Spinal stereotactic body radiotherapy following intralesional curettage with separation surgery for initial or salvage chordoma treatment

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OBJECTIVE

Chordoma is a rare malignant tumor for which en bloc resection with wide margins is advocated as primary treatment. Unfortunately, due to anatomical constraints, en bloc resection to achieve wide or marginal margins is not feasible for many patients as the resulting morbidity would be prohibitive. The objective of this study was to evaluate the efficacy of intralesional curettage and separation surgery followed by spinal stereotactic body radiation therapy (SBRT) in patients with chordomas in the mobile spine.

METHODS

The authors performed a retrospective chart review of all patients with chordoma in the mobile spine treated from 2004 to 2016. Patients were identified from a prospectively collected database. Initially 22 patients were identified with mobile spine chordomas. With inclusion criteria of cytoreductive separation surgery followed closely by SBRT and a minimum of 6 months of follow-up imaging, 12 patients were included. Clinical and pathological characteristics of each patient were collected and data were analyzed. Patients were divided into two cohorts—those undergoing intralesional resection followed by SBRT as initial chordoma treatment at Memorial Sloan Kettering Cancer Center (MSKCC) (Cohort 1) and those undergoing salvage treatment following recurrence (Cohort 2). Treatment toxicities were classified according to the Common Terminology Criteria for Adverse Events version 4.03. Overall survival was analyzed using Kaplan-Meier analysis.

RESULTS

The 12 patients had a median post-SBRT follow-up time of 26 months. Cohort 1 had 5 patients with median post-SBRT follow-up time of 65.9 months and local control rate of 80% at last follow-up. Only one patient had disease progression, at 48.2 months following surgery and SBRT. Cohort 2 had 7 patients who had been treated at other institutions prior to undergoing both surgery and SBRT (salvage therapy) at MSKCC. The local control rate was 57.1% and the median follow-up duration was 10.7 months. One patient required repeat irradiation. Major surgery- and radiation-related complications occurred in 18% and 27% of patients, respectively. Epidural spinal cord compression scores were collected for each patient pre- and postoperatively.

CONCLUSIONS

The combination of surgery and SBRT provides excellent local control following intralesional curettage and separation surgery for chordomas in the mobile spine. Patients who underwent intralesional curettage and spinal SBRT as initial treatment had better disease control than those undergoing salvage therapy. High-dose radiotherapy may offer several biological benefits for tumor control.

ABBREVIATIONSCTCAE = Common Terminology Criteria for Adverse Events; ESCC = epidural spinal cord compression; MSKCC = Memorial Sloan Kettering Cancer Center; SBRT = stereotactic body radiation therapy.

Abstract

OBJECTIVE

Chordoma is a rare malignant tumor for which en bloc resection with wide margins is advocated as primary treatment. Unfortunately, due to anatomical constraints, en bloc resection to achieve wide or marginal margins is not feasible for many patients as the resulting morbidity would be prohibitive. The objective of this study was to evaluate the efficacy of intralesional curettage and separation surgery followed by spinal stereotactic body radiation therapy (SBRT) in patients with chordomas in the mobile spine.

METHODS

The authors performed a retrospective chart review of all patients with chordoma in the mobile spine treated from 2004 to 2016. Patients were identified from a prospectively collected database. Initially 22 patients were identified with mobile spine chordomas. With inclusion criteria of cytoreductive separation surgery followed closely by SBRT and a minimum of 6 months of follow-up imaging, 12 patients were included. Clinical and pathological characteristics of each patient were collected and data were analyzed. Patients were divided into two cohorts—those undergoing intralesional resection followed by SBRT as initial chordoma treatment at Memorial Sloan Kettering Cancer Center (MSKCC) (Cohort 1) and those undergoing salvage treatment following recurrence (Cohort 2). Treatment toxicities were classified according to the Common Terminology Criteria for Adverse Events version 4.03. Overall survival was analyzed using Kaplan-Meier analysis.

RESULTS

The 12 patients had a median post-SBRT follow-up time of 26 months. Cohort 1 had 5 patients with median post-SBRT follow-up time of 65.9 months and local control rate of 80% at last follow-up. Only one patient had disease progression, at 48.2 months following surgery and SBRT. Cohort 2 had 7 patients who had been treated at other institutions prior to undergoing both surgery and SBRT (salvage therapy) at MSKCC. The local control rate was 57.1% and the median follow-up duration was 10.7 months. One patient required repeat irradiation. Major surgery- and radiation-related complications occurred in 18% and 27% of patients, respectively. Epidural spinal cord compression scores were collected for each patient pre- and postoperatively.

CONCLUSIONS

The combination of surgery and SBRT provides excellent local control following intralesional curettage and separation surgery for chordomas in the mobile spine. Patients who underwent intralesional curettage and spinal SBRT as initial treatment had better disease control than those undergoing salvage therapy. High-dose radiotherapy may offer several biological benefits for tumor control.

