Updated Outcome and Analysis of Tumor Response in Mobile Spine and Sacral Chordoma Treated With Definitive High-Dose Photon/Proton Radiation Therapy

doi:10.1016/j.ijrobp.2016.10.006

International Journal of Radiation OncologyBiologyPhysics

Volume 97, Issue 2, 1 February 2017, Pages 254-262

https://doi.org/10.1016/j.ijrobp.2016.10.006 Get rights and content

Purpose

Treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy. In certain circumstances where resection may result in significant neurologic or organ dysfunction, patients can be treated definitively with radiation therapy alone. Herein, we report the outcome and the assessment of tumor response to definitive radiation therapy.

Methods and Materials

A retrospective analysis was performed on 40 patients with unresected chordoma treated with photon/proton radiation therapy. Nineteen patients had complete sets of imaging scans. The soft tissue and bone compartments of the tumor were defined separately. Tumor response was evaluated by the modified Response Evaluation Criteria in Solid Tumors (RECIST) and volumetric analysis.

Results

With a median follow-up time of 50.3 months, the rates of 5-year local control, overall survival, disease-specific survival, and distant failure were 85.4%, 81.9%, 89.4%, and 20.2%, respectively. Eighty-four computed tomographic and magnetic resonance imaging scans were reviewed. Among the 19 patients, only 4 local failures occurred, and the median tumor dose was 77.4 GyRBE. Analysis at a median follow-up time of 18 months showed significant volumetric reduction of the total target volume (TTV) and the soft tissue target volume (STTV) within the first 24 months after treatment initiation, followed by further gradual reduction throughout the rest of the follow-up period. The median maximum percentage volumetric regressions of TTV and STTV were 43.2% and 70.4%, respectively. There was only a small reduction in bone target volume over time. In comparison with the modified RECIST, volumetric analysis was more reliable, more reproducible, and could help in measuring minimal changes in the tumor volume.

Conclusion

These results continue to support the use of high-dose definitive radiation therapy for selected patients with unresected spine and sacral chordomas. Assessment of tumor response to radiation therapy by volumetric analysis is superior to modified RECIST in chordoma patients. Evaluating the soft tissue target volume is an excellent indicator of tumor response.

Introduction

Chordomas are rare malignant tumors, with an incidence of approximately 1% to 4% of all malignant bone tumors. They are known to develop anywhere along the spinal axis (32% from the skull base, 32.8% from the spine, and 29.2% from the sacral region) (1). Surgical resection is the primary treatment of choice, and the quality of surgical margin is the most important risk factor for local control and survival 2, 3, 4. Unfortunately, because of the size of the tumor, its proximity to neurovascular structures, and the complex anatomy of abutting normal tissues, negative surgical margins may be difficult to achieve; they are achievable in only approximately 50% of patients with sacrococcygeal chordomas, for example 3, 4, 5. The local recurrence rate is about 50% to 100% after R1/R2 surgical resection compared with 0% to 53% after en bloc surgical resection with negative margins 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. Hence, treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with neoadjuvant or adjuvant radiation treatment to improve local control.

Radical en bloc resection, especially for tumors at or above S3, may lead to bowel and urinary incontinence in addition to other sensory and motor neurologic dysfunction 15, 16. In certain circumstances where resection may result in significant neurologic or organ dysfunction, patients can be treated definitively with radiation therapy alone. An initial retrospective study, conducted at our institution on 24 patients with unresected mobile spine chordoma who underwent definitive proton beam therapy, showed promising results. The rates of overall survival, chordoma-specific survival, local progression-free survival, and metastases-free survival were 78.1%, 81.5%, 79.8%, and 76.3% at 5 years, respectively (17). High rates of local control have also been reported with definitive carbon ion therapy (18).

The assessment of tumor response to therapy is vital in the quantification and evaluation of treatment efficacy in patients with chordoma who have undergone definitive external beam radiation treatment. In spite of efforts to standardize response metrics, variability in measurement techniques may lead to inconsistencies and misinterpretation of the results. One such traditional approach to evaluate treatment efficacy is measurement of tumor regression by the Response Evaluation Criteria in Solid Tumors (RECIST) (19). Another more accurate technique is volumetric tumor response analysis. The assessment of tumor response may identify patients with potentially nonresponsive tumors and direct future treatment(s).

