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.

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).

Incidence

Chordoma is a very rare tumor of bone that 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]

Molecular Features

Inactivation of the SMARCB1 gene is common in poorly differentiated chordomas of childhood, and it is associated with a poor prognosis.[1]

Prognosis

Younger children appear to have a worse outlook than do older patients.[1-6] The survival rate in children and adolescents ranges from about 50% to 80% for cranial chordomas.[2,3,5] A retrospective literature review and review of institutional patients identified 682 patients with chordomas of the spine, with a median age of 57 years.[7][Level of evidence C1] Age younger than 18 years, location in sacral spine, dedifferentiated pathology, and 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, recurrence or progression, and metastases were associated with a worse overall survival. Histopathology is also an important prognostic factor, with atypical or chondroid pathology having worse outcomes than 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%), and the chordomas were mostly located at the skull base (72.5%). The overall survival (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 (P = .04 for OS and PFS, log-rank). 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.

Clinical Presentation

Patients usually present with pain, with or without neurologic deficits such as cranial or other nerve impairment. Diagnosis is straightforward when the typical physaliferous (soap bubble–bearing) cells are present. Differential diagnosis is sometimes difficult and includes dedifferentiated chordoma and chondrosarcoma. Childhood chordoma has been associated with tuberous sclerosis complex.[1]

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.

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

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 2010, childhood cancer mortality decreased by more than 50%.[3] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[4] 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.[5,6] 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.[7]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancer, melanoma and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinoma, nasopharyngeal carcinoma, and most adult-type carcinomas such as breast cancer, colorectal cancer, etc.).[8] These diagnoses account for about 4% of cancers diagnosed in children aged 0 to 14 years, compared with about 20% of cancers diagnosed in adolescents aged 15 to 19 years.[9]
  Most cancers in subgroup XI are either melanomas or thyroid cancer, with other types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of 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.

Treatment of Childhood Chordoma

Treatment options for childhood chordoma include the following:

1. Surgery.
2. Radiation therapy.

Standard treatment includes surgery and external radiation therapy, often proton-beam radiation.[1,2] Surgery is not commonly curative in children and adolescents because of difficulty obtaining clear margins and the likelihood of the chordoma arising in the skull base, rather than in the sacrum, making them relatively inaccessible to 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.[4-7]; [1,8][Level of evidence C1]; [9][Level of evidence C2]

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.[10,11] The role for chemotherapy in the treatment of this disease is uncertain.

Imatinib mesylate has been studied in adults with chordoma on the basis of the overexpression of PDGFRA, PDGFRB, and KIT in this disease.[12,13] Among 50 adults with chordoma treated with imatinib and evaluated by Response Evaluation Criteria In Solid Tumors (RECIST) guidelines, there was one partial response and 28 additional patients had stable disease at 6 months.[13] 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.[13] Other tyrosine kinase inhibitors and combinations involving kinase inhibitors have been studied in adults.[14-16] One multicenter French retrospective study reported five patients who had partial responses to treatment with either imatinib, sorafenib, or erlotinib, with a median progression-free survival of 36 months.[17]

In a retrospective study of 20 children with skull-based chordomas, the median age at diagnosis was 12 years and the most common presenting symptoms were diplopia, headache, and swallowing difficulties.[18] 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 a gross-total resection, 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, and two of the three patients who died had an elevated index.

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

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, refer to the ClinicalTrials.gov website.

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

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
  Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Changes to This Summary (04/19/2022)

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.

Editorial changes were made to this summary.

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® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary