Welcome to SCIRE Professional
 

Surgery in Combination with Radiotherapy

As mentioned previously, the optimal management of individuals with metastatic spine lesions remains an area of active research. Historically, the standard of care for symptomatic lesions consisted of early radiation therapy along with corticosteroids. In many individuals, this strategy reliably improves pain and prevents neurologic decline in the short term. However, some individuals have better overall prognosis while some lesions are resistant to radiotherapy. In these circumstances, surgical interventions are usually performed. Various groups have studied the efficacy of various treatment approaches. Table 9 summarizes some of the existing literature in this area which aims to determine the utility and cost-effectiveness of decompressive surgery along with varying radiotherapy regimens.

Table 10. Surgery in Combination with Radiotherapy for Compression from Metastatic Lesions

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
Patchell et al. (2005)

USA

RCT

PEDro=6

N=101

Population: Injury etiology: Tumour; Median level of severity: Frankel D. All individuals had metastatic epidural spinal cord compression.

Surgery and Radiotherapy (S+RT, n=50): Mean age: 60.0 yr; Gender: males=33, females=17; Level of injury: Cervical=8, T1-T6=20, T7-T12=22; Mean time since injury: 3 mo. Radiotherapy (RT, n=51): Median age: 60.0 yr; Gender: males=37, females=14; Level of injury: Cervical=5, T1-T6=18, T7-T12=28; Mean time since injury: 7 mo.

Intervention: Participants were randomized to S+RT or RT alone. S+RT were operated within 24 hr of admission via spinal cord decompression and tumour stabilization surgery, followed by RT within 14 days. RT was administered within 24 hr at 30 Gy in 10 fractions. All participant received 100 mg of dexamethasone, followed by 24 mg every 6 hr until S+RT/RT. Corticosteroids were reduced after S+RT/RT but continued until study completion. Outcomes were assessed at baseline, during therapy, 1 day post treatment, and every 4wks until end of trial.

Outcome Measures: Frankel Grade, American Spinal Injury Association Motor Score (AMS), Survival rates, Ambulation status, Urinary continence, Medication use.

1.     Ambulation improved in 84% of individuals in S+RT and 57% in RT. This difference was significant between groups (p<0.001).

2.     Individuals in S+RT retained ambulation significantly longer than RT (median 122 versus 13 days, p=0.003).

3.     Longer ambulation time was significantly associated with surgery (p=0.0017) and Frankel Grade at pre-treatment (p=0.0008).

4.     Ambulatory participants at pre-treatment were able to regain walking ability in 94% in S+RT and 74% (p=0.024) of RT alone. Within this subset, surgery (p=0.0048), Frankel Grade (p=0.016) and breast tumour (p=0.029) were associated with longer ambulation times.

5.     Non-ambulatory participants at pre-treatment were able to regain walking ability in 62% of S+RT and 19% of RT (p=0.012). Individuals within this subset walked longer in S+RT compared to RT (median 59 vs 0 days, p=0.04).

6.     S+RT significantly improved continence (p=.016), muscle strength on AMS (p=0.001), functional ability on Frankel (p=0.0006) survival time (p=0.033), and reduced use of corticosteroids and opioid analgesics (p=0.0093) compared to RT alone.

7.     The trial was stopped early by the data safety and monitoring committee due to proven superiority of the S+RT.

Rades et al. (2010)

Germany

Case Series

N=324

 

Population: Surgery and Radiotherapy (S+RT, n=108): Age: ≤63 yr=55, ≥64 yr=53; Gender: males=73, females=35; Injury etiology: Tumor; Level of severity: Eastern Cooperative Oncology Group (ECOG) 1-2=48, 3-4=60. Radiotherapy (RT, n=216): Age:  ≤63 yr=55, ≥64 yr=53; Gender: males=146, females=70; Injury etiology: Tumor; Level of severity: ECOG 1-2=97, 3-4=119.

Intervention: Participants with metastatic spinal cord compression (MSCC) that underwent decompressive surgery followed by RT were retrospectively analyzed. RT was applied a median of 2 wk postoperatively to the midplane or posterior edge of the vertebral body. Some participants also received stabilization of vertebrae (n=70) or a laminectomy (n=38). Each participant was matched to two participants from a cohort treated with RT alone. All participants received 12-32 mg of dexamethasone per day. Outcomes were assessed preoperatively and up to 6 mo after RT.

