Chordomas: Rare, Indolent and Linked With Poor Outcomes, But Research Efforts Continue

Chordoma is described as an extremely rare sarcoma that attacks the bones of the spine and base of the skull.

Chordoma is described as an extremely rare sarcoma that attacks the bones of the spine and base of the skull. It is the most common tumor of the sacrum and cervical spine, accounting for about 3% of all bone tumors and about 20% of primary spinal tumors.1 These are often slow-growing, asymptomatic tumors that are difficult to treat because they form on critical structures such as the brainstem, spinal cord, and important nerves and arteries.

Worldwide, there are approximately 1 million diagnoses of chordoma annually, including roughly 300 children. At any given time, there are fewer than one in 100,000 people living with chordoma. The 5-year overall age-adjusted relative survival in the United States at 72%, but the risk for morbidity is high.2

“Chordoma in particular…can be very, very devastating. It doesn't seem to be that way because it’s a slow-growing, indolent tumor,” said Karim Masrouha, MD, assistant professor in the Department of Orthopaedic Surgery at NYU Grossman School of Medicine, director of New York Ponseti Clubfoot Center, and an orthopedic surgeon at NYU Langone Health specializing in pediatrics and oncology.

Chordomas fit between orthopedic surgery and neurosurgery and, as an orthopedic surgeon trained in musculoskeletal oncology, he’s developed an interest in managing these tumors. Treating chordomas can be difficult, he said, because the tumor grows so slowly and due to the involved structures.

On the same day of this interview, Masrouha treated a young adult with chordoma. Typically, patients with this tumor tend to be middle aged, he said.

“This patient was found to have [chordoma] in the typical fashion, which is usually when the patient complains of hip pain or back pain, sometimes gastrointestinal symptoms. It’s like an indirect kind of discovery of the of the chordoma,” said Masrouha. “This patient was very lucky that the chordoma was caught at an early stage; it was not very invasive. The treatment, essentially, was purely surgical because we were able to get a wide surgical margin without having any functional deficit or any long-term discomfort for the patient.”

He noted that it can be difficult to generate interest in a disease that affects only a handful of patients annually. “Rare types of cancers…frequently don't get enough attention. Attention frequently means research dollars, which ends up leading to better outcomes for patients overall,” Masrouha said.

He said physicians use every avenue to generate attention including social media, talking to colleagues, and “on the websites of institutions where we work to raise awareness of the existence of these types of tumors and the need for research.”

Treatment Beyond Surgery

Surgery with or without radiation therapy is the standard of care for patients with this disease. Although chemotherapy has shown no benefit, data from 2 studies presented at the 2021 ASCO Annual Meeting data suggests that there may be a role for immunotherapy and targeted therapy in chordoma treatment.

In the multicenter, single-arm, phase 2 AcSé trial (NCT03012620), 94 patients with rare, advanced or metastatic sarcomas, including 34 with chordoma, who were resistant to standard treatment received pembrolizumab (Keytruda) for up to 2 years.3 The primary end point was objective response rate (ORR) via RECIST v1.1 criteria at 12 weeks. Secondary end points included progression-free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate, and safety. The median number of prior lines of therapy was 2.

Patients received a median of 5 cycles (range, 1-35) of pembrolizumab treatment, and all but 2 patients received at least 1 dose. The best overall response was 1 (1%) complete response and 14 (14.3%) partial responses.

Specifically, in patients with chordoma, the ORR was 8.8%; the median PFS was 6.6 months and the 1-year PFS rate was 31.2%. The 1-year OS rate was 76.6% in this subset, and the median OS was not reached.

Investigators concluded that the PD­-1 inhibitor was well tolerated and induced high levels of response and prolonged activity in these patients.

A team from Gustave Roussy presented data from a retrospective analysis of 31 adults with progressive chordoma who received 150 mg daily erlotinib (Tarceva).4 Here, the primary tumor site was sacral (25), lumbar (3) or cervical (3). Twenty-five patients had undergone prior surgery and 29 (94%) had undergone radiotherapy of the primary tumor. Eight patients had received previous systemic treatments including imatinib (Gleevec; n = 4) sorafenib (Nexavar; n = 2), and regorafenib (Stivarga; n = 2).

The best tumor response by RECIST 1.1 was PR (13%). The median PFS was 6.2 months (95% CI, 4.5-12.1) and the median OS was 15.9 months (95% CI, 10.6-20.2). Fourteen patients (45%) remained progression-free after 1 year and 3 (10%) after 2 years under erlotinib.

Thirteen patients (42%) experienced grade 3 skin rash and 4 patients experienced grade 3 diarrhea.

Investigators concluded that “erlotinib has clinically meaningful but unpredictable activity in advanced chordoma” and recommended molecular profiling to identify patients most likely to benefit from treatment with anti-EGFR agents.

Proton beam therapy has also demonstrated efficacy with good safety in this disease. European investigators assessed long-term local control, OS, and prognostic factors in patients with skull-base chordoma treated with pencil beam scanning proton therapy (PBS PT).5 Seventy-seven patients with histologically confirmed disease were treated at the Paul Scherrer Institute in Zurich, Switzerland from October 1998 to September 2014.

After a mean follow-up of 69.2 months (range, 4.6-190.8), investigators recorded 6 (7.8%) local failures, including 2 late failures. The actuarial 8-year local control rate was 89.7% with an actuarial 8-year local control OS rate of 93.5%, respectively.

Six (7.8%) patients experienced grade 3 or higher radiation-induced toxicity. The 8-year high-grade toxicity-free survival was 90.8%. Five (6.5%) patients died during the study, 4 from local progression. One patient with a recurrent tumor died of metastatic adenocarcinoma of the lung.


  1. Chordoma Foundation. Understanding chordoma. Accessed July 27, 2021.
  2. Frezza AM, Botta L, Trama A, Dei Tos AP, Stacchiotti S. Chordoma: update on disease, epidemiology, biology and medical therapies. Curr Opin Oncol. 2019;31(2):114-120. doi: 10.1097/CCO.0000000000000502
  3. Blay J-Y, Penel N, Ray Coquard IL. et al. High clinical activity of pembrolizumab in chordoma, alveolar soft part sarcoma (ASPS) and other rare sarcoma histotypes: The French AcSé pembrolizumab study from Unicancer. J Clin Oncol. 2021;39(suppl 15; abstr 11520). doi:10.1200/JCO.2021.39.15_suppl.11520
  4. Mir O, Briand S, Lazure T et al. Activity of erlotinib in patients (pts) with advanced chordoma: a retrospective study. J Clin Oncol. 2021;39(suppl; abstr 11528). doi:10.1200/JCO.2021.39.15_suppl.11528
  5. Weber DC, Badiyan S, Malyapa R, et al. Long-term outcomes and prognostic factors of skull-base chondrosarcoma patients treated with pencil-beam scanning proton therapy at the Paul Scherrer Institute. Neuro Oncol. 2016;18(2):236-243. doi: 10.1093/neuonc/nov154