The role of radiation therapy in the treatment of spine metastases from hepatocellular carcinoma: a systematic review and meta-analysis

*Gianluca FeriniDepartment of Radiation Oncology, REM Radioterapia srl, Viagrande, Catania, Italy;

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Paolo PalmiscianoDepartment of Neurosurgery, University of Cincinnati, Ohio;

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Gianluca ScaliaDepartment of Neurosurgery, Highly Specialized Hospital of National Importance "Garibaldi," Catania, Italy;

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Ali S HaiderTexas A&M University College of Medicine, Houston, Texas;

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Othman Bin-AlamerKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia;

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Navraj S SagooDepartment of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas;

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Ismail BozkurtDepartment of Neurosurgery, Cankiri State Hospital, Cankiri, Turkey;

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Harsh DeoraDepartment of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India;

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Stefano M PriolaDivision of Neurosurgery, Health Sciences North, Northern Ontario School of Medicine, Sudbury, Ontario, Canada;

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Salah G AounDepartment of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, Texas; and

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Giuseppe E UmanaDepartment of Neurosurgery, Trauma Center, Gamma Knife Center, Cannizzaro Hospital, Catania, Italy

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Free access

OBJECTIVE

Spine hepatocellular carcinoma (HCC) metastases severely worsen quality of life and prognosis, with the role of radiotherapy being controversial. The authors systematically reviewed the literature on radiotherapy for spine metastatic HCCs.

METHODS

The PubMed, Scopus, Web of Science, and Cochrane databases were searched according to the PRISMA guidelines to include studies of radiotherapy for spine metastatic HCCs. Outcomes, complications, and local control were analyzed with indirect random-effect meta-analyses.

RESULTS

The authors included 12 studies comprising 713 patients. The median time interval from diagnosis of HCC to spine metastases was 12 months (range 0–105 months). Most lesions were thoracic (35.9%) or lumbar (24.7%). Radiotherapy was delivered with conventional external-beam (67.3%) or stereotactic (31.7%) techniques. The median dose was 30.3 Gy (range 12.5–52 Gy) in a median of 5 fractions (range 1–20 fractions). The median biologically effective dose was 44.8 Gy10 (range 14.4–112.5 Gy10). Actuarial rates of postradiotherapy pain relief and radiological response were 87% (95% CI 84%–90%) and 70% (95% CI 65%–75%), respectively. Radiation-related adverse events and vertebral fractures had actuarial rates of 8% (95% CI 5%–11%) and 16% (95% CI 10%–23%), respectively, with fracture rates significantly higher after stereotactic radiotherapy (p = 0.033). Fifty-eight patients (27.6%) had local recurrences after a median of 6.8 months (range 0.1–59 months), with pooled local control rates of 61.6% at 6 months and 40.8% at 12 months, and there were no significant differences based on radiotherapy type (p = 0.068). The median survival was 6 months (range 0.1–62 months), with pooled rates of 52.5% at 6 months and 23.4% at 12 months.

CONCLUSIONS

Radiotherapy in spine metastatic HCCs shows favorable rates of pain relief, radiological responses, and local control. Rates of postradiotherapy vertebral fractures are higher after high-dose stereotactic radiotherapy.

ABBREVIATIONS

BED = biologically effective dose ; cEBRT = conventional external-beam radiotherapy ; CR = complete response ; GTV = gross-total volume ; HCC = hepatocellular carcinoma ; LC = local control ; OARs = organs at risk ; OS = overall survival ; PD = progressive disease ; PR = partial response ; SD = stable disease ; SRS = stereotactic radiosurgery ; SRT = stereotactic radiotherapy ; VCF = vertebral compression fracture.

OBJECTIVE

Spine hepatocellular carcinoma (HCC) metastases severely worsen quality of life and prognosis, with the role of radiotherapy being controversial. The authors systematically reviewed the literature on radiotherapy for spine metastatic HCCs.

METHODS

The PubMed, Scopus, Web of Science, and Cochrane databases were searched according to the PRISMA guidelines to include studies of radiotherapy for spine metastatic HCCs. Outcomes, complications, and local control were analyzed with indirect random-effect meta-analyses.

RESULTS

The authors included 12 studies comprising 713 patients. The median time interval from diagnosis of HCC to spine metastases was 12 months (range 0–105 months). Most lesions were thoracic (35.9%) or lumbar (24.7%). Radiotherapy was delivered with conventional external-beam (67.3%) or stereotactic (31.7%) techniques. The median dose was 30.3 Gy (range 12.5–52 Gy) in a median of 5 fractions (range 1–20 fractions). The median biologically effective dose was 44.8 Gy10 (range 14.4–112.5 Gy10). Actuarial rates of postradiotherapy pain relief and radiological response were 87% (95% CI 84%–90%) and 70% (95% CI 65%–75%), respectively. Radiation-related adverse events and vertebral fractures had actuarial rates of 8% (95% CI 5%–11%) and 16% (95% CI 10%–23%), respectively, with fracture rates significantly higher after stereotactic radiotherapy (p = 0.033). Fifty-eight patients (27.6%) had local recurrences after a median of 6.8 months (range 0.1–59 months), with pooled local control rates of 61.6% at 6 months and 40.8% at 12 months, and there were no significant differences based on radiotherapy type (p = 0.068). The median survival was 6 months (range 0.1–62 months), with pooled rates of 52.5% at 6 months and 23.4% at 12 months.

CONCLUSIONS

Radiotherapy in spine metastatic HCCs shows favorable rates of pain relief, radiological responses, and local control. Rates of postradiotherapy vertebral fractures are higher after high-dose stereotactic radiotherapy.

Hepatocellular carcinomas (HCCs) represent the third leading cause of cancer death worldwide.1 Advances in management have led to improved survival and increasing diagnoses of metastases.2 Spine metastases have been estimated to occur in 1.5%–7.3% of patients approximately 13 months after primary HCCs.35 Spine metastases pose a major morbidity and mortality burden, often causing severe epidural spinal cord compression.6 Surgery is performed to relieve cord compression and spine instability, with limited benefits in improving survival.7 Some scoring systems and treatment algorithms have been developed to guide clinicians toward conservative versus operative management, incorporating various clinical factors and treatment strategies.810

Radiotherapy is used in uncomplicated painful spine metastases due to its noninvasiveness, even for radioresistant cancers like HCCs.11 The common palliative doses of 20–30 Gy in 5–10 daily fractions may be inadequate to achieve long-lasting therapeutic goals, as evidenced by the need for retreatment in up to 50% of cases.11,12 Although a dose-response relationship has been validated, the intention to deliver higher doses should be weighed against the risks of serious radiation-related complications including myelopathy and vertebral compression fractures (VCFs).13 Stereotactic radiotherapy (SRT) may offer better planning, allowing for an increase in dose per fraction to specific vertebral volumes, with superior biologically effective doses (BEDs) and lower complication risks than homogeneous high doses.1417

Data in the literature on radiotherapy for spine HCC metastases are heterogeneous and are not adequate to define standardized guidelines. In this systematic review, we comprehensively analyzed the literature on radiotherapy for spine metastatic HCC, focusing on available radiation protocols and their impact on functional outcomes and survival.

Methods

Literature Search

A systematic review was conducted according to the PRISMA statement.18 The PubMed, Web of Science, Scopus, and Cochrane databases were searched from inception to November 20, 2021, using the following search query: [(spinal metastasis OR spine OR vertebral OR vertebra) AND (hepatocarcinoma OR hepatoma OR hepatocellular OR HCC OR liver) AND (radiotherapy OR radiation therapy)]. Studies were uploaded to Mendeley, and duplicates were removed.

Study Selection

Inclusion and exclusion criteria were defined a priori. Studies were included if they met the following criteria: 1) involved ≥ 5 patients receiving radiotherapy for vertebral metastases from histologically proven HCCs; 2) presented data on clinical features, radiation protocols, and postradiotherapy outcomes; and 3) were written in English. Studies were excluded if they met these criteria: 1) were reviews, chapters, or editorials; 2) lacked a clear distinction between patients with spine HCC metastases treated with radiotherapy or not; and 3) had insufficient data on radiation protocols and/or outcomes.

Two independent authors (P.P. and G.S.) reviewed titles and abstracts of all collected articles and appraised full texts of studies meeting the inclusion criteria. A third author (G.E.U.) settled any conflicts. Eligible articles were included and references were searched to retrieve additional relevant studies.

Data Extraction

Data were extracted by one author (P.P.) and then independently confirmed by two additional authors (G.F. and G.E.U.). Data included the following: authors, year, sample size, age, sex, HCC clinical features, time interval to diagnosis of spine metastases, clinicoradiological presentation of spine metastases, radiotherapy protocols, postradiotherapy complications, additional treatments, clinical and radiological outcomes, recurrence, local control (LC), overall survival (OS), and survival status. Clinical outcomes, radiological responses, and radiation-induced complications were assessed at 6 months posttreatment or at last available follow-up. Postradiotherapy radiological responses were evaluated using the SPINO (spine response assessment in neuro-oncology) criteria, describing the following: complete response (CR; complete resolution), partial response (PR; decreased volume), stable disease (SD; no volume change), and progressive disease (PD; increased volume).19 The BEDs were collected when available or calculated from raw data using an α/β ratio of 10.20

Data Synthesis and Quality Assessment

Primary outcomes of interest were postradiotherapy outcomes, survival, and adverse events. For each study, two independent authors (P.P. and G.S.) evaluated the level of evidence based on the 2011 Oxford Centre for Evidence-Based Medicine guidelines, and they assessed the risk of bias using the Joanna Briggs Institute checklists for case series.21,22

Statistical Analysis

Stata version 17.0 (StataCorp LLC) was used and bilateral p values < 0.05 were considered significant. Continuous variables are reported as medians and ranges, and categorical variables as frequencies and percentages. Chi-square tests were performed to compare rates of new postradiotherapy VCFs and recurrences based on conventional external-beam radiotherapy (cEBRT) versus SRT. Indirect meta-analyses were conducted for pain improvement, radiological response, radiation-induced complications, radiation-induced VCFs, and LC rates. Pooled proportions of events (effect size) were used to summarize outcomes, and the Wilson score method was used to calculate confidence intervals, both presented with forest plots.23 The Freeman-Tukey transformation was run to include studies with a 0 or 1 event rate and to stabilize variance, and the DerSimonian and Laird approach for random-effect models was used to account for high between-study variability.24,25 Heterogeneity was appraised using the Higgins I2 and was considered significant for I2 > 75%.26 Publication bias was evaluated by detecting any evident visual asymmetry on generated funnel plots.

Results

Study Selection

Figure 1 illustrates the study selection process. Twelve case series were included based on the prespecified criteria, categorized as level IV evidence (Table 1).12,15,16,2735 Quality assessment returned a low risk of bias for all articles (Supplementary Tables 1 and 2). Publication bias was excluded given that no evident visual asymmetry was noted on the generated funnel plots (Supplementary Fig. 1).

FIG. 1.
FIG. 1.

PRISMA 2020 flow diagram.

TABLE 1.

Overview of all included studies

Case No.Authors & YearNo. of Pts/No. of Males (%)Median Age in Yrs (range)No. & Location of Spine Mets (%)No. of Pts w/ Radiation Protocol (%)Median Dose/ No. of Frs (range)No. of Pts (%)Median Mos to Outcome (range)
PrescribedBED*Postradiation ComplicationsPostradiation VCFsPain ResponseRadiological ResponseLCOS
1Chang et al., 200127102/95 (93.1%)59 (12–82)5 cervical (4.9%); 37 thoracic (36.3%); 28 lumbosacral (27.5%); 32 multi (31.4%)102 cEBRT (100%)30 Gy39 GyNANA60 imp (58.8%); 42 NR (41.2%)33 CR (32.3%); 27 PR (26.5%); 42 PD (41.2%)NA3 (1–48)
2Seong et al., 20052838/33 (86.8%)55 (21–80)NA38 cEBRT (100%)30 Gy (12.5–50)39 Gy (15.6–62.5)NANA29 imp (76.3%); 9 NR (23.7%) 11 CR (28.9%); 19 PR (50%); 8 PD (21.1%)NA5 (0.1–36); 15% at 12 mos; 4% at 24 mos
3Nakamura et al., 20071224/23 (95.8%)62 (43–75)4 cervical (16.7%); 15 thoracic (62.5%); 5 lumbar (20.8%)24 cEBRT (100%)34.3 Gy (30–39)44.8 Gy (39–50.7)NANA15 imp (62.5%); 9 NR (37.5%)7 CR (29.2%); 8 PR (33.3%); 9 PD (37.5%)3.5 (0.1–9.5); 53% at 3 mos; 47% at 6 mos5.1 (0.9–36); 38% at 6 mos; 20% at 12 mos; 8% at 24 mos
4aChang et al., 20142927/25 (92.6%)53 (22–73)7 cervical (25.9%); 12 thoracic (44.4%); 11 lumbar (40.7%); 9 sacral (33.3%)27 CK (100%)28.7 Gy/2 fr (1-5)60 Gy (41–90)10 (37%)5 (18.5%)23 imp (85.2%); 4 NR (14.8%)9 CR (33.3%); 12 PR (44.4%); 6 PD (22.2%)7 (2–49)7 (2–49); 30% at 12 mos
4bChang et al., 20142932/25 (78.1%)57 (37–84)NA32 cEBRT (100%)30 Gy (30–39)/10 fr (10–13)39 GyNANANA10 CR (31.3%); 13 PR (40.6%); 9 PD (28.1%)2 (0.3–51)3 (0.3–62)
5Choi & Seong, 201530192/157 (81.8%)56 (20–82)26 cervical (13.5%); 46 thoracic (24%); 48 lumbar (25%); 8 sacral (4.2%); 68 multi (35.4%)107 cEBRT (55.7%); 67 3D-CRT (34.9%); 18 IMRT (9.4%)NA44.2 Gy (14.4–78)NANA187 imp (97.4%); 5 NR (2.6%)NANA4.5 (0.1–42); 18.1% at 12 mos; 6.3% at 24 mos
6Lee et al., 20153123/22 (95.6%)60 (37–89)5 cervical (21.7%); 19 thoracic (82.6%); 9 lumbar (39.1%); 3 sacral (13%)23 SRT (100%)50 Gy (18–50)/10 fr (1–10)75 Gy (55.1–80)8 (34.8%)6 (26.1%)18 imp (78.3%); 5 NR (21.7%)9 CR (39.1%); 7 PR (30.4%); 5 SD (21.7%); 2 PD (8.7%)78.5% at 12 mos9 (2–16); 60.3% at 6 mos; 25.7% at 12 mos
7Rades et al., 2015328/7 (87.5%)74.5 (50–80)NA8 3D-CRT (100%)30 Gy (20–40)/10 fr (5–20)39 Gy (28–48)NANA5 imp (62.5%); 3 NR (37.5%)NANA5 (0.1–14); 25% at 12 mos; 12.5% at 24 mos
8aSohn et al., 20163328/26 (92.9%)59 (31–82)7 cervical (25%); 7 thoracic (25%); 14 lumbar (50%)28 SRS (100%)35.4 Gy (20–52)/4 fr (1–5)58.4 Gy (45–75)9 (32.1%)5 (17.9%)25 imp (89.3%); 3 NR (10.7%%)8 CR (28.6%); 11 PR (39.3%); 9 PD (32.1%)10 (0.3–58); 80% at 3 mos; 59% at 6 mos; 25% at 12 mos8 (0.1–53)
8bSohn et al., 20163328/26 (92.9%)60 (35–80)6 cervical (21.4%); 11 thoracic (39.3%); 11 lumbar (39.3%)28 cEBRT (100%)31.5 Gy (25–45)/10 fr (5–15)33.7 Gy (25–45)10 (35.7%)1 (3.6%)26 imp (92.9%); 2 NR (7.1%)7 CR (25%); 12 PR (42.9%); 9 PD (32.1%)8 (0.2–25); 78% at 3 mos; 64% at 6 mos; 32% at 12 mos9.7 (1–59); 51.9% at 12 mos
9He et al., 201734100/77 (77%)50 (29–79)18 cervical (18%); 45 thoracic (45%); 34 lumbar (34%); 3 sacral (3%)100 SRT (100%)NANANANANANA7 (0.5–59); 31.1% at 12 mos9 (2–16); 60.3% at 6 mos; 25.7% at 12 mos
10Rim et al., 20173563/59 (93.7%)60 (38–82)2 cervical (3.2%); 13 thoracic (20.6%); 6 lumbar (9.5%); 4 sacral (6.3%); 38 multi (60.3%)39 3D-CRT (61.9%); 24 IMRT (38.1%)NA46 Gy (30–60)NANA41 imp (65.1%); 22 NR (34.9%)NANA5 (0.1–28); 42.8% at 6 mos; 19% at 12 mos
11Yoo et al., 20171529/28 (96.6%)55 (35–74)5 cervical (17.2%); 13 thoracic (44.8%); 4 thoracolumbar (13.8%); 10 lumbar (34.5%); 1 lumbosacral (3.4%)29 SRT (100%)18 Gy (16–45)/1 fr (1–3)50.4 Gy (28.8–112.5)2 (6.9%)6 (20.7%)22 imp (75.9%); 7 NR (24.1%)9 CR (31%); 13 PR (44.8%); 7 PD (24.1%)74.5% at 6 mos; 68.3% at 12 mos7 (0.2–38); 38.9% at 12 mos
12McGee et al., 20191619/18 (94.7%)62 (48–75)10 thoracic (52.6%); 9 lumbar (47.4%)19 SRT (100%)18 Gy (14–18)/11 fr (4–11)20.9 Gy (15.8–20.9)NANA17 imp (89.5%); 2 NR (10.5%)7 CR (36.8%); 7 PR (36.8%); 5 PD (26.3%)11 (2.5–57); 71% at 3 mos; 61% at 6 mos; 41% at 12 mos16.8 (2.5–58.3)

CK = CyberKnife; fr = fraction; imp = improvement; IMRT = intensity-modulated radiation therapy; LOE = level of evidence; mets = metastases; multi = multiple; NA = not available; NR = no response; pts = patients; 3D-CRT = 3D conformal radiation therapy.

Level of evidence was IV in all cases.

For calculation of BED, α/β = 10.

Clinical and Radiological Features

Among the 713 patients included, most were male (87.1%) with a median age of 59 years (range 12–89 years) (Table 2). Most primary HCCs had Child-Pugh class A (62.2%), and, among 294 patients with available data, 138 (46.9%) had concurrent systemic metastases not involving the spine: these were visceral in 79 (57.2%) and bone in 59 (42.8%). The median time interval between primary HCC diagnosis and onset of spine metastases was 12 months (range 0–105 months), with 32.9% of cases being synchronous. Axial pain (97.4%), motor deficits (40.4%), and/or radiculopathy (29.5%) comprised the most frequent symptoms. Among patients with available data, spinal cord compression and pathological VCFs were detected in 38.6% (177/458) and 25.3% (79/312) cases. At initial diagnosis, most patients had multiple spine lesions (54.4%), commonly located in the thoracic (35.9%) and lumbar (24.7%) regions.

TABLE 2.

Summary of clinical characteristics of primary tumors and spine metastases

Characteristics (no. of pts w/ available data)Value
Cohort size713
Demographics
 Median age in yrs, range59, 12–89
 Male sex621 (87.1%)
Primary HCC features
 Child-Pugh class (n = 601)
  A374 (62.2%)
  B161 (26.8%)
  C66 (11%)
 Other systemic mets (n = 294)138 (46.9%)
  Bone; non-spine59 (42.8%)
  Visceral79 (57.2%)
Median time from HCC diagnosis to spine mets in mos, range12, 0–105
 Synchronous spine mets (n = 359)118 (32.9%)
Clinical presentation of spine mets
 Pain (n = 302)294 (97.4%)
 Motor deficit (n = 302)122 (40.4%)
 Radiculopathy (n = 302)89 (29.5%)
 Spinal cord compression (n = 458)177 (38.6%)
 Pathological VCFs (n = 312)79 (25.3%)
No. of spine mets per pt (n = 574)
 Single262 (45.6%)
 Multi312 (54.4%)
Location (n = 635)
 Cervical85 (13.4%)
 Thoracic228 (35.9%)
 Lumbar157 (24.7%)
 Sacral27 (4.3%)
 Multi280 (44.1%)

Unless otherwise indicated, values are expressed as the number of patients (%).