Chordoma is a rare, primary spinal malignant neoplasm that arises from the remnants of the embryonic notochord.23,50,57 Chordoma has a reported incidence of less than 0.1 per 100,000 people per year but is the most frequent of the primary spinal tumors6 and often presents with vague, indolent symptoms.6,23,30 Given their relatively slow malignant growth, chordomas are often diagnosed late in the disease process and involve critical structures, creating challenging treatment needs for these complex cases. Physicians commonly use the Enneking staging system, designed to describe primary musculoskeletal tumors, when discussing treatment and prognosis for spine tumors including chordoma.18 En bloc resection with wide margins to prevent seeding and recurrence has been advocated as the only means to achieve cure,6 whereas intralesional resection without effective adjuvant therapy has proven to be less effective for local control.32,59,62 En bloc resection is invasive and often associated with a high risk for complication, but it has proven to be effective in lengthening survival and maintaining local control better than any other method shown to date.3,4,6,7,9,13,17,20,25,27,34,39,42–44,49,55

While en bloc resection is the treatment of choice for chordoma, not all chordomas are conducive to en bloc resection to achieve marginal or wide margins due to their relationship to other vital structures such as the spinal cord or vertebral arteries.23,31 However, some authors have argued that aggressive resection is indicated even in the face of severe neurological sacrifice. With up to 32% of reported chordomas arising in the mobile spine, there remains a need to explore alternatives to traditional en bloc treatment in such complex cases with unique anatomical constraints.31,38 While traditionally thought to be the quintessential radioresistant tumor, chordomas have recently been shown to respond positively to surgery followed by adjuvant single-fraction stereotactic body radiation therapy (SBRT).31 With improved technology and the ability to define more conformal radiation margins, single-fraction SBRT provides a safer alternative for tumors not amenable to en bloc resection with wide margins while still achieving appropriate tumor control and preventing disease progression.31 We report on a single-institution series of 12 patients who underwent intralesional resection with separation surgery followed by adjuvant SBRT.

Methods

IRB approval was obtained. We identified 22 patients with a histologically confirmed diagnosis of chordoma in the mobile spine who underwent resection followed by SBRT at Memorial Sloan Kettering Cancer Center (MSKCC) from 2004 to 2016. Patients who underwent spinal SBRT within 4 months following surgery were included. Patients were considered to have undergone SBRT if they had received 5 or fewer fractions of high-dose radiation. Of the 22 patients undergoing resection, 13 met inclusion criteria of having undergone resection followed by SBRT treatment as defined above. One patient was excluded because of a lack of follow-up imaging. The remaining 12 patients were subsequently divided into two cohorts: Cohort 1 was composed of those whose initial chordoma treatment was at MSKCC and Cohort 2 was composed of those whose initial treatment was elsewhere and whose current salvage treatment was at MSKCC. Cohort 1 contained 5 patients and Cohort 2 contained 7 patients.

Patient and tumor characteristics, treatments, and follow-up information were collected through a retrospective review of a prospectively maintained database. Each patient had at least one documented imaging modality for review. For each patient, all imaging and radiology reports (CT, MRI, and plain radiography) were reviewed from the time of treatment until last follow-up for evidence of progression. Dates of all posttreatment images showing progression were noted and used for analysis of progression-free survival. Progression-free survival was defined as the time between SBRT and the next imaging modality demonstrating evidence of disease progression. Pretreatment, posttreatment, and follow-up MRI images were further reviewed to determine epidural spinal cord compression (ESCC) scores5 at the time of treatment, immediately posttreatment, and at the time of last follow-up. Treatment complications were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4. IBM SPSS statistical software was used to perform Kaplan-Meier analysis.

Spine SBRT was performed as previously described.61 Briefly, patients underwent simulation with CT images with 2-mm slice thickness. A myelogram or MRI fusion was used to delineate spinal cord anatomy and tumor volumes. Patients were immobilized using a patient-customized cradle for both simulation and treatment.60 Treatment planning was performed using either Top Module (MSKCC, in-house software) or Eclipse (Varian Medical Systems); we used an inverse treatment planning—typically 5–7 radiation beams around a single isocenter with intensity modulation controlled with multileaf collimators. The gross tumor volume was outlined according to CT and MRI images after consensus review by the treating radiation oncologist and neurosurgeon. The clinical target volume encompassed gross tumor volume and areas of potential microscopic spread. The planning target volume was a 2-mm expansion from the clinical target volume, excluding the thecal sac and also the esophagus if abutting gross tumor volume. The prescribed dose ranged from 24 Gy in 1 fraction to 24–36 Gy in 3 fractions, and the dose was prescribed to the 100% isodose line as allowed by dose constraints for organs-at-risk such as the spinal cord, esophagus, and bowels. Treatment was delivered with a LINAC (linear accelerator) using 6-mV and/or 15-mV photons. Cone-beam CT scans were used to verify patient positioning prior to treatment.

Results

Twelve patients met the inclusion criteria. Patient and tumor characteristics are summarized in Table 1. The majority of patients were men (75%), and the median age at surgery was 59 years (range 47–81 years). The median time between surgery and SBRT was 40 days (range 19–124 days). The median follow-up duration from SBRT was 26 months (range 1.7–89 months). Six cervical, 4 thoracic, and 2 lumbar spine tumors were treated.

TABLE 1.

