Childhood Chordoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Incidence

Chordoma is a very rare tumor of bone. It arises from remnants of the notochord within the clivus, spinal vertebrae, or sacrum. The most common site in children is the cranium.[1] The incidence in the United States is approximately 1 case per 1 million people per year. Only 5% of all chordomas occur in patients younger than 20 years.[2,3] Most pediatric patients have the classical or chondroid variant of chordoma, while the dedifferentiated variant is rare in children.[2,4]

References:

1. Sebro R, DeLaney T, Hornicek F, et al.: Differences in sex distribution, anatomic location and MR imaging appearance of pediatric compared to adult chordomas. BMC Med Imaging 16 (1): 53, 2016.
2. Hoch BL, Nielsen GP, Liebsch NJ, et al.: Base of skull chordomas in children and adolescents: a clinicopathologic study of 73 cases. Am J Surg Pathol 30 (7): 811-8, 2006.
3. Lau CS, Mahendraraj K, Ward A, et al.: Pediatric Chordomas: A Population-Based Clinical Outcome Study Involving 86 Patients from the Surveillance, Epidemiology, and End Result (SEER) Database (1973-2011). Pediatr Neurosurg 51 (3): 127-36, 2016.
4. McMaster ML, Goldstein AM, Bromley CM, et al.: Chordoma: incidence and survival patterns in the United States, 1973-1995. Cancer Causes Control 12 (1): 1-11, 2001.

Clinical Presentation and Diagnosis

Patients with chordoma usually present with pain (headache or sacrum) or diplopia. Patients may also present with or without neurological deficits such as cranial or other nerve impairment.[1]

The diagnosis of chordoma is straightforward when the typical physaliferous (soap bubble–bearing) cells are present. The differential diagnosis is sometimes difficult and includes dedifferentiated chordoma and chondrosarcoma. Childhood chordoma has been associated with tuberous sclerosis complex.[2]

References:

1. John L, Smith H, Ilanchezhian M, et al.: The NIH pediatric/young adult chordoma clinic and natural history study: Making advances in a very rare tumor. Pediatr Blood Cancer : e30358, 2023.
2. McMaster ML, Goldstein AM, Parry DM: Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. J Med Genet 48 (7): 444-9, 2011.

Prognosis and Molecular Features

Younger children with chordoma appear to have a worse outlook than older patients.[1,2,3,4,5,6] The survival rate ranges from about 50% to 80% for children and adolescents with cranial chordomas.[2,3,5]

• A retrospective literature review and review of institutional patients identified 682 patients with spinal chordomas. The median age of patients was 57 years.[7][Level of evidence C1]
  • Age younger than 18 years, sacral spine tumor location, dedifferentiated pathology, and treatment with chemotherapy were associated with a lower probability for progression-free survival (PFS).
  • Younger age (<18 years), older age (>65 years), bladder or bowel dysfunction at presentation, dedifferentiated pathology, disease recurrence or progression, and metastatic disease were associated with a worse overall survival (OS).
• Histopathology is also an important prognostic factor. Patients who have tumors with typical or chondroid pathology have worse outcomes than patients who have tumors with classical pathology.[8][Level of evidence C1]
• A multicenter, retrospective study identified 40 children with chordomas (median age, 12 years).[9][Level of evidence C1]
  • Most of the patients had the histologically classical form of chordoma (45.5%).
  • Most of the chordomas were located at the skull base (72.5%).
  • The OS rates were 66.6% at 5 years and 58.6% at 10 years.
  • The PFS rates were 55.7% at 5 years and 52% at 10 years.
  • Total resection correlated with a better outcome (log-rank P = .04 for OS and PFS).
  • Loss of BAF47 immunoexpression appeared to be a significant independent adverse prognostic factor (PFS, P = .033).
• A retrospective analysis identified seven children with poorly differentiated chordomas.[10][Level of evidence C1]
  • The median survival of these patients was 9 months.
  • All poorly differentiated chordomas showed loss of SMARCB1 expression by immunohistochemistry. Copy number profiles were derived from intensity measures of the methylation probes and indicated 22q losses affecting the SMARCB1 region in all poorly differentiated chordomas.