Herein, we report an update of our previously published retrospective cohort (17) to further evaluate the response of such tumors to therapy and to define a reliable technique to characterize the tumor response to treatment in patients with spine and sacral chordoma treated with definitive radiation therapy.

Section snippets

Patient characteristics

A retrospective analysis was completed on 40 consecutive patients with unresected chordoma of the mobile or sacrococcygeal spine between 1975 and 2012. The treatment charts were reviewed to identify patients with chordoma of spine who were treated with primary photon/proton radiation therapy at Massachusetts General Hospital after only biopsy. The median age was 67 years (range, 36-94 years). All patients with recurrent disease or prior debulking, decompression, or partial or complete surgical

Oncologic outcomes

The median maximal tumor diameter was 7.7 cm (range, 1.4-25.5 cm; mean, 8.9 cm), and the median tumor volume was 174.4 cc (range, 4.5-2061 cc; mean, 417.8 cc). Twenty-seven patients had sacrococcygeal chordoma, and the rest of the patients in the cohort had tumors in the mobile spine (9 cervical, 1 thoracic, 3 lumbar). The median follow-up time for the entire cohort was 50.3 months from completion of radiation therapy (range, 2-216.4 months; mean, 65 months). The actuarial rates of overall

Discussion

Local control is paramount in the treatment of spine and sacral chordoma. Treatment usually involves surgical resection, ideally with negative surgical margins, and generally accompanied by neoadjuvant or adjuvant radiation treatment. For patients with localized disease, 5-year survival is approximately 68%, and tumor size plays an important risk factor in overall survival. The most important local control outcome factor for surgically treated patients is a negative surgical margin, which

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Cited by (63)