Patient and tumor characteristics

Patient CharacteristicsAll Patients (n = 12)Cohort 1 (n = 5)Cohort 2 (n = 7)
Age at op, median (range), yrs59 (47–81)61 (56–81)59 (47–78)
Age group, no. (%), yrs
  ≤551 (8)0 (0)2 (28.6)
  55–646 (46)3 (60)2 (28.6)
  ≥656 (46)2 (40)3 (42.8)
Sex, no. (%)
  Male8 (62)2 (40)5 (71.4)
  Female5 (38)3 (60)2 (28.6)
Days btwn op & SBRT, median (range)40 (19–124)40 (22–50)40 (19–124)
Mos btwn SBRT & last FU, median (range)37.3 (1.7–89)65.4 (14–89)10.7 (1.7–82)
Levels treated, no. (%)
  Cervical6 (50)3 (60)3 (42.8)
  Thoracic4 (33.3)1 (20)3 (42.8)
  Lumbar2 (16.7)1 (20)1 (14.3)

FU = follow-up.

Radiation treatment details are shown in Table 2. The majority of patients were treated with either 24 Gy in 1 fraction or 27 Gy in 3 fractions, while the remaining patients were treated in 3 fractions to a total dose ranging from 24 Gy to 36 Gy. Four patients (33%) received p32 plaque brachytherapy intraoperatively at the time of surgical curettage. Six patients overall (50%), all in Cohort 2 (85.7%), had received prior radiation at the site—4 received prior SBRT and 2 received prior radiation therapy with conventional fractionation.

TABLE 2.

Radiation treatment characteristics

Radiation CharacteristicsNo. of Patients (%)
All Patients (n = 12)Cohort 1 (n = 5)Cohort 2 (n = 7)
SBRT dose & fractionation
  24 Gy/1 fraction6 (50)3 (60)3 (42.8)
  24 Gy/3 fractions1 (8.3)0 (0)1 (14.3)
  27 Gy/3 fractions3 (25)2 (40)1 (14.3)
  30 Gy/3 fractions1 (8.3)0 (0)1 (14.3)
  36 Gy/3 fractions1 (8.3)0 (0)1 (14.3)
Intraop p32 plaque brachytherapy
  No8 (67)4 (80)4 (57.1)
  Yes4 (33)1 (20)3 (42.8)
Prior radiation at site
  No6 (50)5 (100)1 (14.3)
  Yes6 (50)0 (0)6 (85.7)
No. of contiguous levels treated w/SBRT
  13 (25)2 (40)1 (14.3)
  21 (8.3)1 (20)0 (0)
  35 (41.7)1 (20)4 (57.1)
  43 (25)1 (20)2 (28.6)

Surgical and SBRT complications are detailed in Table 3. Overall, 75% of patients experienced complications, with 41.7% experiencing CTCAE Grade 3 or higher complications. There were 2 Grade 1 toxicities, 4 Grade 2 toxicities, 4 Grade 3 toxicities, and 1 Grade 4 toxicity reported. There were no reported Grade 5 toxicities. Grade 1 toxicities included dermatitis and fracture. Grade 2 toxicities included dysphagia, xerostomia, spinal cord T2 signal change on MRI, and deep vein thrombosis. Radiation-associated major complications occurred in 27% of patients, and included dysphagia, mucositis, and vocal cord paralysis that occurred 4 years after radiation therapy. Two complications directly related to surgery included a rod fracture that occurred 4 years postoperatively and a wound dehiscence after a reoperation for tumor recurrence in Cohort 2, resulting in a surgical complication frequency of 18%.

TABLE 3.

Surgical and radiation complications

CTCAEAll PatientsCohort 1Cohort 2
No.ToxicityNo.Toxicity
Grade 121Compression fracture1Dermatitis
Grade 244Dysphagia, xerostomia, MRI spinal cord signal change, DVT0NA
Grade 344Dysphagia, mucositis, hardware failure, vocal cord paralysis0NA
Grade 410NA1Wound dehiscence

DVT = deep vein thrombosis; NA = not applicable.

Table 4 provides a summary of clinical information for each patient. Of the 5 patients in Cohort 1, only 1 had local progression at last follow-up, resulting in a local control rate of 80% at last follow-up. Cohort 1 had a median post-SBRT follow-up period of 65.9 months; Cohort 2 had a median follow-up duration of 10.7 months, with 3 patients having progression, for a local control rate of 57.1% at last follow-up.

TABLE 4.

Radiation and surgical characteristics by patient

Patient No.SexAgeTumor LocationNo. of Previous OpsPrevious RT Gy/No. of FractionsSBRT Dose Gy/No. of FractionsESCC ScoreTime to Progression (mos)Overall Survival (mos)Complications (CTCAE Grade)Cause of Death
PreopPostopFU
Cohort 1
1M81T12NANA27/331cNANA52.3NANA
2F57C4–C6NANA24/131b0NA67.9Vocal cord paralysis (3)NA
3F61C1–C3NANA24/131a048.291.9Dysphagia (3)NA
4F56C2NANA24/11c1b1aNA16.0Dysphagia (2), xerostomia (2), mucositis (3), T2 cord signal change (2)GI hemorrhage
5M75L4NANA24/11c00NA72.2L-4 compression fracture (1), rod fracture (3),* DVT (2)*NA
Mean48.260.1
Median48.267.9
Cohort 2
6M77L2127/324/131bNA76.3105.9Wound dehiscence requiring plastic surgery (4)*Sepsis
7M56C4–C6274/4024/331cNA1.963.2RUE paresis (2)Unknown
8M55T5–T7136/324/131a1aNA59.9Dermatitis (1), RT myelitis (1)NA
9M59T3–T4130/330/330NANA1.7RUE paresis (2)Meningitis
10F67T11–L1517.7/527/333NA2.969.5NoneNA
11M78C4–C52NA36/3321bNA27.1RUE paresis (2)NA
12M47T9–T11170/3924/11b1a0NA32.0NoneUnknown
Mean27.051.3
Median2.959.9
Overall
Mean32.355.0
Median25.661.6

GI = gastrointestinal; RT = radiation therapy; RUE = right upper extremity.