  Inactivation of the SMARCB1 gene is common in poorly differentiated chordomas of childhood, and it is associated with a poor prognosis.[10]

References:

1. Coffin CM, Swanson PE, Wick MR, et al.: Chordoma in childhood and adolescence. A clinicopathologic analysis of 12 cases. Arch Pathol Lab Med 117 (9): 927-33, 1993.
2. Borba LA, Al-Mefty O, Mrak RE, et al.: Cranial chordomas in children and adolescents. J Neurosurg 84 (4): 584-91, 1996.
3. Hoch BL, Nielsen GP, Liebsch NJ, et al.: Base of skull chordomas in children and adolescents: a clinicopathologic study of 73 cases. Am J Surg Pathol 30 (7): 811-8, 2006.
4. Jian BJ, Bloch OG, Yang I, et al.: A comprehensive analysis of intracranial chordoma and survival: a systematic review. Br J Neurosurg 25 (4): 446-53, 2011.
5. Yasuda M, Bresson D, Chibbaro S, et al.: Chordomas of the skull base and cervical spine: clinical outcomes associated with a multimodal surgical resection combined with proton-beam radiation in 40 patients. Neurosurg Rev 35 (2): 171-82; discussion 182-3, 2012.
6. Chambers KJ, Lin DT, Meier J, et al.: Incidence and survival patterns of cranial chordoma in the United States. Laryngoscope 124 (5): 1097-102, 2014.
7. Zhou J, Sun J, Bai HX, et al.: Prognostic Factors in Patients With Spinal Chordoma: An Integrative Analysis of 682 Patients. Neurosurgery 81 (5): 812-823, 2017.
8. Tsitouras V, Wang S, Dirks P, et al.: Management and outcome of chordomas in the pediatric population: The Hospital for Sick Children experience and review of the literature. J Clin Neurosci 34: 169-176, 2016.
9. Beccaria K, Tauziède-Espariat A, Monnien F, et al.: Pediatric Chordomas: Results of a Multicentric Study of 40 Children and Proposal for a Histopathological Prognostic Grading System and New Therapeutic Strategies. J Neuropathol Exp Neurol 77 (3): 207-215, 2018.
10. Hasselblatt M, Thomas C, Hovestadt V, et al.: Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis. Acta Neuropathol 132 (1): 149-51, 2016.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.
• Child-life professionals.
• Psychologists.

For information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,4,5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than 2 cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than 2 cases per 1 million people were also included in the very rare group because there is a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group (COG) defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers, colorectal cancers, etc.).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]

  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers in children aged 0 to 14 years and 9.3% of the cancers in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack of clinical trials for adolescents with rare cancers.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed December 15, 2023.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 15, 2023.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 18, 2023.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019.
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.

Treatment of Childhood Chordoma

Treatment options for childhood chordoma include the following:

1. Surgery with or without radiation therapy.
2. Tyrosine kinase inhibitor (TKI) therapy.

Surgery With or Without Radiation Therapy

Standard treatment includes surgery and external radiation therapy, often proton-beam radiation.[1,2] Surgery is often not curative in children and adolescents because of the likelihood of the chordoma arising in the skull base, rather than in the sacrum, making them relatively inaccessible for complete surgical excision. However, if gross-total resection can be achieved, outcome is improved.[3][Level of evidence C1]

The best results have been obtained using proton-beam therapy (charged-particle radiation therapy) because these tumors are relatively radiation resistant, and radiation-dose conformality with protons allows for higher tumor doses while sparing adjacent critical normal tissues.[4,5,6,7]; [1,8][Level of evidence C1]; [9][Level of evidence C2]

Evidence (surgery and/or radiation therapy):

1. In a retrospective study of 20 children with skull-based chordomas, the median age at diagnosis was 12 years. The most common presenting symptoms were diplopia, headache, and swallowing difficulties.[10] Five patients had locally recurrent tumors. Twelve patients underwent surgery with an endoscopic endonasal approach alone, and eight patients underwent other procedures. All but two patients received radiation therapy. Fourteen patients had gross-total resections, ten of whom developed surgical complications.
   • No differences in recurrence rates were seen between patients who presented with a new diagnosis and patients who had recurrent disease or between patients who underwent a gross-total resection and patients who underwent a near-total resection.
   • Of patients who received postoperative radiation therapy, none had a recurrence.
   • Comparatively, of the eleven patients who either did not receive radiation therapy or were treated preoperatively, four had a recurrence (P = .09).
   • Three patients developed distant metastases, and three patients died of disease.
   • A high Ki-67 index was more prevalent among patients with dedifferentiated chordomas. Two of the three patients who died had an elevated Ki-67 index.

Tyrosine Kinase Inhibitor (TKI) Therapy

Chordomas overexpress PDGFRA, PDGFRB, and KIT. Because of this finding, imatinib mesylate has been studied in adults with chordoma.[11,12]

In one study, 50 adults with chordoma were treated with imatinib and evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. One patient had a partial response and 28 additional patients had stable disease at 6 months.[12] The low rate of RECIST responses and the potentially slow natural course of the disease complicate the assessment of the efficacy of imatinib for chordoma.[12]

Other TKIs and combinations involving TKIs have been studied in adults.[13,14,15]

One multicenter French retrospective study reported five patients who had partial responses to treatment with either imatinib, sorafenib, or erlotinib. The median progression-free survival was 36 months.[16]

Chemotherapy

There are only a few anecdotal reports of the use of cytotoxic chemotherapy after surgery alone or surgery plus radiation therapy. Treatment with ifosfamide/etoposide and vincristine/doxorubicin/cyclophosphamide has been reported with some success.[17,18] The role for chemotherapy in the treatment of this disease is uncertain.

