High-dose hypofractionated stereotactic body radiotherapy for spinal chordoma

View More View Less
  • 1 Departments of Radiation Oncology and Molecular Radiation Sciences,
  • | 2 Neurosurgery,
  • | 3 Radiology and Radiological Science, and
  • | 4 Pathology, Johns Hopkins University School of Medicine; and
  • | 5 Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
Free access

OBJECTIVE

Spinal chordoma is locally aggressive and has a high rate of recurrence, even after en bloc resection. Conventionally fractionated adjuvant radiation leads to suboptimal tumor control, and data regarding hypofractionated regimens are limited. The authors hypothesized that neoadjuvant stereotactic body radiotherapy (SBRT) may overcome its intrinsic radioresistance, improve surgical margins, and allow preservation of critical structures during surgery. The purpose of this study is to review the feasibility and early outcomes of high-dose hypofractionated SBRT, with a focus on neoadjuvant SBRT.

METHODS

Electronic medical records of patients with spinal chordoma treated using image-guided SBRT between 2009 and 2019 at a single institution were retrospectively reviewed.

RESULTS

Twenty-eight patients with 30 discrete lesions (24 in the mobile spine) were included. The median follow-up duration was 20.8 months (range 2.3–126.3 months). The median SBRT dose was 40 Gy (range 15–50 Gy) in 5 fractions (range 1–5 fractions). Seventeen patients (74% of those with newly diagnosed lesions) received neoadjuvant SBRT, of whom 15 (88%) underwent planned en bloc resection, all with negative margins. Two patients (12%) developed surgical wound-related complications after neoadjuvant SBRT and surgery, and 4 (two grade 3 and two grade 2) experienced postoperative complications unrelated to the surgical site. Of the remaining patients with newly diagnosed lesions, 5 received adjuvant SBRT for positive or close surgical margins, and 1 received SBRT alone. Seven recurrent lesions were treated with SBRT alone, including 2 after failure of prior conventional radiation. The 2-year overall survival rate was 92% (95% confidence interval [CI] 71%–98%). Patients with newly diagnosed chordoma had longer median survival (not reached) than those with recurrent lesions (27.7 months, p = 0.006). The 2-year local control rate was 96% (95% CI 74%–99%). Among patients with radiotherapy-naïve lesions, no local recurrence was observed with a biologically effective dose ≥ 140 Gy, maximum dose of the planning target volume (PTV) ≥ 47 Gy, mean dose of the PTV ≥ 39 Gy, or minimum dose to 80% of the PTV ≥ 36 Gy (5-fraction equivalent doses). All acute toxicities from SBRT were grade 1–2, and no myelopathy was observed.

CONCLUSIONS

Neoadjuvant high-dose, hypofractionated SBRT for spinal chordoma is safe and does not increase surgical morbidities. Early outcomes at 2 years are promising, although long-term follow-up is pending.

ABBREVIATIONS

BED2 = biologically effective dose; cEBRT = conventionally fractionated external beam radiotherapy; CI = confidence interval; CTCAE = Common Terminology Criteria for Adverse Events; CTV = clinical target volume; D80 = minimum dose to 80% of the PTV; D95 = minimum dose to 95% of the PTV; Dmax = maximum dose of the PTV; Dmean = mean dose of the PTV; Dmin = minimum dose of the PTV; EBL = estimated blood loss; GTR = gross-total resection; GTV = gross tumor volume; ICI = immune checkpoint inhibitor; IDL = isodose line; KPS = Karnofsky Performance Scale; LR = local recurrence; OAR = organs at risk; OS = overall survival; PRV = planning risk volume; PTV = planning target volume; RT = radiotherapy; SBRT = stereotactic body radiotherapy; VATS = video-assisted thoracoscopic surgery.

OBJECTIVE

Spinal chordoma is locally aggressive and has a high rate of recurrence, even after en bloc resection. Conventionally fractionated adjuvant radiation leads to suboptimal tumor control, and data regarding hypofractionated regimens are limited. The authors hypothesized that neoadjuvant stereotactic body radiotherapy (SBRT) may overcome its intrinsic radioresistance, improve surgical margins, and allow preservation of critical structures during surgery. The purpose of this study is to review the feasibility and early outcomes of high-dose hypofractionated SBRT, with a focus on neoadjuvant SBRT.

METHODS

Electronic medical records of patients with spinal chordoma treated using image-guided SBRT between 2009 and 2019 at a single institution were retrospectively reviewed.

RESULTS

Twenty-eight patients with 30 discrete lesions (24 in the mobile spine) were included. The median follow-up duration was 20.8 months (range 2.3–126.3 months). The median SBRT dose was 40 Gy (range 15–50 Gy) in 5 fractions (range 1–5 fractions). Seventeen patients (74% of those with newly diagnosed lesions) received neoadjuvant SBRT, of whom 15 (88%) underwent planned en bloc resection, all with negative margins. Two patients (12%) developed surgical wound-related complications after neoadjuvant SBRT and surgery, and 4 (two grade 3 and two grade 2) experienced postoperative complications unrelated to the surgical site. Of the remaining patients with newly diagnosed lesions, 5 received adjuvant SBRT for positive or close surgical margins, and 1 received SBRT alone. Seven recurrent lesions were treated with SBRT alone, including 2 after failure of prior conventional radiation. The 2-year overall survival rate was 92% (95% confidence interval [CI] 71%–98%). Patients with newly diagnosed chordoma had longer median survival (not reached) than those with recurrent lesions (27.7 months, p = 0.006). The 2-year local control rate was 96% (95% CI 74%–99%). Among patients with radiotherapy-naïve lesions, no local recurrence was observed with a biologically effective dose ≥ 140 Gy, maximum dose of the planning target volume (PTV) ≥ 47 Gy, mean dose of the PTV ≥ 39 Gy, or minimum dose to 80% of the PTV ≥ 36 Gy (5-fraction equivalent doses). All acute toxicities from SBRT were grade 1–2, and no myelopathy was observed.

CONCLUSIONS

Neoadjuvant high-dose, hypofractionated SBRT for spinal chordoma is safe and does not increase surgical morbidities. Early outcomes at 2 years are promising, although long-term follow-up is pending.

ABBREVIATIONS

BED2 = biologically effective dose; cEBRT = conventionally fractionated external beam radiotherapy; CI = confidence interval; CTCAE = Common Terminology Criteria for Adverse Events; CTV = clinical target volume; D80 = minimum dose to 80% of the PTV; D95 = minimum dose to 95% of the PTV; Dmax = maximum dose of the PTV; Dmean = mean dose of the PTV; Dmin = minimum dose of the PTV; EBL = estimated blood loss; GTR = gross-total resection; GTV = gross tumor volume; ICI = immune checkpoint inhibitor; IDL = isodose line; KPS = Karnofsky Performance Scale; LR = local recurrence; OAR = organs at risk; OS = overall survival; PRV = planning risk volume; PTV = planning target volume; RT = radiotherapy; SBRT = stereotactic body radiotherapy; VATS = video-assisted thoracoscopic surgery.

In Brief

The objective of this study was to review the safety and early efficacy of hypofractionated dose-escalated stereotactic body radiotherapy (SBRT) for spinal chordoma. The authors found that SBRT to the dose of 40–50 Gy in 5 fractions could be safely delivered and had a local control rate of 96% at 2 years for spinal chordoma. Neoadjuvant SBRT was not associated with increased risk of postoperative wound complications. This study highlights the promising role of SBRT and can broaden treatment options for patients with spinal chordoma.