Outcome Measures: Local control of MSCC, Motor function, Ambulation rate, Survival rate.

1.     Postoperative motor function was associated with ECOG (p<0.001), type of tumor (p<0.001), number of vertebrae involved (p=0.004), presence of visceral metastases during RT (p<0.001), and preoperative ambulatory status (p<0.001).

2.     Ambulation rates post intervention were 69% in S+RT, where 30% of previously non-ambulatory individuals regained ability to walk. Within RT alone, 68% were ambulatory post intervention and 26% regained ability to walk.

3.     Improvement in local control was significantly associated with absence of visceral metastases (p=0.003).

4.     Improved survival rates were significantly associated with females, better ECOG score, one to two vertebral involvement, absence of other bone and visceral metastases, favourable type of tumour, long intervals between diagnosis and compression, preoperative ambulation, slower development of motor deficits, and longer RT administration (all p<0.001).

Kondo et al. (2008)

Japan

Case Series

N=96

Population: Median age: 64.0 yr; Gender: males=61, females=35; Injury etiology: Tumor; Level of injury: C1-L1; Level of severity: Frankel A=1, B=18, C=88.

Intervention: Participants that underwent posterior decompressive surgery followed by intraoperative radiotherapy (IORT) for epidural metastatic spinal tumors were retrospectively reviewed. IORT consisted of a single dose (20-30Gy) of electron beam irradiation to the lesion for 5 min. Total number of surgeries performed was 107. Outcomes were assessed preoperatively, postoperatively, and at a follow-up period ranging from 0.6-107 mo.

Outcome Measures: Pain, Performance status (PS), Frankel Grade.

1.     Pain improved in 46% of cases, and in 60% when drug dose reductions were considered.

2.     PS improved by one rank in 88% of surgeries.

3.     Neurological status improved by one Frankel Grade in 89% of cases.

4.     Postoperatively, 80% of participants were able to walk. At long-term follow-up, abasia returned in 55% of these participants.

5.     Participants with preoperative Frankel C classification had postoperative ambulation rate of 88%. Those that did not regain ambulation had worsening PS postoperatively.

6.     Of those that survived more than 6 mo (n=60) in Frankel C subgroup, 98% were ambulatory by follow-up. This value was significantly higher than those that did not survive (p<0.001).

7.     Postoperative ambulation was significantly associated with preoperative PS and neurological status (p<0.001) and visceral metastasis to vital organs (p=0.0069).

Furlan et al. (2012)

Canada

Cost-Utility Analysis of Patchell et al. (2005)

N=101

Population: Injury etiology: Tumour; Median level of severity: Frankel D. All individuals had metastatic epidural spinal cord compression.

Surgery and Radiotherapy (S+RT, n=50): Mean age: 60.0 yr; Gender: males=33, females=17; Level of injury: Cervical=8, T1-T6=20, T7-T12=22; Mean time since injury: 3 mo. Radiotherapy (RT, n=51): Median age: 60.0 yr; Gender: males=37, females=14; Level of injury: Cervical=5, T1-T6=18, T7-T12=28; Mean time since injury: 7 mo.

Intervention: An analytic decision model was designed to compare cost-utility analyses between S+RT and RT alone for individuals with metastatic spinal cord compression. Costs for both treatment approaches stemmed from physician fees (Ontario Health Insurance Plan) and hospital fees (Ontario Case Costing Initiative). Baseline and sensitivity analyses were performed.

Outcome Measures: Quality-Adjusted Life Year (QALY), Incremental Cost-Effectiveness Ratio (ICER), Cost-Effectiveness Acceptability Curve (CEAC), Willingness to Pay (WTP).

1.     S+RT costed $1,215,514 US per QALY gained whereas RT alone costed $1,017,373 US per QALY.The expected effectiveness for S+RT was 0.57 QALY compared to 0.46 QALY for RT alone.