Recurrences are usually local but can include distant metastases to the lungs or bone.

References:

1. Yasuda M, Bresson D, Chibbaro S, et al.: Chordomas of the skull base and cervical spine: clinical outcomes associated with a multimodal surgical resection combined with proton-beam radiation in 40 patients. Neurosurg Rev 35 (2): 171-82; discussion 182-3, 2012.
2. DeLaney TF, Liebsch NJ, Pedlow FX, et al.: Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. J Surg Oncol 110 (2): 115-22, 2014.
3. Rassi MS, Hulou MM, Almefty K, et al.: Pediatric Clival Chordoma: A Curable Disease that Conforms to Collins' Law. Neurosurgery 82 (5): 652-660, 2018.
4. Hug EB, Sweeney RA, Nurre PM, et al.: Proton radiotherapy in management of pediatric base of skull tumors. Int J Radiat Oncol Biol Phys 52 (4): 1017-24, 2002.
5. Noël G, Habrand JL, Jauffret E, et al.: Radiation therapy for chordoma and chondrosarcoma of the skull base and the cervical spine. Prognostic factors and patterns of failure. Strahlenther Onkol 179 (4): 241-8, 2003.
6. Lim PS, Tran S, Kroeze SGC, et al.: Outcomes of adolescents and young adults treated for brain and skull base tumors with pencil beam scanning proton therapy. Pediatr Blood Cancer 67 (12): e28664, 2020.
7. Indelicato DJ, Rotondo RL, Mailhot Vega RB, et al.: Local Control After Proton Therapy for Pediatric Chordoma. Int J Radiat Oncol Biol Phys 109 (5): 1406-1413, 2021.
8. Rombi B, Ares C, Hug EB, et al.: Spot-scanning proton radiation therapy for pediatric chordoma and chondrosarcoma: clinical outcome of 26 patients treated at paul scherrer institute. Int J Radiat Oncol Biol Phys 86 (3): 578-84, 2013.
9. Rutz HP, Weber DC, Goitein G, et al.: Postoperative spot-scanning proton radiation therapy for chordoma and chondrosarcoma in children and adolescents: initial experience at paul scherrer institute. Int J Radiat Oncol Biol Phys 71 (1): 220-5, 2008.
10. McDowell MM, Zwagerman NT, Wang EW, et al.: Long-term outcomes in the treatment of pediatric skull base chordomas in the endoscopic endonasal era. J Neurosurg Pediatr 27 (2): 170-179, 2020.
11. Casali PG, Messina A, Stacchiotti S, et al.: Imatinib mesylate in chordoma. Cancer 101 (9): 2086-97, 2004.
12. Stacchiotti S, Longhi A, Ferraresi V, et al.: Phase II study of imatinib in advanced chordoma. J Clin Oncol 30 (9): 914-20, 2012.
13. Lindén O, Stenberg L, Kjellén E: Regression of cervical spinal cord compression in a patient with chordoma following treatment with cetuximab and gefitinib. Acta Oncol 48 (1): 158-9, 2009.
14. Singhal N, Kotasek D, Parnis FX: Response to erlotinib in a patient with treatment refractory chordoma. Anticancer Drugs 20 (10): 953-5, 2009.
15. Stacchiotti S, Marrari A, Tamborini E, et al.: Response to imatinib plus sirolimus in advanced chordoma. Ann Oncol 20 (11): 1886-94, 2009.
16. Lebellec L, Chauffert B, Blay JY, et al.: Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF). Eur J Cancer 79: 119-128, 2017.
17. Dhall G, Traverso M, Finlay JL, et al.: The role of chemotherapy in pediatric clival chordomas. J Neurooncol 103 (3): 657-62, 2011.
18. Al-Rahawan MM, Siebert JD, Mitchell CS, et al.: Durable complete response to chemotherapy in an infant with a clival chordoma. Pediatr Blood Cancer 59 (2): 323-5, 2012.

Treatment Options Under Clinical Evaluation for Childhood Chordoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• PEPN2121 (NCT05286801) (Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1- or SMARCA4-Deficient Tumors): This study is evaluating the combination of a PD-L1 targeting antibody (atezolizumab) with a TIGIT targeting antibody (tiragolumab) for patients with SMARCB1- or SMARCA4-deficient tumors.

Latest Updates to This Summary (12 / 15 / 2023)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Clinical Presentation and Diagnosis

Added John et al. as reference 1.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric chordoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Chordoma Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• William H. Meyer, MD
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• D. Williams Parsons, MD, PhD (Texas Children's Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Chordoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/bone/hp/child-chordoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 31909945]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2023-12-15