Chordoma of the spine is a rare locally aggressive cancer, and the cornerstone of its treatment is en bloc resection with wide margins.1,2 However, wide excision is often difficult to achieve, and may cause significant morbidities due to involvement of important neurovascular structures.3,4 Five-year local recurrence is approximately 25% even with wide surgical margins, and may be as high as 70% after intralesional resection.5,6 One study demonstrated significantly lower recurrence with wide or marginal resections (14% vs 46%) rather than intralesional excisions, highlighting the importance of an appropriate surgical approach.7 Adjuvant radiotherapy (RT) is often adopted in cases of positive or close resection margins to decrease the risk of recurrence, or in place of surgery in cases in which resection is not possible.8 However, conventionally fractionated external beam radiotherapy (cEBRT) has shown limited success in the treatment of chordoma, with 5-year local control rates as low as 10%–40%.9–11 RT dose escalation using proton therapy is increasingly utilized due to its ability to deliver high doses to targets in close proximity to critical structures, such as the spinal cord.12–14 However, proton therapy remains more costly and less widely accessible to many patients compared to x-ray RT techniques.15 Moreover, in some series, proton therapy has been associated with high rates of wound complications.16,17 In contrast, highly conformal x-ray techniques such as stereotactic body radiotherapy (SBRT) are being increasingly adopted for various disease sites, including the spine.18,19 In single-institution series, single-fraction SBRT provides encouraging local control rates as high as 90% at 5 years.20–23

Compared to single-fraction treatments, hypofractionated SBRT (in 3–5 fractions) may improve the therapeutic ratio by allowing for interfraction repair of critical organs and increase tumor control by exploiting beneficial radiobiology of fractionation.24,25 In addition, neoadjuvant RT prior to definitive surgery may sterilize microscopic tumor invasion, improve the likelihood of en bloc resection with negative margins, and reduce the need to sacrifice functionally important neurovascular structures. From a practical standpoint, the treatment target is clearly delineated preoperatively, allowing for more confined target volumes than postoperative RT. Based on these rationales, neoadjuvant hypofractionated SBRT may be a valuable approach that has not been widely explored for chordoma. The purpose of this study is to review the feasibility and early efficacy outcomes of patients with spinal chordoma treated with hypofractionated SBRT, including the largest cohort of patients reported to date receiving neoadjuvant SBRT.

Methods

Patients

This is a retrospective review of patients with chordoma of the mobile spine and sacrum treated at the Johns Hopkins Hospital between 2009 and 2019. Patients with newly diagnosed or recurrent chordoma of the spine were reviewed by a multidisciplinary spine oncology group, consisting of neurosurgeons, radiation oncologists, neuroradiologists, and a pathologist. Definitive en bloc surgery with curative intent was offered to the patients without contraindications. Patients with locally invasive tumors were selected for neoadjuvant SBRT to improve the likelihood of negative margins and spare critical neurovascular structures (see below) during surgery. Adjuvant SBRT was offered in cases of close or positive margins. In patients for whom en bloc resection was medically inappropriate or would render concern for significant functional deficits, nononcologic surgeries such as gross-total resection (GTR) with positive margins or debulking/separation surgeries were undertaken, often in the context of neoadjuvant or adjuvant SBRT. Patients with advanced age, poor functional status, and/or recurrent tumors not amenable to curative resections were offered definitive SBRT with the goal of long-term tumor control and/or symptom relief.

Patients were included if they received image-guided SBRT over 1–5 fractions with ≥ 5 Gy per fraction. Patients who received only cEBRT (1.8–2 Gy per fraction), proton therapy, or other RT modalities were excluded. Clinical variables recorded include gender, age, Karnofsky Performance Scale (KPS) score, dates of diagnosis and treatments, spine levels involved, pretreatment symptoms, and imaging evidence of local invasiveness. Locally invasive tumors were defined as those with nerve root impingement/encasement, epidural extension, invasion of the posterior element or paraspinal space, and vascular involvement. Surgical details were obtained through operative reports, including time interval between SBRT and surgery, type of surgery (en bloc resection vs GTR with positive margins vs debulking/separation surgery), staged operations, whether spinal nerve roots were sacrificed during surgery, whether anterior reconstruction and/or a soft tissue flap was required, total procedural time, and estimated blood loss (EBL). Surgical margins were determined from the original pathology reports and were categorized as widely negative, close (< 2 mm), or positive (tumor cells at margins or intralesional incision). Postoperative complications within 90 days of the surgery were graded as per the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0).

SBRT Treatment and Dosimetry

Image-guided SBRT was delivered using either a robotic system or linear accelerator according to institutional guidelines, as previously described.26 All patients underwent MRI with gadolinium contrast, which was rigidly registered to the planning CT for delineation of the gross tumor volume (GTV), the spinal cord, and sacral nerves. For postoperative lesions above the sacrum with significant MRI artifact due to surgical instrumentation, CT myelography was obtained and rigidly registered with the planning CT to identify the spinal cord. In the adjuvant setting, the preoperative MRI was coregistered with the planning CT to ensure the clinical target volume (CTV) encompassed the entire preoperative tumor extent. Delineation of the CTV followed principles similar to the consensus contouring guidelines for intact and postoperative spinal metastases and typically included the gross disease, the entire involved anatomical segment, as well as the immediately adjacent anatomical segments.27,28 The planning target volume (PTV) included a 1–2-mm expansion of the CTV, excluding a planning risk volume (PRV) of spinal cord plus 2 mm (for lesions above the conus) or the thecal sac (for lesions below the conus). Maximum spinal cord dose was limited to < 25.3 Gy in 5 fractions.29 Dose constraints to other organs at risk (OAR), including uninvolved spinal nerves, followed the thresholds specified by the American Association of Physicists in Medicine Task Group report 101.30 For neoadjuvant treatments, the involved spinal nerves that would be sacrificed during surgery were identified by the treating neurosurgeon and radiation oncologist in a multidisciplinary setting prior to SBRT planning, and standard dose constraints were not applied to these with the goal of optimizing the gross tumor coverage. Treatment parameters recorded include total dose, number of fractions, biologically effective dose (BED2), prescription isodose line (IDL), prescription dose coverage (percentage of target volume), minimum (Dmin) and mean dose (Dmean) of the PTV, as well as the maximum (Dmax) and D95 and D80 (minimum dose to 95% and 80%) of the PTV. To account for different fractionation schemes, BED2 of the prescription dose was calculated under a linear quadratic model assuming an α/β ratio of 2 for chordoma.31–33 Target and OAR doses were converted to 5-fraction equivalent doses using the same equation.

Follow-Up and Outcomes

After SBRT, patients were followed using MRI every 3–6 months for the first 2 years, every 6–12 months for years 3–5, and every 1–2 years thereafter. Other imaging modalities, such as CT of the chest/abdomen/pelvis with contrast, were performed for initial staging, in the setting of recurrent disease, or when clinically indicated. Overall survival (OS) and local recurrence (LR) were calculated from the completion of SBRT. LR was defined as enlargement of the treated lesion and/or increase in contrast enhancement on MRI, as determined by the multidisciplinary spinal oncology team. Distant metastasis was defined as new lesions at new noncontiguous spinal levels or other organs of the body. SBRT toxicities were retrospectively reviewed from patient records and graded per CTCAE (version 5.0).

Statistics

Clinical and dosimetric parameters were presented as number (percentage total) or median (range). Kaplan-Meier survival analysis was performed for OS and LR. For LR, patients were censored at the time of recurrence of the SBRT-treated lesion only. The log-rank test was used to compare OS of subgroups and LR by dosimetric parameters. Wilcoxon rank-sum tests were used to compare dosimetric parameters between different fractionation schemes. A p value < 0.05 was considered statistically significant.

Results

Patient Population and Treatment Paradigms

Twenty-eight patients with 30 discrete lesions were treated with SBRT. The median follow-up duration was 20.8 months (range 2.3–126.3 months). The median patient age was 56 years (range 27–82 years), and 82% of the patients were male (Table 1). The majority of the treated lesions were in the mobile spine, including 7 in the cervical, 6 in the thoracic, and 11 in the lumbar spine. Four patients had sacral lesions. Twenty-three patients had newly diagnosed lesions, 17 of whom received neoadjuvant SBRT followed by surgery, 5 received adjuvant SBRT after surgery, and 1 received SBRT alone. The 7 recurrent lesions were treated using SBRT alone. The majority of patients (27/30) were symptomatic from the index lesion prior to treatment, and the most common symptoms included back pain (50%) and radiculopathy (57%).