Indicates surgical complication.

Kaplan-Meier curves for overall survival are shown in Fig. 1. At 2 years, actuarial overall survival was 80% for Cohort 1 and 85.7% for Cohort 2. The mean actuarial estimations of overall survival were 76.6 months (95% CI 50.1–103.2 months) and 68.6 months (95% CI 32–104.6 months) for Cohort 1 and for Cohort 2, respectively. Analysis of combined cohort data revealed an estimated overall survival of 77.6 months (95% CI 52–103.3 months).

FIG. 1.
FIG. 1.

Kaplan-Meier curve for overall survival for Cohorts 1 (blue) and 2 (green) after surgery followed by SBRT.

Illustrative Cases

Cohort 1

A 57-year-old woman presented with a 6-month history of neck stiffness and hand clumsiness. She also reported a 1-month history of anterior thigh hyperesthesia but denied weakness, numbness, or vesicorectal dysfunction. MRI of the cervical spine, ordered by her primary care physician, revealed a mass involving the C-5 and C-6 vertebral bodies (Fig. 2A) with a large epidural component and severe spinal cord compression (ESCC Grade 3) with spinal cord edema. Examination revealed full strength throughout but diminished dexterity in both hands. She underwent CT-guided needle biopsy, the results of which revealed a chordoma. She was started on a course of dexamethasone and scheduled for surgery. She underwent C4–7 laminectomies, resection of the epidural component of the tumor, posterior C2–T2 instrumented fusion, C-5 and C-6 corpectomies, placement of a Harms titanium mesh cage (DePuy Spine), and anterior plate fixation (Fig. 3). A p32 plaque was also placed intraoperatively to deliver temporary high-dose irradiation. Her immediate postoperative ESCC grade was 1b (Fig. 2B). She had, as anticipated, self-limited mild dysphagia in the perioperative period, and her hand coordination improved. She underwent adjuvant single-fraction radiation treatment, to 24 Gy, 2 months postoperatively. Most recent imaging, 5.25 years later, showed continued tumor control, with ESCC score of 0 (Fig. 2C). She developed delayed radiation-associated unilateral vocal cord paralysis several years postoperatively, for which she underwent a vocal cord medialization and for which symptomatic recovery was good. She remains ambulatory and had a Karnofsky Performance Scale score of 90 at last follow-up.

FIG. 2.
FIG. 2.

Imaging for Patient 2 in Cohort 1. A: Preoperative axial and sagittal MR images demonstrating ESCC Grade 3. B: Postoperative axial MR image demonstrating ESCC Grade 1b. C: Long-term follow-up axial MR image demonstrating progressive resolution of chordoma, now ESCC Grade 0.

FIG. 3.
FIG. 3.

Anteroposterior (A) and lateral (B) postoperative radiographs demonstrating anterior and posterior instrumented fixation.

Cohort 2

A 78-year-old man with a history of melanoma initially presented to an outside institution with progressive right hand pain. MRI of the spine revealed a C-5 centered mass with cranial and caudal epidural extension as well as high-grade spinal cord compression. He underwent C-5 corpectomy with intralesional curettage and C3–7 laminectomies and placement of posterior instrumentation at the outside institution. Intraoperative pathological examination revealed chordoma. He was recommended radiotherapy at that time but refused, electing for observation. Five months later, MRI showed progression of his residual tumor. Subsequent MRI, then 8 months after surgery, demonstrated significant progression of disease (ESCC Grade 3), with encasement and displacement of the right vertebral artery, and encasement of the C-5 and C-6 nerve roots on the right. He underwent repeat resection and decompression of the spinal cord at the same outside institution. He subsequently sought care at MSKCC when his right hand pain returned and he developed proximal Grade 3/5 right upper-extremity weakness. MRI demonstrated aggressive recurrence with ESCC Grade 3 (Fig. 4A). He then underwent repeat anterior and posterior cervical resection with removal of epidural tumor and intraoperative radiation with a p32 plaque. Postoperatively his ESCC score was 2 (Fig. 4B). One month postoperatively he received SBRT (total dose 36 Gy given in 3 fractions). His most recent imaging study (9 months) revealed excellent tumor control with ESCC score of 1b (Fig. 4C). His proximal right upper-extremity weakness did not improve and he has home health assistance.

FIG. 4.
FIG. 4.

Imaging for Patient 11 in Cohort 2. A: Preoperative axial and sagittal MR images demonstrating ESCC Grade 3. B: Postoperative axial MR image demonstrating ESCC Grade 2. C: Axial MR image 8 months post-SBRT demonstrating continued retraction of the tumor and ESCC 1b.