2.     ICER of S+RT compared to RT alone was $250,307 US, but analyses determined that no therapy was dominant.

3.     From baseline analyses, RT alone was more cost-effective than S+RT at WTP of $50,000 US. From a one-way sensitivity analysis, S+RT became cost-effective at the threshold of $50,000 US when initial costs of S+RT within first 60 days was less than $29,439 US.

4.     Monthly hospice care, from a two-way sensitivity analysis, favoured RT alone. There was a small chance for non-ambulatory individuals with urinary incontinence in S+RT to have higher utility than those in RT alone.

5.     Upon Monte Carlo simulation, probabilistic sensitivity analyses revealed that S+RT was more effective than RT alone: S+RT was more cost-effective in 24.02% of the simulations at WTP of $50,000 US.

6.     CEAC revealed 55.9% of ICERs were under $100,000 US per additional QALY.

7.     Portion of ICERs covered by WTP reached a maximum of 91.1% at $1,604,800 US per one additional QALY.

Table 11. Systematic Reviews Examining Surgery with Radiotherapy for Metastatic Lesions

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
Lee et al.  (2014)

Korea

 

Meta-analysis of published articles between 2005-2013

 

AMSTAR=6

N=5 studies

Methods: A comprehensive literature search was conducted. Inclusion criteria followed: adults with metastatic epidural spinal cord compression (MESCC), compared radiotherapy (RT) to direct decompressive surgical resection paired with RT (DDSR+RT), and reported ambulation status.

Databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews. Key terms included: epidural, metastasis/metastases, surgery, surgical resection, radiation, and radiotherapy (RT).

Levels of evidence: High quality: RCTs. Low quality: observational studies.

Questions/Measures/Hypothesis:

1.     To compare the effects of DDSR+RT to RT alone on ambulation status and survival rates for MESCC.

Outcome measure: ambulation status, survival rate.

1.     A total of 238 participants underwent DDSR+RT therapy and 1137 for RT alone.

2.     In DDSR+RT, the mean age was 63.3 yr and the most common site of tumor was lung (28.6%), prostate (12.4%) and breast (10.9%).

3.     In RT alone, mean age was 66.8 yr and the most common site of tumor was lung (24.4%), prostate (23.2%), and breast (15.4%).

4.     Preoperatively, the rate of participants that could move independently (Frankel Grade D) were 62.2% of DDSR+RT and 74.2% of RT alone.

5.     Postoperatively, the DDSR+RT group improved significantly in ambulation status compared to RT alone (p=0.001), with moderate heterogeneity (I2=57.7%).

6.     Ambulation status deteriorated in RT alone compared to DDSR+RT (p=0.002), with low heterogeneity (I2=7%).

7.     Survival rate was significantly prolonged in DDSR+RT compared to RT alone by 6 mo (n=5 studies, p<0.001, small heterogeneity I2=34.3%) and by 12 mo (n=4 studies, p=0.001, moderate heterogeneity I2=48.3%).

Kim et al. (2012)

USA

 

Systematic review of published articles between 1970-2007

 

AMSTAR=2

N=33

Methods: A literature search of published articles reporting on the use of surgery, radiotherapy (RT), or both for treatment of spine metastasis. Inclusion criteria followed: surgery with stabilization, minimum 25 participants, multiple tumor types, and reported ambulation status.

Databases: MEDLINE with key terms: metastasis, spinal cord compression, surgery, surgical decompression, radiotherapy, and radiation.

Levels of evidence: Not reported.

Questions/Measures/Hypothesis:

1.     To compare effectiveness of RT alone or in combination with surgical decompression and stabilization (S+RT) to improve clinical outcomes from pre to post treatment.

Outcome measures: ambulatory status, pain relief, neurological function, survival rates.

1.     In total, 1249 individuals received S+RT and 1246 received RT. Spinal metastasis occurred most often in thoracic (65%), then lumbosacral (25%) and cervical (10%) spine.

2.     Prostate cancer was most often treated with RT whereas genitourinary sarcoma was more likely to be treated with S+RT.

3.     In non-ambulatory individuals, 64% were able to ambulate following S+RT compared to 29% following RT (p≤0.001).

4.     In paraplegic individuals, 42% regained ambulation following S+RT compared to 10% following RT (p≤0.001).

5.     Deterioration in ambulation status to pre-treatment levels was not common:1% of S+RT and 9% of RT were non-ambulatory post intervention (p=0.003).