TABLE 1.

Patient characteristics and treatment paradigms

VariableValue
No. of lesions30
No. of pts28
Median age (range), yrs56 (27–82)
Males, n (%)23 (82)
Median KPS score (range)90 (60–100)
Spinal level, n (%)
 Cervical7 (23)
 Thoracic6 (20)
 Lumbar11 (37)
 Sacral4 (13)
 Coccygeal2 (7)
Type of lesions, n (%)
 New23 (77)
 Recurrent
  Local4 (13)
  Distant3 (10)
Prior RT, n (%)2 (7)
Pretreatment symptoms, n (%)
 Back pain15 (50)
 Radiculopathy17 (57)
 Pathologic fracture3 (10)
 Dysphagia1 (3)
 Asymptomatic3 (10)
Treatment paradigm, n (%)
 Neoadjuvant SBRT17 (57)
 Adjuvant SBRT5 (17)
 SBRT alone8 (26)

Surgical Outcomes After Neoadjuvant SBRT

The majority of patients with newly diagnosed chordoma (17/23, 74%) received neoadjuvant SBRT. Table 2 summarizes tumor and surgical characteristics in this group. The majority were in the mobile spine, including 5 in the cervical, 2 in the thoracic, and 8 in the lumbar spine. Evidence of local invasiveness included nerve root impingement/encasement (76%), extension into the epidural space (59%), posterior vertebral elements (53%) or paraspinal soft tissue (41%), and vascular involvement (29%).

TABLE 2.

Tumor characteristics and surgical parameters for neoadjuvant SBRT

VariableValue
No. undergoing neoadjuvant SBRT17
Spinal level, n (%)
 Cervical5 (29)
 Thoracic2 (12)
 Lumbar8 (47)
 Sacral1 (6)
 Coccygeal1 (6)
Evidence of invasiveness, n (%)
 Nerve root involvement13 (76)
 Epidural extension10 (59)
 Posterior element extension9 (53)
 Paraspinal invasion7 (41)
 Vascular involvement5 (29)
Median time to surgery (days)26 (6–64)
Type of surgery, n (%)
 En bloc resection15 (88)
 GTR1 (6)
 Debulking/separation surgery1 (6)
Staged surgery for en bloc resection, n (%)
 Yes12 (80)
 No3 (20)
Nerve root sacrifice, n (%)8 (47)
Anterior cage reconstruction, n (%)15 (88)
Soft-tissue flap closure, n (%)9 (53)
Median total procedural time (range), mins
 En bloc resection1000 (303–1870)
 GTR or debulking568 (446–691)
Median total EBL (range), ml
 En bloc resection2100 (250–9000)
 GTR or debulking525 (150–900)
Surgical margins for en bloc resection, n (%)
 Widely negative13 (87)
 Close2 (13)
 Positive0

Neoadjuvant SBRT was delivered in 5 fractions to a dose of 40–50 Gy for 11 patients (65%), 18–21 Gy in 3 fractions for 5 patients (29%), and 16 Gy ×1 for 1 patient (6%). The median time from completing SBRT to surgery was 26 days (range 6–64 days). Fifteen patients (88%) underwent en bloc resection, all with negative margins, and 8 (47%) underwent planned sacrifice of the involved nerve roots during surgery. Fifteen patients (88%) received anterior cage reconstruction, and 9 (53%) required complex soft tissue flap closure. The median total procedural time was 1000 minutes (range 303–1870 minutes), and median EBL was 2100 ml (range 250–9000 ml) for en bloc resections. Two patients with cervical lesions underwent planned nononcologic resection (1 with debulking and 1 with GTR) due to significant medical comorbidities and involvement of bilateral or the dominant vertebral arteries. After a median follow-up of 22.2 months (range 2.3–126.3 months), no patient in the neoadjuvant group experienced LR.

The rate of wound-related complications, which may be due to both neoadjuvant SBRT and surgery, was 12% (2/17, Table 3). These occurred after en bloc resection and complex plastic surgery closure for a cervical and a sacral lesion. Four patients experienced complications unrelated to the surgical site or SBRT (two grade 3 and two grade 2). One patient developed empyema in an area remote from the radiation field, and underwent evacuation by video-assisted thoracoscopic surgery (VATS). Other complications included large bowel obstruction treated with endoscopic decompression, and stroke and pulmonary embolism, both managed conservatively. SBRT dose and fractionation did not appear to be associated with postoperative complications.

TABLE 3.

Postoperative complications after neoadjuvant SBRT and surgery

Age (yrs), SexKPS ScorePreexisting Comorbid ConditionsSpinal LevelTumor Size (cm3)SBRT Dose & FractionationType of SurgeryFlap ReconstructionPostop ComplicationsComplication GradeTx for Complications
55, M100StrokeCervical5.440 Gy in 5 fractionsEn blocNoWound infection3Wound washout & revision
65, M90HyperlipidemiaSacral519.640 Gy in 5 fractionsEn blocYesWound infection3Wound washout & revision
46, M90AsthmaThoracic65.021 Gy in 3 fractionsEn blocNoEmpyema3VATS
80, M80Coronary artery diseaseLumbar63.921 Gy in 3 fractionsEn blocNoLarge bowel obstruction3Endoscopic decompression
82, F60Diabetes, hypertension, strokeCervical109.540 Gy in 5 fractionsDebulkingNoStroke2Medical management
67, M90Hypertension, hyperlipidemiaLumbar25.350 Gy in 5 fractionsEn blocYesPulmonary embolism2Medical management

Tx = treatment.

Adjuvant and Standalone SBRT

Of the remaining 6 patients with newly diagnosed chordoma, 5 received adjuvant SBRT after surgery due to intralesional resection (n = 3), or positive (n = 1) or close margins (n = 1) after en bloc resection. All adjuvant SBRT treatments were delivered in 5 fractions to a median dose of 40 Gy (range 30–50 Gy). The median time from surgery to SBRT was 79 days (range 34–376 days). Postoperative wound complications occurred in 2 patients in the adjuvant group (40%), including 1 before and 1 after SBRT, and both required reoperations. One patient with newly diagnosed sacral chordoma received SBRT alone using 18 Gy in 1 fraction and was alive with no evidence of disease 31.2 months after SBRT.

Seven patients had recurrent disease, including 2 locally recurrent tumors after definitive surgery, two locally recurrent tumors after surgery and cEBRT (70.2 Gy), and 3 distant recurrences not previously treated. For patients with RT-naïve recurrent lesions, SBRT was delivered in 1–5 fractions to 15–50 Gy, with a median BED2 of 200 Gy (range 87.5–300 Gy). For the 2 patients receiving re-irradiation with SBRT, the doses were 25 Gy and 40 Gy in 5 fractions.

Five patients with recurrent disease received systemic therapy. Four received an immune checkpoint inhibitor (ICI), including nivolumab (n = 3) and pembrolizumab (n = 1), which were initiated 1 week before to 9 months after SBRT. The median duration of ICI treatment was 4 months (range 4–14 months). Three patients receiving ICI died, with a median survival of 25.7 months (range 14.4–27.7 months), while 1 remained alive at 18.0 months. Four patients received targeted therapies, including imatinib (n = 4), sirolimus (n = 2), other tyrosine kinase inhibitors (pazopanib, n = 1; regorafenib, n = 1), and palbociclib (n = 1).

Overall Survival and Local Control

Figure 1A demonstrates OS after SBRT in the entire cohort. The 2-year OS was 92% (95% confidence interval [CI] 71%–98%). Patients with newly diagnosed lesions had a significantly higher rate of 2-year OS (95%, 95% CI 69%–99%) than those with recurrent lesions (83%, 95% CI 27%–97%, Fig. 1B). The median survival was not reached (95% CI 85.2 months–infinity) among patients with newly diagnosed lesions, compared to 27.7 months (95% CI 14.4 months–infinity) for patients with recurrent disease (p = 0.006, log-rank test).

FIG. 1.
FIG. 1.

Kaplan-Meier estimates of overall survival in the entire cohort (A), overall survival stratified by new versus recurrent lesions (B), and incidence of LR in the entire cohort (C). The gray areas in panels A and C indicate 95% CIs of the Kaplan-Meier estimates.

The 2-year local control rate was 96% (95% CI 74%–99%, Fig. 1C). Two LRs occurred in the entire cohort, both in radiation naïve sites, 1 after intralesional resection and adjuvant SBRT (30 Gy in 5 fractions, BED2 120 Gy), and the other after SBRT alone (15 Gy ×1, BED2 127.5 Gy) to a metastatic lesion in the setting of widely progressive disease. Both LRs were in-field (within the SBRT prescription IDL). Among the RT-naïve lesions, there was no LR (0/21) among patients who received BED2 ≥ 140 Gy (equivalent to 70 Gy in 35 fractions or 33 Gy in 5 fractions), compared to 2 LRs in 7 patients receiving BED2 < 140 Gy (p = 0.14, log-rank test). Similarly, no LR occurred with PTV Dmax ≥ 47 Gy, Dmean ≥ 39 Gy and D80 ≥ 36 Gy (0/21), compared with 2 LRs at PTV Dmax < 47 Gy, Dmean < 39 Gy, and D80 < 36 Gy (2/7, p = 0.14).

SBRT Fractionation

Table 4 summarizes SBRT dosimetric parameters stratified by fractionation schemes. The median tumor volume was 57.5 cm3 (range 0.6–2052.4 cm3), and the median PTV was 76.8 cm3 (range 6.2–2486.4 cm3). The most common prescription dose was 40–50 Gy (BED2 200–300 Gy) in 5 fractions. Nine lesions (30%) were treated with single-fraction (n = 3) or 3-fraction (n = 6) SBRT, while the rest (70%) were treated in 5 fractions. GTV and PTV were similar between 5-fraction and < 5-fraction treatments. For the RT-naïve lesions, the maximum doses to the spinal cord and spinal cord PRV (in 5-fraction equivalent doses) were similar between 5-fraction (median spinal cord Dmax 20.34 Gy, spinal cord PRV Dmax 25.23 Gy) and < 5-fraction plans (median spinal cord Dmax 21.21 Gy, p = 0.68; spinal cord PRV Dmax 24.10 Gy, p = 0.50). However, 5-fraction SBRT plans were prescribed to significantly higher marginal doses (median BED2 247.5 Gy, range 120–300 Gy), compared to < 5-fraction treatment plans (median BED2 94.5 Gy, range 72–180 Gy, p < 0.001). Furthermore, 5-fraction SBRT plans achieved greater intratumoral dose heterogeneity (median Dmax 73.77 vs 41.24 Gy, p < 0.001), higher PTV Dmean (median 48.69 vs 31.18 Gy, p < 0.001), as well as higher D80 (median 42.69 vs 29.33 Gy, p < 0.001) and D95 (median 33.10 vs 26.14 Gy, p = 0.011), compared to < 5-fraction plans (Table 4, all in 5-fraction equivalent doses). PTV Dmin was not significantly different between 5-fraction and < 5-fraction plans, likely due to constraints by the nearby spinal cord. In summary, 5-fraction SBRT plans achieved higher intratumoral doses, especially in the parameters potentially associated with tumor control (BED2, Dmax, Dmean, and D80), compared to less-fractionated plans, without increasing spinal cord dose.

TABLE 4.

SBRT dosimetric parameters

ParameterOverallRT-Naïvep Value*Prior RT
5 Fractions<5 Fractions
No. of lesions301992
No. of fractions, n (%)
 13 (10)NA3 (33)0
 36 (20)NA6 (67)0
 521 (70)19 (100)NA2 (100)
GTV size, cm357.50 (0.60–2052.40)67.70 (0.60–2052.40)45.75 (12.70–72.00)0.4699.25 (18.70–179.80)
PTV size, cm376.80 (6.20–2486.40)85.60 (6.20–2486.40)60.30 (19.90–128.70)0.23154.65 (45.40–263.90)
Total dose, Gy40.00 (15.00–50.00)45.00 (30.00–50.00)18.00 (15.00–27.00)<0.00132.50 (25.00–40.00)
Prescription IDL, %64 (51–86)60 (51–86)67 (55–85)0.05865.5 (64–67)
BED2, Gy200.0 (72.0–300.0)247.5 (120.0–300.0)94.5 (72.0–180.0)<0.001143.8 (87.5–200.0)
PTV Dmax, Gy64.14 (33.68–89.29)73.77 (44.11–89.29)41.24 (33.68–54.89)<0.00149.91 (37.31–62.50)
PTV Dmean, Gy45.55 (27.34–60.66)48.69 (32.62–60.66)31.18 (27.34–43.10)<0.00137.80 (28.83–46.78)
PTV D80, Gy39.42 (24.72–55.63)42.69 (30.23–55.63)29.33 (24.72–40.52)<0.00135.67 (27.30–44.04)
PTV D95, G30.95 (17.05–50.40)33.10 (22.70–50.40)26.14 (17.05–38.61)0.01127.95 (26.00–29.90)
PTV Dmin, Gy16.90 (6.53–47.28)17.24 (6.53–47.28)16.36 (6.83–34.74)0.7515.01 (7.30–22.72)
Spinal cord Dmax, Gy20.34 (8.84–26.00)20.34 (14.96–26.00)21.21 (10.09–21.69)0.688.84 (8.84–8.84)
Spinal cord PRV Dmax, Gy24.87 (2.09–34.21)25.23 (2.09–30.02)24.10 (13.95–34.21)0.5016.69 (16.69–16.69)

NA = not applicable. Data are given as median (range) unless otherwise specified.

p values were from Wilcoxon rank-sum tests between RT-naïve 5-fraction and <5-fraction treatments.

Doses to the target and organs at risk were converted to 5-fraction equivalent doses using the linear quadratic equation assuming an α/β ratio of 2.

SBRT Complications

SBRT treatments were well tolerated. No grade 3 or higher toxicity was observed. The most common acute toxicity was transient pain flare (13%), usually within the first 2 weeks after treatment, and the majority resolved spontaneously, except for 1 patient requiring a short course of corticosteroids. Other side effects included gastrointestinal discomfort (7%) and skin erythema (3%), all grade 1. There was no apparent association between SBRT dose and fractionation scheme with acute toxicity. Importantly, no long-term toxicity attributable to SBRT was observed, including radiation-induced myelopathy, fracture, or hardware failure.

Discussion

In this study, we present the largest series to date of patients with chordoma of the mobile spine and those treated with high-dose hypofractionated SBRT. With a median follow-up of 20.4 months, early patient outcomes are encouraging, with 2-year OS of 92% and local control of 96%. Notably, all patients treated with neoadjuvant SBRT followed by en bloc resection had negative margins. Moreover, neoadjuvant SBRT did not increase the risk of subsequent surgery, with only 12% grade 3 wound-related complications. We propose several target dose levels that may correlate with local control, including BED2 ≥ 140 Gy, PTV Dmax ≥ 47 Gy, Dmean ≥ 39 Gy, and D80 ≥ 36 Gy in 5 fractions. We also demonstrate improved BED2, Dmax, Dmean, and D80 with 5-fraction SBRT compared to plans delivered in < 5 fractions, without compromising spinal cord safety. Taken together, neoadjuvant high-dose hypofractionated SBRT may be a promising treatment option for this challenging disease.