A Prospective Phase I/II Clinical Trial of High-Dose Proton Therapy for Chordomas and Chondrosarcomas
2024, Advances in Radiation Oncology
The purpose of this study was to evaluate the feasibility and safety of dose-escalated proton beam therapy for treating chordomas and chondrosarcomas of the skull base and spine. Methods: A prospective cohort of 54 patients (42 with chordomas and 12 with chondrosarcomas) was enrolled between 2010 and 2018. The primary endpoints were feasibility and <20% rate of acute grade ≥3 toxicity, and secondary endpoints included cancer-specific outcomes and toxicities. Patients were followed with magnetic resonance imaging or computed tomography at 3-month intervals. Proton beam therapy was delivered with doses up to 79.2 Gy using protons only, combination protons/intensity modulated radiation therapy (IMRT), or IMRT only.
Feasibility endpoints were met, with only 2 out of 54 patient radiation therapy plans failing to meet dosimetric constraints with protons, and 4 out of 54 experiencing a delay or treatment break >5 days, none for toxicities related to treatment. There were no grade 4 acute toxicities and 1 grade 3 acute toxicity (sensory neuropathy). The only 2 grade 3 late toxicities recorded, osteoradionecrosis and intranasal carotid blowout (mild and not emergently treated), occurred in a single patient. We report overall survival as 83% at 5 years, with local failure-free survival and progression-free survival rates of 72% and 68%, respectively. Five patients developed distant disease, and among the 9/54 patients who died, 4 deaths were not attributed to treatment or recurrence.
Our findings suggest that high-dose proton therapy alone or in combination with IMRT is a safe and effective treatment option for chordomas and chondrosarcomas of the skull base and spine.
Clinical outcomes and toxicities of 100 patients treated with proton therapy for chordoma on the proton collaborative group prospective registry
2023, Radiotherapy and Oncology
We present efficacy and toxicity outcomes among patients with chordoma treated on the Proton Collaborative Group prospective registry.
Consecutive chordoma patients treated between 2010–2018 were evaluated. One hundred fifty patients were identified, 100 had adequate follow-up information. Locations included base of skull (61%), spine (23%), and sacrum (16%). Patients had a performance status of ECOG 0–1 (82%) and median age of 58 years. Eighty-five percent of patients underwent surgical resection. The median proton RT dose was 74 Gy (RBE) (range 21–86 Gy (RBE)) using passive scatter proton RT (PS-PBT) (13%), uniform scanning proton RT (US-PBT) (54%) and pencil beam scanning proton RT (PBS-PBT) (33%). Rates of local control (LC), progression-free survival (PFS), overall survival (OS) and acute and late toxicities were assessed.
2/3-year LC, PFS, and OS rates are 97%/94%, 89%/74%, and 89%/83%, respectively. LC did not differ based on surgical resection (p = 0.61), though this is likely limited by most patients having undergone a prior resection. Eight patients experienced acute grade 3 toxicities, most commonly pain (n = 3), radiation dermatitis (n = 2), fatigue (n = 1), insomnia (n = 1) and dizziness (n = 1). No grade ≥ 4 acute toxicities were reported. No grade ≥ 3 late toxicities were reported, and most common grade 2 toxicities were fatigue (n = 5), headache (n = 2), CNS necrosis (n = 1), and pain (n = 1).
In our series, PBT achieved excellent safety and efficacy outcomes with very low rates of treatment failure. CNS necrosis is exceedingly low (<1%) despite the high doses of PBT delivered. Further maturation of data and larger patient numbers are necessary to optimize therapy in chordoma.
Definitive high-dose, proton-based radiation for unresected mobile spine and sacral chordomas
2022, Radiotherapy and Oncology
Citation Excerpt :
Our previous publication utilizing high dose definitive proton/photon radiation to treat chordoma reported a median follow up of 50.3 months with over all 3- and 5-year survival of 89.1% and 81.9% respectively. The 3 year and 5-year local control was reported at 96.9% and 85.4% respectively [16]. Additionally the HR for OS and LC for total dose per 1 Gy were 0.88 and 0.84 respectively, demonstrating a positive trend with higher doses of radiation therapy.
Treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy. In certain locations, resection may result in significant neurological dysfunction, so definitive radiation has been used as an alternative to surgery. The purpose of this study is to report the results of high-dose, proton-based definitive radiotherapy for unresected spinal and sacral chordomas.
Retrospective review of 67 patients with newly diagnosed, unresected spinal chordomas treated with high-dose definitive, proton-based radiotherapy at our center from 1975 to 2019.
Reasons for radiotherapy alone included medical inoperability and/or concern for neurological dysfunction based on spine level or patient choice. Tumor locations included cervical (n = 10), thoracic (n = 1), lumbar (n = 4) spine, and sacrum (n = 52). Median maximal tumor diameter was 7.4 cm (range 1.8–25 cm). Median total dose was 77.4 Gy (RBE) (range 73.8–85.9 Gy RBE). Analysis with median follow-up of 56.2 months (range, 4–171.7 months) showed overall survival of 83.5 % (95%CI: 69.4–91.5%) and 65.9% (95%CI: 47.3–79.3%), disease-free survival of 64% (95%CI: 49.3–75.4) and 44.1% (95%CI: 27.8–59.2%), local control of 81.8% (95%CI: 67.6–90.2%) and 63.6% (95%CI: 44.7–77.5%), and distant control of 77.4% (95%CI: 63.6–86.5%) and 72.5% (95%CI: 55.7–83.8%) at 5 and 8 years respectively. The most common late side effect was insufficiency fracture.
These results continue to support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected mobile spine or sacrococcygeal chordomas. There is a trend towards better disease-free survival with doses > 78 Gy (RBE).
Single-institution clinical experience using robust intensity modulated proton therapy in chordoma and chondrosarcoma of the mobile spine and sacrum: Feasibility and need for plan adaptation: Robust planning in chordoma of spine and sacrum