Management Strategies

All patients underwent spine radiotherapy, comprising cEBRT (67.3%), including 3D conformal radiotherapy (16%) and intensity-modulated radiotherapy (5.9%), and SRT (31.7%), including CyberKnife (7.7%) (Table 3). Most protocols targeted the gross-total volume (GTV) and the affected vertebral body, involving the adjacent vertebral segments above and below only in 3 studies.28,30,32 In case of lesions abutting to or < 3 mm away from the dura mater, multiple fractionations were planned to reduce single-fraction equivalent doses and limit spinal cord radiation injuries.15,29,33 In patients receiving cEBRT, the median prescribed radiation dose was 30 Gy (range 12.5–50 Gy) delivered with a median of 10 fractions (range 5–15 fractions), and the median BED was 44.2 Gy10 (range 14.4–78 Gy10). In patients receiving SRT, the median prescribed radiation dose was 20 Gy (range 14–52 Gy) delivered with a median of 5 fractions (range 1–20 fractions), and the median BED was 50.4 Gy10 (range 15.8–112.5 Gy10). A total of 148 patients (20.7%) underwent spine surgery, including decompressive laminectomy (19.9%) or vertebroplasty (0.8%), and 179 patients received chemotherapy (25.1%), including sorafenib in 60 (8.4%).

TABLE 3.

Summary of management strategies

Characteristics (no. of pts w/ available data)Value
Radiation therapy type (n = 713)
 cEBRT479 (67.3%)
  3D-CRT114 (16%)
  IMRT42 (5.9%)
 SRT226 (31.7%)
  CK55 (7.7%)
Median no. w/ radiotherapy protocol, range (n = 613)
 cEBRT
  Prescribed dose in Gy30, 12.5–50
  BED in Gy1044.2, 14.4–78
  No. of frs10, 5–15
 SRT
  Prescribed dose in Gy20, 14–52
  BED in Gy1050.4, 15.8–112.5
  No. of frs5, 1–20
Additional treatment (n = 713)
 Surgery148 (20.7%)
  Decompressive142 (19.9%)
  Vertebroplasty6 (0.8%)
 Chemotherapy179 (25.1%)
  Sorafenib60 (8.4%)
  Other agents127 (17.8%)

Unless otherwise indicated, values are expressed as the number of patients (%).

Treatment Outcomes and Complications

The median follow-up was 12 months (range 3–62 months) (Table 4). Postradiotherapy pain relief was noted in 468 patients (80.5%), with actuarial rates of 87% (95% CI 84%–90%) (Fig. 2A). Actuarial rates of radiological responses were 70% (95% CI 65%–75%) (Fig. 2B), comprising CR (31.4%), PR (36.8%), and SD (1.4%). A total of 41 patients (12.5%) experienced radiation-induced complications, with actuarial rates of 8% (95% CI 5%–11%) (Fig. 2C) and mostly including esophagitis/dysphagia (5.2%), nausea (2.4%), and pharyngitis/sore throat (2.1%). Postradiotherapy VCFs were reported in 24 patients (7.3%), with actuarial rates of 16% (95% CI 10%–23%) (Fig. 2D). Rates of postradiotherapy VCFs were significantly higher after SRT (20.6%) than after cEBRT (3.5%) (p = 0.033). Local spine recurrences occurred in 58 patients (27.6%), with actuarial rates of 27% (95% CI 21%–33%) (Fig. 2E). No statistical differences were noted in local recurrences between cEBRT (34.5%) and SRT (23%) (p = 0.068). The median time to LC was 6.8 months (range 0.1–59 months), with pooled rates of 71.2% at 3 months, 61.6% at 6 months, and 40.8% at 12 months. At last follow-up most patients had died (90.8%), with a median OS of 6 months (range 0.1–62 months) and pooled rates of 52.5% at 6 months, 23.4% at 12 months, and 6.3% at 24 months.

TABLE 4.

Summary of treatment outcomes

Characteristics (no. of pts w/ available data)Value
Pain response (n = 581)
 Imp468 (80.5%)
 NR113 (19.5%)
Radiological response (n = 350)
 CR110 (31.4%)
 PR129 (36.8%)
 SD5 (1.4%)
 PD106 (30.3%)
Radiation-induced complications (n = 327)
 New VCFs24 (7.3%)
 Esophagitis/dysphagia17 (5.2%)
 Nausea8 (2.4%)
 Pharyngitis/sore throat7 (2.1%)
 Enteritis/diarrhea5 (1.5%)
 Leukopenia/anemia3 (0.9%)
Local recurrence (n = 210)58 (27.6%)
Outcomes
 Median FU in mos, range (n = 713)12, 3–62
 Median time to LC in mos, range (n = 210)6.8, 0.1–59
  At 3 mos71.2%
  At 6 mos61.6%
  At 12 mos40.8%
 Median OS in mos, range (n = 713)6, 0.1–62
  At 6 mos52.5%
  At 12 mos23.4%
  At 24 mos6.3%
Survival status (n = 513)
 Alive47 (9.2%)
 Dead466 (90.8%)

FU = follow-up.