Even with aggressive en bloc resection, long-term control of chordoma remains difficult.5,6 However, en bloc surgery is only achievable in as few as 55%–60% of patients, even in the hands of experienced spine surgeons.34,35 The rate of en bloc resection in the mobile spine may be even lower. In a large series of 52 cases of chordoma of the mobile spine, only 17 (33%) were able to undergo en bloc resection, 6 of whom had positive margins.3 Furthermore, even after wide excision, the rate of LR can still be as high as 50%.3,5,34,36 Using a dose-escalated (mean dose 72.4 Gy), mixed photon-proton regimen, one study demonstrated significantly higher 5-year local control with neoadjuvant RT: 72% versus 54% for the entire cohort, and 85% versus 56% for primary tumors.17 These data support the use of preoperative therapies with the goal of improving the likelihood of oncological resections and tumor control. Consistent with this hypothesis is the finding that 88% of patients who received neoadjuvant SBRT in our series were able to undergo en bloc resection, all with negative margins and no LR.

Chordoma is a locally invasive tumor, which contributes to the need for wide surgical margins. Microscopically, chordoma cells can often infiltrate the connective tissue spaces surrounding nerves and blood vessels.37 As a result, en bloc resection sacrificing the involved nerves and vasculature often leads to significant functional deficit. The impact of chordoma surgery on patients’ daily function is evident in a study of 42 patients with resected sacral chordoma, 74% of whom required self-catheterization and 38% needing bowel training.4 Characteristics of its invasiveness can often be identified radiographically, such as involvement of the spinal nerve roots and blood vessels, and invasion into the epidural space, posterior vertebral elements, and paraspinal soft tissue. These radiographic signs were present in all patients who were selected for neoadjuvant SBRT in our series, most commonly nerve root involvement (76%). Interestingly, only 8 patients (47%) required sacrifice of nerve roots during their surgery. Instead, after multidisciplinary discussion, the full SBRT prescription dose was delivered to the at-risk nerves with the intent of enhancing local control. No patient developed neurological deficit resulting from this aggressive regimen, although radiation-induced neuropathy is a late effect and may require longer follow-up. Our data provide strong rationales for neoadjuvant SBRT as a method for sterilizing microscopic invasion, sparing functionally important neurovascular structures, and preserving patients’ normal function and quality of life.

Our approach of neoadjuvant SBRT followed by en bloc resection also did not lead to excessive surgical risks. Postoperative complications were observed in 6 patients, and only 2 (12%) developed wound dehiscence and infection and required reoperations. The interval between SBRT and surgery and technological factors may have played an important role in minimizing postoperative complications. Previous studies suggest that intervals shorter than 7 days or greater than 60 days may be related to increased risk of wound complications after preoperative radiation, especially high-dose radiation.38,39 In our series, 82% of patients underwent surgery within 7–60 days of neoadjuvant SBRT, which may have helped to minimize the risk of wound healing complications. In addition, careful SBRT planning may allow better skin sparing compared to other RT modalities. For example, in a large retrospective study of patients treated with high-dose proton-based RT, the rate of grade 3 or higher wound infection and dehiscence was 22% for patients receiving neoadjuvant treatment.17 Therefore, neoadjuvant SBRT for chordoma may be a safe and effective adjunct therapy for resection.

The intrinsic radioresistance of chordoma may be mediated by distinct cellular pathways that regulate DNA damage repair and cancer stem cell renewal.40–42 Postoperatively, tumor bed hypoxia also increases its resistance to adjuvant RT. This radioresistance is evident clinically, because a dose as high as 70 Gy is required for moderate local control with cEBRT.11 Prior to the advent of highly conformal x-ray RT techniques, such as intensity-modulated radiotherapy and SBRT, proton therapy was required to safely deliver such high doses without endangering the spinal cord.12–14,43 However, access to proton therapy may be restricted by its higher cost and limited geographic distribution of proton therapy centers.15 Moreover, skin toxicity and wound healing complications may be of concern after proton therapy.16,17 Conversely, SBRT represents an emerging approach to radiation dose escalation for spine malignancies.19 Only a few limited series of SBRT for spinal chordoma have been reported in the literature, which are summarized in Table 5. Earlier reports mostly applied relatively low-dose regimens (median BED2 144–180 Gy) in small, heavily pretreated patient populations. Tumor control in these studies was less optimal, in the range of 70%–75%.20,22,32 In contrast, a large series of de novo chordoma of the spine utilized dose-escalated single-fraction SBRT (median dose 24 Gy, BED2 312 Gy), and observed far superior local control (96% at 3 years and 90% at 5 years).21,23 These reports highlight the importance of dose escalation, not only with cEBRT, but also in the setting of SBRT.

TABLE 5.

Summary of published studies on SBRT for spinal chordoma

Authors & YearNo.*Follow-up (mos)En bloc Resection & MarginsGTV Size (cm3)PTV Size (cm3)Total Dose (Gy)No of FractionsBED2 (Gy)PTV D05/Dmax (Gy)PTV D90/ D95 (Gy)Local ControlOS
Henderson et al., 20093211/13/10/046 (7–65)NA128.0 (12.0–457.3)NA35 (24–40)5 (5–5)157.5 (81.6–200)NANA75% at 2 yrs, 59% at 5 yrs87% at 2 yrs, 75% at 5 yrs
Jiang et al., 2012227/7/4/NA34 (2–131)NA22.0 (10.6–46.0)NA30 (25–42.5)5 (3–5)180 (87.5–223.1)37.7 (25.0–42.5)NA71% (total)75% at 2 yrs, 52% at 5 yrs
Yamada et al., 20132124/24/14/624 (6–51)NA81 (20–859)NA24 (18–24)1 (1–1)312 (180–312)NAD90: 50.9

(29.7–54.6)
95% at 2 yrsNA
Jung et al., 2017208/12/10/NA9.7 (0.5–84)NA48 (1–304)NA16 (11–16)1 (1–1)144 (71.5–144)36.8 (25.1–40.0)NA75% (total)NA
Jin et al., 20202335/35/17/1238.8 (2.0–122.9)En bloc: 15 planned, 11 actual; margins: 8 wide, 2 close, 1 positive61.2 (1.2–335.5)155.6 (29.2–903.8)24 (18–24)1 (1–1)312 (180–312)D05: 55.4

(40.2–62.2)
D95: 51.0

(34.3–53.1)
> 95% at 2 yrs97% at 1 yr, 90% at 3 yrs, 84% at 5 yrs
Current study28/30/24/1720.8 (2.3–126.3)En bloc: 15 planned, 15 actual; margins: 13 wide, 2 close57.5 (0.6–2052.4)76.8 (6.2–2486.4)40 (15–50)5 (1–5)200 (72–300)Dmax: 64.1

(33.7–89.3)
D90: 35.4

(22.0–51.8);

D95: 30.9

(17.0–50.4)
96% at 2 yrs92% at 2 yrs

D95/D90/D05 = minimum dose to 95%/90%/5% of target volume.

Total number of patients/spinal lesions/mobile spine lesions/lesions treated with neoadjuvant SBRT.

Median (range).

Doses converted to 5-fraction equivalent dose.

Unlike prior studies, we employed a dose-escalation approach using hypofractinated SBRT, mostly 5-fraction regimens. Theoretically, hypofractionated SBRT may improve target dose distribution and can enhance tumor control by ablating the tumor vascular bed and stimulating antitumor immunity.24,25,44 By comparing different fractionation schemes in our cohort, our data support the dosimetric benefit of hypofractionation. For example, the maximum doses to the spinal cord and spinal cord PRV were similar in 5-fraction plans and < 5-fraction plans. However, 5-fraction plans were prescribed to a higher marginal dose (median BED2 200 Gy) and attained significantly higher intratumoral dose, especially PTV Dmax, Dmean and D80, all of which may be associated with better tumor control. The importance of intratumoral dose escalation is further supported by the fact that both cases of LR occurred in-field. Therefore, hypofractionated SBRT may be dosimetrically advantageous in achieving dose escalation for chordoma.