2022, Radiotherapy and Oncology
Due to its specific physical characteristics, proton irradiation is especially suited for irradiation of chordomas and chondrosarcoma in the axial skeleton. Robust plan optimization renders the proton beam therapy more predictable upon individual setup errors. Reported experience with the planning and delivery of robustly optimized plans in chordoma and chondrosarcoma of the mobile spine and sacrum, is limited. In this study, we report on the clinical use of robustly optimized, intensity modulated proton beam therapy in these patients.
We retrospectively reviewed patient, treatment and acute toxicity data of all patients with chordoma and chondrosarcoma of the mobile spine and sacrum, treated between 1 April 2019 and 1 April 2020 at our institute. Anatomy changes during treatment were evaluated by weekly cone-beam CTs (CBCT), supplemented by scheduled control-CTs or ad-hoc control-CTs. Acute toxicity was scored weekly during treatment and at 3 months after therapy according to CTCAE 4.0.
17 chordoma and 3 chondrosarcoma patients were included. Coverage of the high dose clinical target volume was 99.8% (range 56.1–100%) in the nominal and 80.9% (range 14.3–99.6%) in the voxel-wise minimum dose distribution. Treatment plan adaptation was needed in 5 out of 22 (22.7%) plans. Reasons for plan adaptation were either reduced tumor coverage or increased dose to the OAR.
Robustly optimized intensity modulated proton beam therapy for chordoma and chondrosarcoma of the mobile spine is feasible. Plan adaptations due to anatomical changes were required in approximately 23 percent of treatment courses.
Clinical Outcome of Sacral Chordoma Patients Treated with Pencil Beam Scanning Proton Therapy
2021, Clinical Oncology
Sacral chordomas are locally aggressive, radio-resistant tumours. Proton therapy has the potential to deliver high radiation doses, which may improve the therapeutic ratio when compared with conventional radiotherapy. We assessed tumour control and radiation-induced toxicity in a cohort of sacral chordoma patients treated with definitive or postoperative pencil beam scanning proton therapy.
Sixty patients with histologically proven sacral chordoma treated between November 1997 and October 2018 at the Paul Scherrer Institute with postoperative (n = 50) or definitive proton therapy (n = 10) were retrospectively analysed. Only 10 (17%) patients received combined photon radiotherapy and proton therapy. Survival rates were calculated using the Kaplan–Meier actuarial method. The Log-rank test was used to compare different functions for local control, freedom from distant recurrence and overall survival. Acute and late toxicity were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
The median follow-up was 48 months (range 4–186). Local recurrence occurred in 20 (33%) patients. The 4-year local control, freedom from distant recurrence and overall survival rates were 77%, 89% and 85%, respectively. On univariate analysis, subtotal resection/biopsy (P = 0.02), tumour extension restricted to bone (P = 0.01) and gross tumour volume >130 ml (P = 0.04) were significant predictors for local recurrence. On multivariate analysis, tumour extension restricted to bone (P = 0.004) and gross total resection (P = 0.02) remained independent favourable prognostic factors for local recurrence. Twenty-four (40%), 28 (47%) and eight (11%) patients experienced acute grade 1, 2 and 3 toxicities, respectively. The 4-year late toxicity-free survival was 91%. Two patients developed secondary malignancies to the bladder 3–7 years after proton therapy.
Our data indicate that pencil beam scanning proton therapy for sacral chordomas is both safe and effective. Gross total resection, tumour volume <130 ml and tumour restricted to the bone are favourable prognostic factors for local tumour control.
Chordoma: Current status, problems, and future directions
2021, Current Problems in Cancer
Chordoma is a rare tumor that occurs along the axial spine in pediatrics and adults, with an incidence of approximately 350 cases per year in the United States. While typically described as slow-growing, many patients will eventually develop loco-regional relapse or metastatic disease with few treatment options. Despite numerous efforts over the last 10+ years, effective treatments for patients are lacking. As subtypes of chordoma are identified and described in more detail, further knowledge regarding the natural history of each type, tumor location, age differences, genomic variability, and an overall better understanding of chordoma may be the key to developing meaningful clinical trials and effective therapies for patients with chordoma.

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: Conflict of interest: none.

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Clinical InvestigationUpdated Outcome and Analysis of Tumor Response in Mobile Spine and Sacral Chordoma Treated With Definitive High-Dose Photon/Proton Radiation Therapy

Purpose

Methods and Materials

Results

Conclusion

Introduction

Section snippets

Patient characteristics

Oncologic outcomes

Discussion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Chordoma: Incidence and survival patterns in the United States, 1973-1995

Cancer Causes Control

Prognostic factors of sacral chordoma after surgical therapy: A study of 36 patients

Spinal Cord

Operative management of sacral chordoma

J Bone Joint Surg Am

Clinical significance of a wide excision policy for sacrococcygeal chordoma

J Cancer Res Clin Oncol

Sacral chordoma: 40-year experience at a major cancer center

Neurosurgery

Chordoma: Natural history and results in 28 patients treated at a single institution

Ann Surg Oncol

Prognostic factors in chordoma of the sacrum and mobile spine: A study of 39 patients

Cancer

Chordoma of the mobile spine: Fifty years of experience

Spine

Clinical Investigation
Updated Outcome and Analysis of Tumor Response in Mobile Spine and Sacral Chordoma Treated With Definitive High-Dose Photon/Proton Radiation Therapy