6.     In 21 studies, 88% of S+RT compared to 74% of RT were relieved of pain (p≤0.001).

7.     In 20 studies, the 30 day mortality rate for S+RT was 5%; reporting was limited for RT.

8.     Lung cancer, melanoma, or tumor of unknown origin had poor survival rates regardless of treatment (1-8 mo). For all tumor types, the median survival rate was higher for S+RT than RT (17 versus 3 mo).

9.     Regardless of treatment condition, ambulatory participants had 5-6 times greater survival than non-ambulatory participants.

Klimo et al. (2005)

USA

 

Meta-analysis of published articles between 1984-2002

 

AMSTAR=7

N=28 studies

Methods: A literature search of published articles reporting on the use of surgery, radiotherapy (RT), or both for treatment of spine metastasis. Inclusion criteria followed: published in English, retrospective or prospective cohorts, and reported ambulation status.

Databases: MEDLINE with key terms: spine, metastases, radiation, surgery, treatment, cancer, decompression, and vertebrectomy.

Levels of evidence: Moderate quality: Prospective cohort studies with internal controls; Low quality: Uncontrolled retrospective and prospective cohort studies.

Questions/Measures/Hypothesis:

1.     To determine the effectiveness of surgery alone or with RT (S±RT) compared to RT alone on ambulation status.

Outcome measures: Primary outcomes-ambulation status via success rate (maintained/regained) and rescue rate (regained). Secondary outcomes-pain control, sphincter function, survival rates.

1.     In S±RT, 999 individuals were treated, average age was 56.4 yr, 52% were male, and the three primary sites (>50%) of tumors were breast, kidney, and lung.

2.     In RT, 543 individuals were treated, average age was 62.5 yr, 49% were male, and the three primary sites (>70%) of tumors were breast, lung, and prostate.

3.     Thoracic spine (68%) was the most common metastatic location, followed by lumbosacral (21-33%) and cervical spine (6-11%).

4.     Surgical approaches to the spine include: anterior (55%), posterior (39%), and combined (6%). RT was delivered in a dose that ranged from 2800-3200cGy for 7-12 days.

5.     Success rate for ambulation was greater in S±RT than RT alone, with S±RT having 1.3 times greater chance of being ambulatory (p<0.001).

6.     Ambulation rescue rate was superior in S±RT than RT, with a 2 times greater chance of regaining ambulation (p<0.001).

7.     In 21 studies, an improvement in pain was noted in 90% for S±RT and 70% for RT.

8.     Sphincter rescue rate was 66% in S±RT and 26% in RT; however this outcome was only reported in 5 studies.

9.     One yr survival was an average of 41% in S±RT and 24% in RT, with breast and renal cancer having more favorable survival outcomes across all participants.

Discussion

The overall aim of treatments for symptomatic spinal metastases is to relieve symptoms and, where possible, prevent further neurologic deficits. Three separate systematic reviews (Kim et al., 2012; Klimo et al., 2005; Lee et al., 2014) have summarized the evidence and provided support for surgery and radiotherapy over radiotherapy alone. Numerous studies have confirmed that younger individuals, those with better pre-morbid functional status, or individuals with radio-resistant tumors should be offered surgery to decompress and stabilize the spine. For example, Patchell et al. (2005) conducted an randomized controlled trial to study the benefit of early surgery in addition to radiotherapy. The trial was discontinued because of the significant benefits within the surgical group which included longer ambulation and improved survival at 3 and 6 months. A study by Furlan et al. (2012) found comparable cost-effectiveness between either approach.

Conclusion

There is level 1b evidence (from several studies) that radiotherapy and steroids, with or without surgery, improves pain from symptomatic metastatic spine compression. Additionally, for individuals younger than 65 years, the addition of surgical decompression to radiotherapy and steroids improves ambulation and survival.

  • Radiotherapy and surgery for the management of symptomatic metastatic spine compression is effective; early surgical intervention to decompress the spine should be performed after considering tumor features and patient status.