Several limitations of our study should be noted. First, the median duration of follow-up was relatively short. As demonstrated by both our study and previous studies, chordoma can recur years after treatment.3,5 Therefore, longer-term follow-up will be essential to confirm our findings. Another limitation is the heterogeneity in our patient cohort and treatment regimen, mainly due to the rarity of spinal chordoma and the paucity of data on the role of SBRT. At our institution, dose-escalated SBRT (45–50 Gy in 5 fractions) is currently the preferred regimen based on our data. Finally, definitive radiotherapy or a combination of aggressive SBRT and less-extensive resection warrant further investigation as they may be reasonable alternatives to en bloc wide excision in appropriately selected patients. However, given the long disease course and exceedingly high recurrence rate with suboptimal surgery, longer-term follow-up is crucial before a dramatic change in practice pattern is initiated globally as the likelihood of cure is exceptionally low in patients with recurrent chordoma.6,7 Future prospective studies should also evaluate the appropriateness of our patient selection criteria, the proposed dose levels, and functional outcomes after neoadjuvant SBRT and surgery.

Conclusions

We present the largest series to date of patients with spinal chordoma treated with dose-escalated neoadjuvant SBRT. Early results indicate a favorable safety profile and promising efficacy. Neoadjuvant SBRT increases the likelihood of successful en bloc resection and may allow preservation of important patient functions after surgery. We identified the minimum dose levels required for tumor control, including marginal dose BED2 ≥ 140 Gy, PTV Dmax ≥ 47 Gy, Dmean ≥ 39 Gy, and D80 ≥ 36 Gy in 5 fractions. Hypofractionated SBRT may offer greater dosimetric advantage by enhancing these dose levels without compromising the safety of the spinal cord. Longer follow-up is needed to confirm these findings.

Disclosures

Dr. Bettegowda reported consulting service for DePuy-Synthes and Bionaut Pharmaceuticals. Dr. Hu performed consulting for Merck & Co., outside the submitted work. Dr. Kleinberg received research grants from Novocure, Arbor, and Accuray; has performed consulting for Novocure and Accuray; and is on an advisory board for Novocure, outside the submitted work. Dr. Sciubba performed consulting for Medtronic, DePuy-Synthes, Stryker, and Baxter, outside the submitted work. Dr. Redmond received research funding and travel expenses from Accuray and Elekta AB; honoraria from Accuray and NCCN; travel expenses from Brainlab; and served on the data safety monitoring board for BioMimetix, outside the submitted work.

Author Contributions

Conception and design: Redmond, Chen. Acquisition of data: Chen. Analysis and interpretation of data: Redmond, Chen. Drafting the article: Chen. Critically revising the article: Redmond, Chen, Lo, Bettegowda, Hu, Kleinberg, Sciubba. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Redmond. Statistical analysis: Chen, Hu. Study supervision: Redmond.

References

  • 1

    Walcott BP, Nahed BV, Mohyeldin A, et al. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69e76.

  • 2

    Radaelli S, Fossati P, Stacchiotti S, et al. The sacral chordoma margin. Eur J Surg Oncol. 2020;46(8):14151422.

  • 3

    Boriani S, Bandiera S, Biagini R, et al. Chordoma of the mobile spine: fifty years of experience. Spine (Phila Pa 1976). 2006;31(4):493503.

  • 4

    Schwab JH, Healey JH, Rose P, et al. The surgical management of sacral chordomas. Spine (Phila Pa 1976). 2009;34(24):27002704.

  • 5

    Stacchiotti S, Casali PG, Lo Vullo S, et al. Chordoma of the mobile spine and sacrum: a retrospective analysis of a series of patients surgically treated at two referral centers. Ann Surg Oncol. 2010;17(1):211219.

    • Search Google Scholar
    • Export Citation
  • 6

    Radaelli S, Stacchiotti S, Ruggieri P, et al. Sacral chordoma: long-term outcome of a large series of patients surgically treated at two reference centers. Spine (Phila Pa 1976). 2016;41(12):10491057.

    • Search Google Scholar
    • Export Citation
  • 7

    Gokaslan ZL, Zadnik PL, Sciubba DM, et al. Mobile spine chordoma: results of 166 patients from the AOSpine Knowledge Forum Tumor database. J Neurosurg Spine. 2016;24(4):644651.

    • Search Google Scholar
    • Export Citation
  • 8

    Dea N, Fisher CG, Reynolds JJ, et al. Current treatment strategy for newly diagnosed chordoma of the mobile spine and sacrum: results of an international survey. J Neurosurg Spine. 2018;30(1):119125.

    • Search Google Scholar
    • Export Citation
  • 9

    Pennicooke B, Laufer I, Sahgal A, et al. Safety and local control of radiation therapy for chordoma of the spine and sacrum: a systematic review. Spine (Phila Pa 1976). 2016;41(Suppl 20):S186S192.

    • Search Google Scholar
    • Export Citation
  • 10

    Yolcu Y, Wahood W, Alvi MA, et al. Evaluating the role of adjuvant radiotherapy in the management of sacral and vertebral chordoma: results from a national database. World Neurosurg. 2019;127:e1137e1144.

    • Search Google Scholar
    • Export Citation
  • 11

    Houdek MT, Rose PS, Hevesi M, et al. Low dose radiotherapy is associated with local complications but not disease control in sacral chordoma. J Surg Oncol. 2019;119(7):856863.

    • Search Google Scholar
    • Export Citation
  • 12

    Rich TA, Schiller A, Suit HD, Mankin HJ. Clinical and pathologic review of 48 cases of chordoma. Cancer. 1985;56(1):182187.

  • 13

    Hug EB, Loredo LN, Slater JD, et al. Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg. 1999;91(3):432439.

    • Search Google Scholar
    • Export Citation
  • 14

    Noël G, Habrand JL, Mammar H, et al. Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: the Centre de Protonthérapie D’Orsay experience. Int J Radiat Oncol Biol Phys. 2001;51(2):392398.

    • Search Google Scholar
    • Export Citation
  • 15

    Weber DC, Lim PS, Tran S, et al. Proton therapy for brain tumours in the area of evidence-based medicine. Br J Radiol. 2020;93(1107):20190237.

  • 16

    Wagner TD, Kobayashi W, Dean S, et al. Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys. 2009;73(1):259266.

    • Search Google Scholar
    • Export Citation
  • 17

    Rotondo RL, Folkert W, Liebsch NJ, et al. High-dose proton-based radiation therapy in the management of spine chordomas: outcomes and clinicopathological prognostic factors. J Neurosurg Spine. 2015;23(6):788797.

    • Search Google Scholar
    • Export Citation
  • 18

    Konieczkowski DJ, DeLaney TF, Yamada YJ. Radiation strategies for spine chordoma: proton beam, carbon ions, and stereotactic body radiation therapy. Neurosurg Clin N Am. 2020;31(2):263288.

    • Search Google Scholar
    • Export Citation
  • 19

    Vellayappan BA, Chao ST, Foote M, et al. The evolution and rise of stereotactic body radiotherapy (SBRT) for spinal metastases. Expert Rev Anticancer Ther. 2018;18(9):887900.

    • Search Google Scholar
    • Export Citation
  • 20

    Jung EW, Jung DL, Balagamwala EH, et al. Single-fraction spine stereotactic body radiation therapy for the treatment of chordoma. Technol Cancer Res Treat. 2017;16(3):302309.

    • Search Google Scholar
    • Export Citation
  • 21

    Yamada Y, Laufer I, Cox BW, et al. Preliminary results of high-dose single-fraction radiotherapy for the management of chordomas of the spine and sacrum. Neurosurgery. 2013;73(4):673680.

