significance in MESCC. However, given the lack of published data on utilities for each subgroup of their study decision tree, Furlan et al25 had to assume that the utilities of all health states were independent of each other to be able to derive an estimate of the combined utilities for each of the branch of their analytic decision model. This is a limitation to the analysis of their primary outcome measure (incremental cost per QALY) because it is highly improbable that these utilities are independent of each other and patients with MESCC most likely adjust to their global condition.
Both studies stated their perspective: societal26 and publicly funded health care system.25 The perspective adopted by the economic analysis is an important element because it determines which costs and benefits are collected; as a general rule CEA and CUA necessitate only health care costs collection.30 Both perspectives are consistent with the research question and objective. Although the societal perspective is preferred because it uses a wider range of cost information sources allowing a more accurate grasp at the general cost, Thomas et al26 did not clearly report considering indirect costs, such as productivity losses.
Although using clinical data from a single RCT limits the generalizability of the results of these analyses, the study by Patchell et al15 is the only available study that compared the clinical outcomes of surgery combined with radiotherapy to radiotherapy alone, and it has robust internal validity.31 Unfortunately, Patchell et al15 did not prospectively collect the overall direct and indirect costs. Thus, both studies retrospectively estimated costs from available information. Consequently, care received at outside institutions, such as emergency department or primary care physician visits, was potentially missed.
Quality of life outcome suits the MESCC population better than walking and survival outcomes. In their CUA, Furlan et al25 reported that treatment involving surgery would cost an additional $250,307 per QALY gained. In both analyses, Monte Carlo simulations for the surgical option provided approximately 18% chance to provide 1 QALY gain at no extra cost, but in 1 study,25 they also had about 30% probability to be less effective and more costly.
Given that both studies obtained a total QHES score higher than 75, these full economic evaluations are viewed as being of high quality.32,33 Thus, the evidence suggests that surgery followed by radiotherapy is more effective but more costly than radiotherapy alone. An acceptable threshold of $100,000 per QALY is often reported in the literature.34 From this rather narrow perspective, surgery followed by radiotherapy would not be considered a cost-effective treatment. However, this cut-off value is not based on any strong evidence, originates from the 1980s, and inflation was not taken into account.34 Moreover, this threshold arguably is better applied for benign chronic conditions as opposed to disorders such as cancer that cause significant suffering but limit lifespan.
One should be cautious when interpreting economic evaluations in the MESCC population. The paucity of published data and the relatively small sample size are major limiting factors in drawing any kind of definitive conclusion. In addition, evaluating if a treatment provides “good value for the money” (CEA) or measuring benefits in terms of QALYs raises particular issues in palliative populations. Minor quality of life gains might have a significant positive impact, which would not translate in increasing QALYs. Consequently, economic evaluations in such populations should consider using the “Quality of life left” as the key measure to assess value.
Patients with MESCC form a heterogeneous population for which there is not yet any generally accepted predictive tool, limiting the accuracy of any economic analysis. To gain confidence in the validity of economic analysis in this population, further study is required to identify key predictive factors and integrate them to validated scoring systems, such as spinal instability neoplastic score,35 to better stratify patients to assist patient-oriented management.
The treatment options for patients with MESCC are diversifying rapidly. Therefore, more research is needed to adequately compare cost-effectiveness across different therapeutic modalities used to treat these patients, including vertebroplasty, kyphoplasty, minimally invasive versus open decompressive and/or reconstructive surgery, and stereotaxic radiosurgery. Prospective, multicenter comparative effectiveness studies should be conducted to evaluate the impact of these alternatives with regard to functional outcomes, quality of life, survival, and direct and indirect costs, which should be collected prospectively in a granular manner. We also recommend the creation of a prospective international registry of MESCC cases to facilitate further economic evaluations, focusing specifically on spinal stabilization for oncological spinal instability. Of note, this effort has now been instituted by AOSpine International through the Spine Oncology Knowledge Forum.36
- Evidence suggests that decompressive spinal surgery followed by radiotherapy is not only more effective, but also more costly than radiotherapy alone in the management of MESCC.
- We advise caution in interpreting economic evaluation in MESCC given the paucity of published data, relatively small sample size studied, and the heterogeneity of this population.
- We recommend identifying key prognostic factors to stratify patients with MESCC and then proceeding with prospective studies to evaluate the impact of various therapeutic modalities.
- We recommend the creation of a prospective international registry of MESCC cases.
- The lack of cost-effectiveness data for the role of spinal stabilization in the management of oncological spinal instability is a major knowledge gap and constitutes an opportunity for future research.
The authors thank Ned Sherry, BS, for assistance with literature searching, data abstraction, and critical appraisal of included studies.
Supplemental digital content is available for this article. Direct URL citations appearing in the printed text are provided in the HTML and PDF version of this article on the journal's web site (www.spinejournal.com).
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