Chordoma Treatment & Management

Updated: May 03, 2022
  • Author: Cheryl Ann Palmer, MD; Chief Editor: Brian H Kopell, MD  more...
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Treatment

Medical Therapy

Currently, there is no approved medical treatment for individuals with diagnosed chordoma. Surgical en bloc resection with negative margins is the only curative treatment for this disease. High-dose irradiation, particularly with protons and carbon ions, is a therapeutic alternative in cases of inoperable tumor. Clinical trials exploring additional therapeutic modalities are ongoing. [3]

In a systematic review of 33 studies that reported on use of molecular targeted therapy (MTT) for advanced chordoma, the investigators extracted and analyzed data on clinical outcomes, such as median overall survival, progression-free survival, response rate, and adverse events. They found that imatinib and erlotinib were the most frequently used molecular targeted inhibitors for chordoma, and that for PDGFR-positive and/or EGFR-positive chordomas, clinical benefits were achieved with acceptable adverse events. They stated that monotherapy is preferred as first-line treatment, and combined drug therapy as second-line treatment. Tyrosine kinase inhibitor (TKI) monotherapy is recommended for first-line management, and combination therapy (2 TKIs or 1 TKI plus 1 mTOR inhibitor) may be the choice for drug-resistant chordoma. Brachyury vaccine is a promising therapeutic strategy; additional clinical trials must be undertaken to evaluate its safety and efficacy. [25]

Despite the fact that surgery remains the cornerstone of treatment, total resection is not reasonable for all patients with chordoma. For this reason, adjuvant treatment is highly important to ensure local control. If the residual tumor is of small volume, stereotactic body radiation therapy (SBRT) may provide advantages. [30]  Chordoma is a chemoresistant disease; in advanced disease, imatinib has a role.

In a case report of a 48-year-old man with a sacral chordoma who underwent partial sacrectomy followed by postoperative radiotherapy, the patient received palliative radiotherapy and imatinib treatment upon recurrence. When the disease was refractory to imatinib, he was started on treatment with erlotinib, showing partial response on imaging at 2 months. As seen in previously reported cases, erlotinib is a therapeutic option in advanced chordoma, even in imatinib-refractory cases, and thus exploration of its therapeutic role in prospective clinical trials is warranted. [31]

Research is ongoing, and surgery remains the standard treatment for chordoma. Adjuvant radiation therapy is used in cases in which incomplete resection is suspected. Traditional chemotherapy has not been shown to be effective.

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Surgical Therapy

Contraindications to surgery for excision of a chordoma primarily are related to general health of the patient and preexisting medical conditions. The patient should be evaluated for cardiac, pulmonary, hematologic, and endocrine disorders, as well as coagulation status. These disorders must be addressed and managed prior to surgery.

Surgical resection remains the primary mode of treatment for both diagnostic and therapeutic purposes. The prognosis for patients with chordoma generally depends on extent and completeness of tumor excision.

Success often depends on extent and location of the tumor. In general, more complete removal with wide excision delays the time interval between surgery and eventual recurrence. The natural history and the effectiveness of different types of therapy for chordoma are not well understood because of its rare incidence and slow-growing nature.

Radical resection of tumors with clean margins is associated with a longer disease-free interval. If subtotal excision is the only option (generally due to location and proximity to delicate anatomy), added radiation therapy can lengthen the interval to recurrence. In cases in which radiation therapy is utilized without surgical resection, an average of only 50% of patients attain 10-year local control of skull-based and cervical spine tumors.

Preoperative details

Imaging of the tumor prior to surgery can reveal the extent of the tumor by showing both extent of bone involvement or erosion and depth of expansion of the tumor into adjacent soft tissues. This information can be important in planning the most advantageous resection possible.

As for any surgical patient, preoperative history and physical examination are required. Other medical problems (eg, cardiovascular, respiratory) must be stabilized or addressed. Laboratory studies, including electrolytes, coagulation status, and blood count, are needed. Radiologic studies (x-ray, CT scan, MRI) can be used for both evaluation of the tumor and assessment of other medical problems. Chest radiograph, electrocardiography, and blood crossmatch may be important.

Intraoperative details

Evaluation of tumor margins is essential for assessment of the status of resection as the resection proceeds. Knowledge of the completeness of the tumor resection helps the clinician to predict patient outcomes in terms of length of the disease-free interval and to determine the need for adjunctive therapy such as radiation.

Postoperative details

General postoperative complications relevant to this or any surgery include wound infection and infection of the operative bed (abscess), shock, pulmonary complications (respiratory failure, atelectasis, infection), and bladder infection or urinary retention.