    • Search Google Scholar
    • Export Citation
  • 22

    Jiang B, Veeravagu A, Lee M, et al. Management of intracranial and extracranial chordomas with CyberKnife stereotactic radiosurgery. J Clin Neurosci. 2012;19(8):11011106.

    • Search Google Scholar
    • Export Citation
  • 23

    Jin CJ, Berry-Candelario J, Reiner AS, et al. Long-term outcomes of high-dose single-fraction radiosurgery for chordomas of the spine and sacrum. J Neurosurg Spine. 2020;32(1):7988.

    • Search Google Scholar
    • Export Citation
  • 24

    Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):53795388.

    • Search Google Scholar
    • Export Citation
  • 25

    Redmond KJ, Sahgal A, Foote M, et al. Single versus multiple session stereotactic body radiotherapy for spinal metastasis: the risk-benefit ratio. Future Oncol. 2015;11(17):24052415.

    • Search Google Scholar
    • Export Citation
  • 26

    Chen X, Gui C, Grimm J, et al. Normal tissue complication probability of vertebral compression fracture after stereotactic body radiotherapy for de novo spine metastasis. Radiother Oncol. 2020;150:142149.

    • Search Google Scholar
    • Export Citation
  • 27

    Cox BW, Spratt DE, Lovelock M, et al. International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012;83(5):e597e605.

    • Search Google Scholar
    • Export Citation
  • 28

    Redmond KJ, Robertson S, Lo SS, et al. Consensus contouring guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor malignancies to the spine. Int J Radiat Oncol Biol Phys. 2017;97(1):6474.

    • Search Google Scholar
    • Export Citation
  • 29

    Sahgal A, Weinberg V, Ma L, et al. Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. Int J Radiat Oncol Biol Phys. 2013;85(2):341347.

    • Search Google Scholar
    • Export Citation
  • 30

    Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys. 2010;37(8):40784101.

    • Search Google Scholar
    • Export Citation
  • 31

    Uhl M, Edler L, Jensen AD, et al. Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma—the ISAC trial protocol. Radiat Oncol. 2014;9:100.

    • Search Google Scholar
    • Export Citation
  • 32

    Henderson FC, McCool K, Seigle J, et al. Treatment of chordomas with CyberKnife: Georgetown University experience and treatment recommendations. Neurosurgery. 2009;64(2)(suppl):A44A53.

    • Search Google Scholar
    • Export Citation
  • 33

    Elsässer T, Krämer M, Scholz M. Accuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo. Int J Radiat Oncol Biol Phys. 2008;71(3):866872.

    • Search Google Scholar
    • Export Citation
  • 34

    Ruggieri P, Angelini A, Ussia G, et al. Surgical margins and local control in resection of sacral chordomas. Clin Orthop Relat Res. 2010;468(11):29392947.

    • Search Google Scholar
    • Export Citation
  • 35

    Yamada Y, Gounder M, Laufer I. Multidisciplinary management of recurrent chordomas. Curr Treat Options Oncol. 2013;14(3):442453.

  • 36

    Fourney DR, Rhines LD, Hentschel SJ, et al. En bloc resection of primary sacral tumors: classification of surgical approaches and outcome. J Neurosurg Spine. 2005;3(2):111122.

    • Search Google Scholar
    • Export Citation
  • 37

    Oikawa S, Kyoshima K, Goto T, et al. Histological study on local invasiveness of clival chordoma. Case report of autopsy. Acta Neurochir (Wien). 2001;143(10):10651069.

    • Search Google Scholar
    • Export Citation
  • 38

    Ghogawala Z, Mansfield FL, Borges LF. Spinal radiation before surgical decompression adversely affects outcomes of surgery for symptomatic metastatic spinal cord compression. Spine (Phila Pa 1976). 2001;26(7):818824.

    • Search Google Scholar
    • Export Citation
  • 39

    Keam J, Bilsky MH, Laufer I, et al. No association between excessive wound complications and preoperative high-dose, hypofractionated, image-guided radiation therapy for spine metastasis. J Neurosurg Spine. 2014;20(4):411420.

    • Search Google Scholar
    • Export Citation
  • 40

    Kato TA, Tsuda A, Uesaka M, et al. In vitro characterization of cells derived from chordoma cell line U-CH1 following treatment with X-rays, heavy ions and chemotherapeutic drugs. Radiat Oncol. 2011;6:116.

    • Search Google Scholar
    • Export Citation
  • 41

    Zhang C, Wang B, Li L, et al. Radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector. Exp Ther Med. 2017;14(3):21712179.

    • Search Google Scholar
    • Export Citation
  • 42

    Shah SR, David JM, Tippens ND, et al. Brachyury-YAP regulatory axis drives stemness and growth in cancer. Cell Rep. 2017;21(2):495507.

  • 43

    O’Connell JX, Renard LG, Liebsch NJ, et al. Base of skull chordoma. A correlative study of histologic and clinical features of 62 cases. Cancer. 1994;74(8):22612267.

    • Search Google Scholar
    • Export Citation
  • 44

    Macià i Garau M. Radiobiology of stereotactic body radiation therapy (SBRT). Rep Pract Oncol Radiother. 2017;22(2):8695.

Images from Shimizu et al. (pp 616–623).

  • View in gallery

    Kaplan-Meier estimates of overall survival in the entire cohort (A), overall survival stratified by new versus recurrent lesions (B), and incidence of LR in the entire cohort (C). The gray areas in panels A and C indicate 95% CIs of the Kaplan-Meier estimates.

  • 1

    Walcott BP, Nahed BV, Mohyeldin A, et al. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69e76.

  • 2

    Radaelli S, Fossati P, Stacchiotti S, et al. The sacral chordoma margin. Eur J Surg Oncol. 2020;46(8):14151422.

  • 3

    Boriani S, Bandiera S, Biagini R, et al. Chordoma of the mobile spine: fifty years of experience. Spine (Phila Pa 1976). 2006;31(4):493503.

  • 4

    Schwab JH, Healey JH, Rose P, et al. The surgical management of sacral chordomas. Spine (Phila Pa 1976). 2009;34(24):27002704.

  • 5

    Stacchiotti S, Casali PG, Lo Vullo S, et al. Chordoma of the mobile spine and sacrum: a retrospective analysis of a series of patients surgically treated at two referral centers. Ann Surg Oncol. 2010;17(1):211219.

    • Search Google Scholar
    • Export Citation
  • 6

    Radaelli S, Stacchiotti S, Ruggieri P, et al. Sacral chordoma: long-term outcome of a large series of patients surgically treated at two reference centers. Spine (Phila Pa 1976). 2016;41(12):10491057.

    • Search Google Scholar
    • Export Citation
  • 7

    Gokaslan ZL, Zadnik PL, Sciubba DM, et al. Mobile spine chordoma: results of 166 patients from the AOSpine Knowledge Forum Tumor database. J Neurosurg Spine. 2016;24(4):644651.

    • Search Google Scholar
    • Export Citation
  • 8

    Dea N, Fisher CG, Reynolds JJ, et al. Current treatment strategy for newly diagnosed chordoma of the mobile spine and sacrum: results of an international survey. J Neurosurg Spine. 2018;30(1):119125.

    • Search Google Scholar
    • Export Citation
  • 9

    Pennicooke B, Laufer I, Sahgal A, et al. Safety and local control of radiation therapy for chordoma of the spine and sacrum: a systematic review. Spine (Phila Pa 1976). 2016;41(Suppl 20):S186S192.

    • Search Google Scholar
    • Export Citation
  • 10

    Yolcu Y, Wahood W, Alvi MA, et al. Evaluating the role of adjuvant radiotherapy in the management of sacral and vertebral chordoma: results from a national database. World Neurosurg. 2019;127:e1137e1144.

    • Search Google Scholar
    • Export Citation
  • 11

    Houdek MT, Rose PS, Hevesi M, et al. Low dose radiotherapy is associated with local complications but not disease control in sacral chordoma. J Surg Oncol. 2019;119(7):856863.