Discussion

While data accumulate on proton58 and carbon ion radiotherapy29,52 for treatment of chordoma, there is growing evidence for high-dose-perfraction conformal photon irradiation as well. Single-fraction high-dose spinal radiosurgery has been shown to achieve local control in greater than 90% of metastatic tumors, even to traditionally classified radioresistant tumors such as melanoma and renal cell carcinoma.60 Additionally, several small studies have demonstrated promising results using radiosurgery for skull base chordomas,35–37 as well as mobile spine and sacral chordomas.61 Photon therapy has advantages compared with particle radiation in that it is more accessible, and spinal hardware does not diminish photon therapy efficacy while hardware does affect the efficacy of particle therapy.46 In this series we present effective control of chordoma without the use of en bloc resection with wide margins, but with curettage, intralesional resection or separation surgery followed by high-dose conformal radiation therapy. As seen in the two case examples, tumor volume decreases following intralesional surgery and high-dose SBRT as evidenced by the change in ESCC score. Patients are spared morbidity but achieve adequate tumor control. While chordomas have been considered radioresistant, the response to high-dose SBRT is encouraging. High-dose-perfraction radiation may offer radiobiological advantages compared with conventionally fractionated radiotherapy when treating chorodmas.61 Higher doses may result in greater irreparable and lethal DNA damage10 and may also have the additional advantage of inducing tumor endothelial dysfunction, a phenomenon observed in high-dose treatments.22 Additionally, high-dose-perfraction radiation may stimulate a cytotoxic T-cell–mediated immunogenic effect, further potentiating radiotherapy.33

Molina et al. presented a multiinstitutional case series in which en bloc resection of cervical chordomas was attempted.40 Upper cervical spine (C-1 and C-2) chordomas were associated with a dramatically higher rate of complications compared with subaxial chordomas (71% vs 22%, respectively) and higher rates of recurrence. Given the complex vascular, osseoligamentous, and important neuroanatomy that presents unique surgical challenges in cases of atlantoaxial chordomas, and given the significantly higher rate of complications, the authors advocated intralesional resection for C-1 and C-2 chordomas rather than en bloc resection. Our study provides further support to their conclusion, as the one recurrence in Cohort 1 occurred in the case of a C1–3 chordoma. This patient has obtained durable control after intralesional curettage and high-dose-perfraction photon irradiation in a follow-up period of nearly 92 months. Following 48.2 months of progression-free survival after initial surgery and SBRT, the patient then underwent a second radiation treatment in which 27 Gy of radiation was delivered in 3 fractions without further surgery, providing an additional 43.6 additional months of local control while sparing the patient the increased risk of neurological morbidity from attempted en bloc resection.

In this series, patients in Cohort 1 experienced better outcomes with a local tumor control rate of 80%, while patients in Cohort 2 had a local tumor control rate of 57.1%. Furthermore, among patients who had disease progression, the median time to progression was 48.2 months compared to a median of 2.9 months in Cohort 2 (Table 4). Since local control was greater than 50% in both cohorts, a median time to failure was not reached. Of those in Cohort 2 whose treatment failed, 2 of the 3 patients had rapid disease progression following treatment. Patients with chordoma often undergo multiple operations, and the first operation is the best chance at optimal outcome.6 Our data are consistent with this “first shot” principle and with Choi et al., who found that patients who had undergone prior resections at outside institutions before seeking treatment at specialized centers had lower survival rates.12

Although the possibility of “seeding” was previously described as strong evidence for en bloc resection,2 it is noteworthy that no patients in this study demonstrated recurrence along the surgical tract of the surgical wound, despite intralesional curettage surgical technique.

We found that 42% of patients had significant complications associated with surgery and radiation therapy. Surgery for primary tumors of the spine carries a significant risk of morbidity. C1–2 chordomas have been reported to have a 71% risk of complications.40 The authors of a series reviewing the complications of 220 en bloc spinal operations reported that 33% of their patients had major surgical complications, with those harboring primary malignant spinal tumors having a higher risk of complications.8 One study with long-term follow-up after proton radiotherapy for chordoma noted a Grade 3–4 toxicity risk of 13%.15 The surgical complication frequency of 18% reported in the present series, which included a delayed rod fracture 4 years after surgery, compares favorably with the surgical complication frequency reported in other series. Furthermore, none of our patients experienced the severe neurological and systemic complication reported after en bloc surgery. Among the radiation-associated complications currently reported, 2 patients had self-limited complications and only 1 patient had a persisting complication (vocal cord paralysis). Currently used esophageal dose constraints have resulted in a significantly decreased risk of esophageal toxicity.14

In the coming era, quality of life may become an increasing consideration in the treatment of chordoma, particularly in light of potentially effective adjuvant approaches on the horizon. A focus on targeted therapy including via receptor tyrosine kinase blockade as justified by the involvement of canonical oncological mechanisms, for example via the PI3K-AKT-mTOR and RAS-MAPK pathways, has yielded some promising early reports of response.1,11,16,24,47,51,53,54,56 Preclinical success with direct inhibition of the master transcription factor brachyury has led to optimism that this may be used as a therapeutic vulnerability clinically.28 Additionally, interest in radiosensitization, vaccines, and immunotherapies, and with novel mechanistic insight from emerging from epigenetic discovery approaches, may potentially allow for future therapy abrogating the need for strategies emphasizing surgical cure via wide marginal excision.19,21,26,41,45,48

Conclusions

Intralesional debulking and separation surgery followed by SBRT for chordoma of the mobile spine provides excellent local control for patients in whom aggressive en bloc resection with wide margins is not feasible. High-dose-perfraction irradiation may provide biological benefits compared with conventional radiotherapy. Data from our series compare favorably with those in existing literature concerning local control.