Unless otherwise indicated, values are expressed as the number of patients (%).

FIG. 2.
FIG. 2.

Forest plots of pain response (A), radiological response (B), radiation-induced complications (C), radiation-induced vertebral fractures (D), and LC (E) following radiation therapy for spine metastases from primary HCC. Squares define the proportions (effect size [ES]) of individual studies and horizontal lines mark the 95% CIs. Diamonds indicate the pooled effect size with 95% CI using the random-effect model meta-analyses.

Discussion

Spine HCC metastases are challenging, severely worsening quality of life and prognosis in affected patients. Decompressive spine surgery is necessary for VCFs and/or spinal cord compression and may offer rapid symptom relief, but patients are often ineligible due to the high risks of perioperative coagulopathy and mortality.7 In patients with uncomplicated spine metastases, poor performance status, or limited life expectancy, radiotherapy represents a therapeutic cornerstone, with positive benefit-risk balances compared to surgery or percutaneous ablation.10,36 Postradiotherapy outcomes vary widely, and postradiation VCFs may occur. Newer SRT protocols and patient-tailored dose planning seem to correlate with improved functional outcomes and LC,16,29,33 similarly to other lesions benefitting from a stereotactic approach.3739 In this review, we found that spine metastatic HCCs show favorable postradiotherapy clinical and radiological responses, with acceptable complication rates.

The advent of new molecules for treating HCC prolonged life expectancy and led to increased rates of spine metastases.40 The rising incidence of spine metastases, occurring in 40% of all patients with stage IV cancer, requires appropriate multidisciplinary strategies for relieving symptoms and improving survival.41 The spine represents the most frequent site of bone HCC metastases, accounting for 60% of all cases.42 Spine metastatic HCCs mostly occur in male patients in their 4th–6th decade of life and preferentially involve thoracic and lumbar regions, as we also found in this review.7 Such preferential localization is deemed to correlate with the HCC-related portal hypertension, which favors the development of collateral vessels through the vertebral venous system, and the shared arteriovenous supply between primary HCCs and the thoracolumbar spine, including the Batson venous plexus.7,43 Similarly to other bone metastases, clinical presentation is characterized by debilitating bone pain related to the spine axis, caused by tumoral release of cytokines and neuropeptides.44 Lesions compressing the nerve roots and spinal cord may result in radiculopathy and myelopathy with motor deficits, further worsening functional status.7 As noted in our cohort, spine metastases are frequently detected within the first 2 years after the primary tumors’ diagnosis and are commonly suspected in patients with a history of HCCs and new spine symptoms. Synchronous metastases may be identified at imaging in patients with normal liver function, absence of gastrointestinal symptoms, and sudden axial pain and/or motor weakness. Given that 32.9% of our pooled patients experienced synchronous HCC spine involvement, we advise clinicians treating patients with chronic liver disease to consider and closely monitor such potential progression. Spine HCC metastases may dramatically worsen functional status by causing rapid osteolytic vertebral changes and serious neurological deficits following spinal cord compression and/or VCFs. The presence of tumor-related spinal cord compression and fractures may also challenge the planning of surgical and/or radiotherapy approaches, and thus should be carefully considered at pretreatment diagnostic assessment.15

The goals of surgery include histology confirmation, spinal cord decompression, and preservation or restoration of spine mechanical stability to favor patients’ mobilization.44 In spine metastatic tumors with neurological function–threatening skeletal-related events, early surgical decompression with or without stabilization is to be preferred over upfront radiotherapy. Surgery may provide prompt clinical responses and rapid ambulatory improvement, highly predicting long-term quality-of-life prognosis.6,42 This is especially true in lesions causing spinal cord compression and/or VCFs, as reported across our included studies.45 Our pooled cohort of patients undergoing surgery mirrored that of patients presenting with motor deficits, radiculopathy, spinal cord compression, or pathological VCFs, all with a major clinical impact. Patients with metastatic HCCs frequently suffer from liver dysfunction and coagulopathy, which are responsible for high postsurgical morbidity and mortality risks following extensive intraoperative blood loss, sepsis, and reoperation for wound dehiscence.6,7 In the present work, the lack of granular data hindered us in determining whether a poor liver function (Child-Pugh classes B and C), multiple spine lesions, and/or concomitant bone and visceral metastases—all suggesting limited life expectancy and poor performance status—may lead to the choice of radiotherapy over surgery in some cases.12,29,33