    • Search Google Scholar
    • Export Citation
  • 12

    Rich TA, Schiller A, Suit HD, Mankin HJ. Clinical and pathologic review of 48 cases of chordoma. Cancer. 1985;56(1):182187.

  • 13

    Hug EB, Loredo LN, Slater JD, et al. Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg. 1999;91(3):432439.

    • Search Google Scholar
    • Export Citation
  • 14

    Noël G, Habrand JL, Mammar H, et al. Combination of photon and proton radiation therapy for chordomas and chondrosarcomas of the skull base: the Centre de Protonthérapie D’Orsay experience. Int J Radiat Oncol Biol Phys. 2001;51(2):392398.

    • Search Google Scholar
    • Export Citation
  • 15

    Weber DC, Lim PS, Tran S, et al. Proton therapy for brain tumours in the area of evidence-based medicine. Br J Radiol. 2020;93(1107):20190237.

  • 16

    Wagner TD, Kobayashi W, Dean S, et al. Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys. 2009;73(1):259266.

    • Search Google Scholar
    • Export Citation
  • 17

    Rotondo RL, Folkert W, Liebsch NJ, et al. High-dose proton-based radiation therapy in the management of spine chordomas: outcomes and clinicopathological prognostic factors. J Neurosurg Spine. 2015;23(6):788797.

    • Search Google Scholar
    • Export Citation
  • 18

    Konieczkowski DJ, DeLaney TF, Yamada YJ. Radiation strategies for spine chordoma: proton beam, carbon ions, and stereotactic body radiation therapy. Neurosurg Clin N Am. 2020;31(2):263288.

    • Search Google Scholar
    • Export Citation
  • 19

    Vellayappan BA, Chao ST, Foote M, et al. The evolution and rise of stereotactic body radiotherapy (SBRT) for spinal metastases. Expert Rev Anticancer Ther. 2018;18(9):887900.

    • Search Google Scholar
    • Export Citation
  • 20

    Jung EW, Jung DL, Balagamwala EH, et al. Single-fraction spine stereotactic body radiation therapy for the treatment of chordoma. Technol Cancer Res Treat. 2017;16(3):302309.

    • Search Google Scholar
    • Export Citation
  • 21

    Yamada Y, Laufer I, Cox BW, et al. Preliminary results of high-dose single-fraction radiotherapy for the management of chordomas of the spine and sacrum. Neurosurgery. 2013;73(4):673680.

    • Search Google Scholar
    • Export Citation
  • 22

    Jiang B, Veeravagu A, Lee M, et al. Management of intracranial and extracranial chordomas with CyberKnife stereotactic radiosurgery. J Clin Neurosci. 2012;19(8):11011106.

    • Search Google Scholar
    • Export Citation
  • 23

    Jin CJ, Berry-Candelario J, Reiner AS, et al. Long-term outcomes of high-dose single-fraction radiosurgery for chordomas of the spine and sacrum. J Neurosurg Spine. 2020;32(1):7988.

    • Search Google Scholar
    • Export Citation
  • 24

    Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):53795388.

    • Search Google Scholar
    • Export Citation
  • 25

    Redmond KJ, Sahgal A, Foote M, et al. Single versus multiple session stereotactic body radiotherapy for spinal metastasis: the risk-benefit ratio. Future Oncol. 2015;11(17):24052415.

    • Search Google Scholar
    • Export Citation
  • 26

    Chen X, Gui C, Grimm J, et al. Normal tissue complication probability of vertebral compression fracture after stereotactic body radiotherapy for de novo spine metastasis. Radiother Oncol. 2020;150:142149.

    • Search Google Scholar
    • Export Citation
  • 27

    Cox BW, Spratt DE, Lovelock M, et al. International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012;83(5):e597e605.

    • Search Google Scholar
    • Export Citation
  • 28

    Redmond KJ, Robertson S, Lo SS, et al. Consensus contouring guidelines for postoperative stereotactic body radiation therapy for metastatic solid tumor malignancies to the spine. Int J Radiat Oncol Biol Phys. 2017;97(1):6474.

    • Search Google Scholar
    • Export Citation
  • 29

    Sahgal A, Weinberg V, Ma L, et al. Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. Int J Radiat Oncol Biol Phys. 2013;85(2):341347.

    • Search Google Scholar
    • Export Citation
  • 30

    Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys. 2010;37(8):40784101.

    • Search Google Scholar
    • Export Citation
  • 31

    Uhl M, Edler L, Jensen AD, et al. Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma—the ISAC trial protocol. Radiat Oncol. 2014;9:100.

    • Search Google Scholar
    • Export Citation
  • 32

    Henderson FC, McCool K, Seigle J, et al. Treatment of chordomas with CyberKnife: Georgetown University experience and treatment recommendations. Neurosurgery. 2009;64(2)(suppl):A44A53.

    • Search Google Scholar
    • Export Citation
  • 33

    Elsässer T, Krämer M, Scholz M. Accuracy of the local effect model for the prediction of biologic effects of carbon ion beams in vitro and in vivo. Int J Radiat Oncol Biol Phys. 2008;71(3):866872.

    • Search Google Scholar
    • Export Citation
  • 34

    Ruggieri P, Angelini A, Ussia G, et al. Surgical margins and local control in resection of sacral chordomas. Clin Orthop Relat Res. 2010;468(11):29392947.

    • Search Google Scholar
    • Export Citation
  • 35

    Yamada Y, Gounder M, Laufer I. Multidisciplinary management of recurrent chordomas. Curr Treat Options Oncol. 2013;14(3):442453.

  • 36

    Fourney DR, Rhines LD, Hentschel SJ, et al. En bloc resection of primary sacral tumors: classification of surgical approaches and outcome. J Neurosurg Spine. 2005;3(2):111122.

    • Search Google Scholar
    • Export Citation
  • 37

    Oikawa S, Kyoshima K, Goto T, et al. Histological study on local invasiveness of clival chordoma. Case report of autopsy. Acta Neurochir (Wien). 2001;143(10):10651069.

    • Search Google Scholar
    • Export Citation
  • 38

    Ghogawala Z, Mansfield FL, Borges LF. Spinal radiation before surgical decompression adversely affects outcomes of surgery for symptomatic metastatic spinal cord compression. Spine (Phila Pa 1976). 2001;26(7):818824.

    • Search Google Scholar
    • Export Citation
  • 39

    Keam J, Bilsky MH, Laufer I, et al. No association between excessive wound complications and preoperative high-dose, hypofractionated, image-guided radiation therapy for spine metastasis. J Neurosurg Spine. 2014;20(4):411420.

    • Search Google Scholar
    • Export Citation
  • 40

    Kato TA, Tsuda A, Uesaka M, et al. In vitro characterization of cells derived from chordoma cell line U-CH1 following treatment with X-rays, heavy ions and chemotherapeutic drugs. Radiat Oncol. 2011;6:116.

    • Search Google Scholar
    • Export Citation
  • 41

    Zhang C, Wang B, Li L, et al. Radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector. Exp Ther Med. 2017;14(3):21712179.

    • Search Google Scholar
    • Export Citation
  • 42

    Shah SR, David JM, Tippens ND, et al. Brachyury-YAP regulatory axis drives stemness and growth in cancer. Cell Rep. 2017;21(2):495507.

  • 43

    O’Connell JX, Renard LG, Liebsch NJ, et al. Base of skull chordoma. A correlative study of histologic and clinical features of 62 cases. Cancer. 1994;74(8):22612267.

    • Search Google Scholar
    • Export Citation
  • 44

    Macià i Garau M. Radiobiology of stereotactic body radiation therapy (SBRT). Rep Pract Oncol Radiother. 2017;22(2):8695.

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 112 112 112
PDF Downloads 109 109 109
EPUB Downloads 0 0 0