Acknowledgments

This work was supported in part by the MSKCC Support Grant (NIH/NCI P30 CA008748).

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    Hsu KYZucherman JFMortensen NJohnston JOGartland J: Follow-up evaluation of resected lumbar vertebral chordoma over 11 years: a case report. Spine (Phila Pa 1976) 25:253725402000

  • 28

    Hsu WMohyeldin AShah SRap Rhys CMJohnson LFSedora-Roman NI: Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target. J Neurosurg 115:7607692011

  • 29

    Imai RKamada TTsuji HYanagi TBaba MMiyamoto T: Carbon ion radiotherapy for unresectable sacral chordomas. Clin Cancer Res 10:574157462004

  • 30

    Jemal ASiegel RWard EMurray TXu JThun MJ: Cancer statistics, 2007. CA Cancer J Clin 57:43662007

  • 31

    Jung EWJung DLBalagamwala EHAngelov LSuh JHDjemil T: Single-fraction spine stereotactic body radiation therapy for the treatment of chordoma. Technol Cancer Res Treat [epub ahead of print]2016

  • 32

    Kaloostian PEGokaslan ZL: Surgical management of primary tumors of the cervical spine: surgical considerations and avoidance of complications. Neurol Res 36:5575652014

  • 33

    Kaur PAsea A: Radiation-induced effects and the immune system in cancer. Front Oncol 2:1912012

  • 34

    Kayani BSewell MDTan KAHanna SAWilliams RPollock R: Prognostic factors in the operative management of sacral chordomas. World Neurosurg 84:135413612015

  • 35

    Krishnan SFoote RLBrown PDPollock BELink MJGarces YI: Radiosurgery for cranial base chordomas and chondrosarcomas. Neurosurgery 56:7777842005

  • 36

    Lunsford LDNiranjan AMartin JJSirin SKassam AKondziolka D: Radiosurgery for miscellaneous skull base tumors. Prog Neurol Surg 20:1922052007

  • 37

    Martin JJNiranjan AKondziolka DFlickinger JCLozanne KALunsford LD: Radiosurgery for chordomas and chondrosarcomas of the skull base. J Neurosurg 107:7587642007

  • 38

    McMaster MLGoldstein AMBromley CMIshibe NParry DM: Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12:1112001

  • 39

    Meng TYin HLi BLi ZXu WZhou W: Clinical features and prognostic factors of patients with chordoma in the spine: a retrospective analysis of 153 patients in a single center. Neuro Oncol 17:7257322015

  • 40

    Molina CAAmes CPChou DRhines LDHsieh PCZadnik PL: Outcomes following attempted en bloc resection of cervical chordomas in the C-1 and C-2 region versus the subaxial region: a multiinstitutional experience. J Neurosurg Spine 21:3483562014

  • 41

    Moussazadeh NBerman SHLaufer IGounder MZheng YSommer J: Epigenetic profiling reveals a unique histone code in chordoma. Neurosurgery 63:Suppl 12082016. (Abstract #365)

  • 42

    Mukherjee DChaichana KLAdogwa OGokaslan ZAaronson OCheng JS: Association of extent of local tumor invasion and survival in patients with malignant primary osseous spinal neoplasms from the Surveillance, Epidemiology, and End Results (SEER) database. World Neurosurg 76:5805852011

  • 43

    Mukherjee DChaichana KLGokaslan ZLAaronson OCheng JSMcGirt MJ: Survival of patients with malignant primary osseous spinal neoplasms: results from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2003. J Neurosurg Spine 14:1431502011

  • 44

    Ozaki THillmann AWinkelmann W: Surgical treatment of sacrococcygeal chordoma. J Surg Oncol 64:2742791997

  • 45

    Patel SSSchwab JH: Immunotherapy as a potential treatment for chordoma: a review. Curr Oncol Rep 18:552016

  • 46

    Pennicooke BLaufer ISahgal AVarga PPGokaslan ZLBilsky MH: Safety and local control of radiation therapy for chordoma of the spine and sacrum: a systematic review. Spine (Phila Pa 1976) 41:Suppl 20S186S1922016

  • 47

    Presneau NShalaby AIdowu BGikas PCannon SRGout I: Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway. Br J Cancer 100:140614142009

  • 48

    Rhomberg WEiter HBöhler FDertinger S: Combined radiotherapy and razoxane in the treatment of chondrosarcomas and chordomas. Anticancer Res 26:240724112006

  • 49

    Ruggieri PAngelini AUssia GMontalti MMercuri M: Surgical margins and local control in resection of sacral chordomas. Clin Orthop Relat Res 468:293929472010

  • 50

    Samson IRSpringfield DSSuit HDMankin HJ: Operative treatment of sacrococcygeal chordoma. A review of twenty-one cases. J Bone Joint Surg Am 75:147614841993

  • 51

    Schwab JAntonescu CBoland PHealey JRosenberg ANielsen P: Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma. Anticancer Res 29:186718712009