Radiotherapy, alone or combined with surgery, has proven effective in the palliative treatment of bone metastases, especially those involving the spine, by relieving pain, shrinking tumors, and providing long-term LC.44 Such effects are mediated by radiation directly killing tumor cells and changing the local tumor microenvironment with inhibition of bone resorption.11,46 Palliative cEBRT has been historically used in spine metastatic HCCs, but such a histology is classified as radioresistant due to the low sensitivity to radiation damage.16 This calls for dose escalation in the context of concern regarding the radiation tolerance threshold of neighboring organs at risk (OARs), especially the spinal cord.29 SRT allows practitioners to precisely deliver high radiation doses to GTV while sharply limiting injurious doses to contiguous OARs, thanks to a distinctive dose delivery capable of sparing OARs centered inside the radiotherapy target,47,48 such as the spinal cord surrounded by the metastatic vertebra.49 The current literature advocates fractionated SRT if single-fraction stereotactic radiosurgery (SRS) is unsafe for tumors abutting the spinal cord, in order to deliver a high BED better tolerated by OARs.14,46 The combined use of proton and photon-beam radiotherapy can be convenient, working by exploiting particle therapy’s greater relative biological effectiveness and ability to safeguard OARs.50 The high variability in dose and fractionation schemes in our included articles derives from the lack of definite radiotherapy guidelines in spine metastatic HCCs. Higher BED of stereotactic schedules, coupled with steep dose falloff toward the neighboring OARs, has shown good safety and better efficacy than cEBRT. Target volumes, represented only by GTV and/or vertebra segment containing GTV in SRT and encompassing also adjacent vertebrae above and below in cEBRT, may also differ between SRT and cEBRT, based on the supposed need for simultaneously treating macroscopic lesions and microscopic tumor invasion through marrow spaces.15,16 The impact of metallic spine fixation implants on radiation planning has not been analyzed among our included studies. This aspect should be investigated in the future, given that the efficacy of radiotherapy in patients undergoing spine fixation may be underestimated due to the intrinsic difficulties at follow-up radiological assessments.51,52 The recent introduction of carbon PEEK spine instrumentation has preliminarily been shown to improve radiation planning and radiological follow-up in patients with spine metastases, with potential benefits also for spine HCCs.53,54 The combined use of the advanced radiotherapy techniques and radiolucent implants for spine fixation surgery may greatly improve patient’s care and prognosis.

Postradiotherapy symptom improvement, radiological response, and LC comprise the most important outcomes in patients with spine metastases.44,46 We noted that spine radiotherapy for metastatic HCCs led to favorable rates of pain relief (87%) and radiological tumor response (70%), showing a dose-response relationship similar to spine metastases from other radioresistant tumors such as renal cell carcinomas and sarcomas.16,29,55 Patients treated with a higher BED had superior rates of pain relief and complete tumor response, which were achieved earlier with stereotactic schemes and were optimal in patients with epidural compression not amenable to surgery.15,16,31,32 Chang et al.29 and Sohn et al.33 compared cEBRT and SRT protocols, reporting that SRT correlated with better clinicoradiological responses and LC rates by allowing safer radiation delivery to targeted spine lesions. Our pooled postradiotherapy LC rates were inferior as opposed to other spine metastases, probably due to the related difficulties in planning the high radiation doses necessary for such radioresistant lesions, while not exceeding the tolerance of adjacent OARs.56

Spine HCC metastases may have an accelerated local progression accounting for the detection of much larger lesions than in other histologies. In the SRS study of McGee et al.,16 the median HCC-derived spine GTV was almost twice that of non-HCC metastases (17.96 cm3 vs 9.98 cm3), implying two major issues. First, the worsening dose-volume effect related to larger lesions entails a greater risk of radiation-induced damage to OARs, especially to the spinal cord, so that radiation oncologists may decide to underdose the part of GTV abutting the OARs to preserve their function, but with possible loss of LC. Second, large metastases rarely receive homogeneous oxygen supplies, and thus are capable of developing more radioresistant hypoxic tumor niches.57,58 These could explain our worse pooled rates of post-SRT outcomes in spine HCC metastases as compared to spine metastases from tumors with other histologies. Inappropriate radiation doses have been also held accountable for the poor postradiotherapy ambulatory rates, highlighting the importance of better assessment of clinical prognostic factors predicting posttreatment outcomes in metastatic spine HCCs.12,29 In Rades et al.,32 none of the classic palliative schedules showed superior outcomes, all leading to no improvement of preradiotherapy motor function. Nakamura et al.12 noted that a median BED of 44.8 Gy10 is insufficient to prevent progression of metastases toward paralysis. Seong et al.28 also found that rates of pain relief significantly increased with increasing BED, from 70% for BED ≤ 43 Gy10 to 96% for BED > 43 Gy10 (p = 0.013) Because the survival benefits of spine radiotherapy should be weighed against the risk of radiation-induced complications, most authors recommended higher doses only in patients with higher life expectancy and good prognostic factors, including younger age, favorable baseline performance status, Child-Pugh class A, single metastases, pretreatment ambulatory status, and well-controlled primary HCCs.28,30

The major radiotherapy challenges in radioresistant spine metastases comprise the risks of severe radiation-induced spinal cord injury and VCFs. Although no cases of radiation-induced myelopathy were described in our pooled cohort, we found that actuarial rates of postradiotherapy VCFs were 16%, and were superior in SRT (20.6%) as compared to cEBRT (3.5%) (p = 0.033).15,30,31,33 VCFs mostly occurred as acute or subacute complications, and were probably secondary to radiation-induced inflammatory reaction, microvascular endothelial dysfunction, and bone necrosis within the vertebral body, presenting with new or worsening axial pain and/or neurological deficits.29,33,46,59 Our findings were comparable to those in the general population of radiation-treated spine metastases, with rates of radiation-induced VCFs ranging from 20% to 40% after SRT and from 3% to 10% after cEBRT.59