  • 52

    Serizawa IImai RKamada TTsuji HKishimoto RKandatsu S: Changes in tumor volume of sacral chordoma after carbon ion radiotherapy. J Comput Assist Tomogr 33:7957982009

  • 53

    Stacchiotti SMarrari ATamborini EPalassini EVirdis EMessina A: Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol 20:188618942009

  • 54

    Stacchiotti STamborini ELo Vullo SBozzi FMessina AMorosi C: Phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol 24:193119362013

  • 55

    Sundaresan NSteinberger AAMoore FSachdev VPKrol GHough L: Indications and results of combined anterior-posterior approaches for spine tumor surgery. J Neurosurg 85:4384461996

  • 56

    Tamborini EVirdis ENegri TOrsenigo MBrich SConca E: Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. Neuro Oncol 12:7767892010

  • 57

    Tzortzidis FElahi FWright DNatarajan SKSekhar LN: Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas. Neurosurgery 59:2302372006

  • 58

    Wagner TDKobayashi WDean SGoldberg SIKirsch DGSuit HD: 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 73:2592662009

  • 59

    Wang YXiao JWu ZHuang QHuang WZhu Q: Primary chordomas of the cervical spine: a consecutive series of 14 surgically managed cases. J Neurosurg Spine 17:2922992012

  • 60

    Yamada YBilsky MHLovelock DMVenkatraman ESToner SJohnson J: High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 71:4844902008

  • 61

    Yamada YLaufer ICox BWLovelock DMMaki RGZatcky JM: Preliminary results of high-dose single-fraction radiotherapy for the management of chordomas of the spine and sacrum. Neurosurgery 73:6736802013

  • 62

    Yao KCBoriani SGokaslan ZLSundaresan N: En bloc spondylectomy for spinal metastases: a review of techniques. Neurosurg Focus 15:5E62003

Disclosures

Dr. Yamada is a consultant for Varian Medical Systems and on the Speakers' Bureau of the Institute for Medical Education. Dr. Laufer receives consulting fees from DePuy/Synthes, SpineWave, and Globus. Dr. Bilsky receives consulting fees from DePuy/Synthes, Globus, and BrainLab. Dr. Lis reports being a consultant for Medtronic.

Author Contributions

Conception and design: Bilsky, Yamada, Schmitt, Laufer. Acquisition of data: Bilsky, DT Lockney, Shub, Hopkins, Lis, Yamada, Higginson. Analysis and interpretation of data: Bilsky, DT Lockney, Hopkins, NA Lockney, Lis, Schmitt, Higginson, Laufer. Drafting the article: DT Lockney, Hopkins, NA Lockney, Moussazadeh, Laufer. Critically revising the article: Bilsky, DT Lockney, Shub, Hopkins, NA Lockney, Moussazadeh, Schmitt, Laufer. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Bilsky. Statistical analysis: DT Lockney, NA Lockney, Laufer. Administrative/technical/material support: Bilsky. Study supervision: Bilsky, Laufer.

Supplemental Information

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Article Information

INCLUDE WHEN CITING DOI: 10.3171/2016.9.FOCUS16373.

Correspondence Mark Bilsky, Department of Neurological Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065. email: bilskym@mskcc.org.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Kaplan-Meier curve for overall survival for Cohorts 1 (blue) and 2 (green) after surgery followed by SBRT.

  • View in gallery

    Imaging for Patient 2 in Cohort 1. A: Preoperative axial and sagittal MR images demonstrating ESCC Grade 3. B: Postoperative axial MR image demonstrating ESCC Grade 1b. C: Long-term follow-up axial MR image demonstrating progressive resolution of chordoma, now ESCC Grade 0.

  • View in gallery

    Anteroposterior (A) and lateral (B) postoperative radiographs demonstrating anterior and posterior instrumented fixation.

  • View in gallery

    Imaging for Patient 11 in Cohort 2. A: Preoperative axial and sagittal MR images demonstrating ESCC Grade 3. B: Postoperative axial MR image demonstrating ESCC Grade 2. C: Axial MR image 8 months post-SBRT demonstrating continued retraction of the tumor and ESCC 1b.

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Hsu KYZucherman JFMortensen NJohnston JOGartland J: Follow-up evaluation of resected lumbar vertebral chordoma over 11 years: a case report. Spine (Phila Pa 1976) 25:253725402000

28

Hsu WMohyeldin AShah SRap Rhys CMJohnson LFSedora-Roman NI: Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target. J Neurosurg 115:7607692011

29

Imai RKamada TTsuji HYanagi TBaba MMiyamoto T: Carbon ion radiotherapy for unresectable sacral chordomas. Clin Cancer Res 10:574157462004

30

Jemal ASiegel RWard EMurray TXu JThun MJ: Cancer statistics, 2007. CA Cancer J Clin 57:43662007

31

Jung EWJung DLBalagamwala EHAngelov LSuh JHDjemil T: Single-fraction spine stereotactic body radiation therapy for the treatment of chordoma. Technol Cancer Res Treat [epub ahead of print]2016

32

Kaloostian PEGokaslan ZL: Surgical management of primary tumors of the cervical spine: surgical considerations and avoidance of complications. Neurol Res 36:5575652014

33

Kaur PAsea A: Radiation-induced effects and the immune system in cancer. Front Oncol 2:1912012

34

Kayani BSewell MDTan KAHanna SAWilliams RPollock R: Prognostic factors in the operative management of sacral chordomas. World Neurosurg 84:135413612015

35

Krishnan SFoote RLBrown PDPollock BELink MJGarces YI: Radiosurgery for cranial base chordomas and chondrosarcomas. Neurosurgery 56:7777842005

36

Lunsford LDNiranjan AMartin JJSirin SKassam AKondziolka D: Radiosurgery for miscellaneous skull base tumors. Prog Neurol Surg 20:1922052007

37

Martin JJNiranjan AKondziolka DFlickinger JCLozanne KALunsford LD: Radiosurgery for chordomas and chondrosarcomas of the skull base. J Neurosurg 107:7587642007

38

McMaster MLGoldstein AMBromley CMIshibe NParry DM: Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control 12:1112001

39

Meng TYin HLi BLi ZXu WZhou W: Clinical features and prognostic factors of patients with chordoma in the spine: a retrospective analysis of 153 patients in a single center. Neuro Oncol 17:7257322015

40

Molina CAAmes CPChou DRhines LDHsieh PCZadnik PL: Outcomes following attempted en bloc resection of cervical chordomas in the C-1 and C-2 region versus the subaxial region: a multiinstitutional experience. J Neurosurg Spine 21:3483562014

41

Moussazadeh NBerman SHLaufer IGounder MZheng YSommer J: Epigenetic profiling reveals a unique histone code in chordoma. Neurosurgery 63:Suppl 12082016. (Abstract #365)

42

Mukherjee DChaichana KLAdogwa OGokaslan ZAaronson OCheng JS: Association of extent of local tumor invasion and survival in patients with malignant primary osseous spinal neoplasms from the Surveillance, Epidemiology, and End Results (SEER) database. World Neurosurg 76:5805852011

43

Mukherjee DChaichana KLGokaslan ZLAaronson OCheng JSMcGirt MJ: Survival of patients with malignant primary osseous spinal neoplasms: results from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2003. J Neurosurg Spine 14:1431502011

44

Ozaki THillmann AWinkelmann W: Surgical treatment of sacrococcygeal chordoma. J Surg Oncol 64:2742791997

45

Patel SSSchwab JH: Immunotherapy as a potential treatment for chordoma: a review. Curr Oncol Rep 18:552016

46

Pennicooke BLaufer ISahgal AVarga PPGokaslan ZLBilsky MH: Safety and local control of radiation therapy for chordoma of the spine and sacrum: a systematic review. Spine (Phila Pa 1976) 41:Suppl 20S186S1922016

47

Presneau NShalaby AIdowu BGikas PCannon SRGout I: Potential therapeutic targets for chordoma: PI3K/AKT/TSC1/TSC2/mTOR pathway. Br J Cancer 100:140614142009

48

Rhomberg WEiter HBöhler FDertinger S: Combined radiotherapy and razoxane in the treatment of chondrosarcomas and chordomas. Anticancer Res 26:240724112006

49

Ruggieri PAngelini AUssia GMontalti MMercuri M: Surgical margins and local control in resection of sacral chordomas. Clin Orthop Relat Res 468:293929472010

50

Samson IRSpringfield DSSuit HDMankin HJ: Operative treatment of sacrococcygeal chordoma. A review of twenty-one cases. J Bone Joint Surg Am 75:147614841993

51

Schwab JAntonescu CBoland PHealey JRosenberg ANielsen P: Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma. Anticancer Res 29:186718712009

52

Serizawa IImai RKamada TTsuji HKishimoto RKandatsu S: Changes in tumor volume of sacral chordoma after carbon ion radiotherapy. J Comput Assist Tomogr 33:7957982009

53

Stacchiotti SMarrari ATamborini EPalassini EVirdis EMessina A: Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol 20:188618942009

54

Stacchiotti STamborini ELo Vullo SBozzi FMessina AMorosi C: Phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol 24:193119362013

55

Sundaresan NSteinberger AAMoore FSachdev VPKrol GHough L: Indications and results of combined anterior-posterior approaches for spine tumor surgery. J Neurosurg 85:4384461996

56

Tamborini EVirdis ENegri TOrsenigo MBrich SConca E: Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. Neuro Oncol 12:7767892010

57

Tzortzidis FElahi FWright DNatarajan SKSekhar LN: Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas. Neurosurgery 59:2302372006

58

Wagner TDKobayashi WDean SGoldberg SIKirsch DGSuit HD: 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 73:2592662009

59

Wang YXiao JWu ZHuang QHuang WZhu Q: Primary chordomas of the cervical spine: a consecutive series of 14 surgically managed cases. J Neurosurg Spine 17:2922992012

60

Yamada YBilsky MHLovelock DMVenkatraman ESToner SJohnson J: High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys 71:4844902008

61

Yamada YLaufer ICox BWLovelock DMMaki RGZatcky JM: Preliminary results of high-dose single-fraction radiotherapy for the management of chordomas of the spine and sacrum. Neurosurgery 73:6736802013

62

Yao KCBoriani SGokaslan ZLSundaresan N: En bloc spondylectomy for spinal metastases: a review of techniques. Neurosurg Focus 15:5E62003

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