The occurrence of postradiotherapy VCFs has been correlated with single-fraction higher radiation doses (≥ 20 Gy) and dose escalation schedules in SRT, which induce soft-tissue and osteolytic changes that are responsible for making the affected vertebrae less resistant to the axial compressive stress.15 Surgery and prophylactic stabilization may be offered in selected patients, but the HCC-related risks of perioperative complications should be considered and weighed against the prognosis and expected functional outcomes. Less invasive procedures, such as percutaneous tumor ablation with vertebral augmentation, may minimize the risks of post-SRT VCFs.10 Due to the lack of data in some studies, we could not calculate postradiotherapy rates of new VCFs consequent to tumor recurrence or progression as compared to those directly caused by radiation. A total of 25.3% of our pooled patients presented with pathological VCFs even before receiving radiotherapy.

We cautiously suggest that SRT might be the preferable radiation approach in spine HCC metastases, given that higher doses led to superior LC rates as compared to cEBRT. We also note that the higher rates of post-SRT VCFs may have resulted from an intrinsic selection bias of our included articles, with a somewhat unclear distinction of patients with prior or new VCFs.15 Interestingly, ultrahypofractionated radiotherapy may also produce other abnormal findings at follow-up imaging.60 Additional minor radiation toxicities have been reported in a few patients, including nausea, dysphagia, and sore throat.15,2931,33 Although these may alter patients’ quality of life, they are mostly transient and easily manageable in routine settings. As suggested by Sohn et al.,33 SRT may be preferable also for preventing these minor adverse events, in view of its more conformed dose delivery sculpting the target as compared to cEBRT.

The recent introduction of the tyrosine kinase inhibitors sorafenib and lenvatinib in advanced HCCs has been correlated with significant improvement in survival rates.61 However, only a few studies have reported the use of such agents in the treatment of spine metastatic HCCs, showing controversial and not generalizable results.30,34 In patients with spine HCCs, chemotherapy and targeted therapies may be used in combination with spine surgery and/or radiotherapy to assist the systemic disease control, but future studies are needed to shed some light on their actual role in quality of life and survival improvement.

Limitations

Our review has some limitations. Studies were retrospective case series likely to have been exposed to selection bias and published within an 18-year time period characterized by advances in radiation techniques, which may have introduced some chronological bias. The within-study heterogeneity in radiotherapy types and schedules prevented us from performing comparative meta-analyses between the different radiation protocols, in particular between cEBRT and SRT. Assessments of postradiotherapy clinical and radiological responses were not recorded using objective scales, which is likely to have introduced some confounding variables. Due to the lack of granular data, we could not evaluate the prognostic values of classification scores (e.g., Child-Pugh, Tomita, Frankel); the role of adjacent-level radiation delivery in affecting LC and pain relief; or the postradiotherapy changes in objective scores of ambulatory status and quality of life. Similarly, we could not assess the correlation between BED and VCF rates, and thus we were not able to define safe BED thresholds. Future studies should focus on the BED-VCF relationship for providing better recommendations on BED thresholds and radiation safety.

Conclusions

The rising incidence and complex management of spine metastatic HCCs require better treatments for relieving pain symptoms, improving LC, and reducing complications. In this meta-analysis we found that radiotherapy is safe and effective, showing favorable rates of clinicoradiological responses and LC. Rates of postradiotherapy VCFs are similar to those in spine metastases from other histological tumor types and higher in patients receiving high-dose SRS. In routine settings, radiation planning should weigh benefits against complications based on patients’ functional status. Future studies should analyze the role of newer systemic therapies in the multidisciplinary management of spine metastatic HCCs, especially focusing on their interaction with current radiation schemes.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Umana. Acquisition of data: Palmisciano. Analysis and interpretation of data: Ferini, Palmisciano. Drafting the article: Ferini, Palmisciano. Critically revising the article: Scalia, Haider, Bin-Alamer, Sagoo, Bozkurt, Deora, Priola, Aoun. Approved the final version of the manuscript on behalf of all authors: Umana. Statistical analysis: Palmisciano. Administrative/technical/material support: Scalia, Haider, Bin-Alamer, Sagoo, Bozkurt, Deora, Priola, Aoun. Study supervision: Umana, Ferini.

Supplemental Information

Online-Only Content

Supplemental material is available online.

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  • View in gallery
    FIG. 1.

    PRISMA 2020 flow diagram.

  • View in gallery
    FIG. 2.

    Forest plots of pain response (A), radiological response (B), radiation-induced complications (C), radiation-induced vertebral fractures (D), and LC (E) following radiation therapy for spine metastases from primary HCC. Squares define the proportions (effect size [ES]) of individual studies and horizontal lines mark the 95% CIs. Diamonds indicate the pooled effect size with 95% CI using the random-effect model meta-analyses.

  • 1

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394424.

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