Complications particular to cranial neurosurgery include the possibility of intracranial hemorrhage, meningitis, osteomyelitis, seizures, hydrocephalus, increased intracranial pressure, hematoma formation, swollen eyelids, keratitis, and facial palsy.

Rehabilitation may be necessary in the case of sacral surgery if damage to the spinal cord has occurred and if the level of presurgical functioning requires it.

Patients with chordoma who are admitted to inpatient rehabilitation facilities after surgical tumor resection experience improvement in multiple functional domains and a high rate of acute hospital transfer, but this is comparable to that seen with other cancer rehabilitation populations. Understanding the characteristics of the postoperative chordoma population is essential for those who will direct future studies regarding cancer rehabilitation. [32]

Recovery from sacral or cranial procedures depends on extent of tumor removal and level of intraoperative injury to adjacent neural structures. Problems may include, but are not limited to, facial palsies, incontinence, and difficulty walking.

Complications occur at a higher rate after radical resection than after subtotal resection and depend somewhat on the location of the tumor.

Morbidity from surgery can be very mild or severe. With resection of sacrococcygeal chordoma, dysfunction of bowel and bladder is the most frequent complication.

 

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Follow-up

Frequent follow-up is required because of the high rate of recurrence of these tumors. Tumor recurrence identified early is easier to treat. The average interval to recurrence is 3.8 years for radically resected tumors, 2.1 years for subtotal resection followed by radiation therapy, and 8 months for subtotal excision without adjuvant therapy. The interval of follow-up, including repeat MRI or CT, depends on completeness of the resection. Because residual tumor drastically shortens recurrence time, patients with known or suspected residual tumor need to be evaluated more frequently.

A retrospective single-institution study explored the usefulness of tumor growth rate (TGR) as a preoperative radiologic marker for chordoma recurrence. Tumor growth rate is an image-based calculation that provides quantitative information on changes in tumor volume over time and has been shown to predict progression-free survival in other tumor types. Researchers have concluded that TGR may be considered a preoperative radiologic indicator of tumor proliferation and seems to preoperatively identify more aggressive tumors with a higher tendency to recur. Study findings suggest that the therapeutic strategy and the clinical-radiologic follow-up of patients with chordoma can be adapted according to this new parameter. [33]

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Outcome and Prognosis

Chordomas are relatively benign-appearing neoplasms; however, because of their tendency to erode bone and invade soft tissues, they usually display malignant behavior. In addition, the location of the tumor influences the ability of the surgeon to achieve complete resection. Chordomas often grow in inaccessible sites, and their margins within soft tissue often are not well defined. As a result, complete excision of chordomas is difficult at best.

Despite the low-grade status of chordomas, they have a high recurrence rate and involve significant mortality. Five-year survival is approximately 50% overall but is improved to 65% with complete resection with negative margins. Surgical resection with positive margins is associated with approximately 50% 5-year survival, and if the chordoma is inoperable, 5-year survival is approximately 40%. [1]

Multivariate analysis of a US population with chordoma revealed that older age, greater tumor size, and distant metastasis were correlated with decreased survival, whereas surgical resection was correlated with increased survival. Patients receiving radiation therapy also showed decreased survival—likely an indication of the patients' advanced stage of disease, making them poor surgical candidates. [15, 16]

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Future and Controversies

Chordoma is a complex disease because of its rarity, biological heterogeneity, and peculiar clinical behavior. Despite the progress made, outcomes of this disease remain unsatisfactory, and identification of active systemic treatments remains an urgent unmet medical need. Significant steps forward have enhanced our comprehension of chordoma complexity, with insights gained into the biology and morphology of this disease. New entities have been described, and potentially druggable molecular targets identified. This is becoming all the more relevant today, as new potentially active agents are under development. [17]

With increasing prevalence of cancer survivors, improving function during and after cancer treatment is extremely important. Chordoma patients who are admitted to inpatient rehabilitation facilities after surgical tumor resection experience improvement in multiple functional domains. Chordoma patients admitted to inpatient rehabilitation facilities experience a high rate of acute hospital transfer, but this is comparable to that of other cancer rehabilitation populations. Understanding the characteristics of the postoperative chordoma population is essential for those who will direct future studies regarding cancer rehabilitation. [32]

Castiglione and associates described a combined one-stage robot-assisted sacral chordoma resection. They reported that the tumor was en bloc removed by a combined one-stage anterior laparoscopic robot-assisted and posterior open lumbosacral approach with continued intraoperative neurophysiologic monitoring of sacral and pudendal plexuses in a 64-year-old woman with a histologic diagnosis of chordoma. After surgery, the patient reported pain relief and total recovery of bowel function, with good 11-month follow-up outcomes. Researchers concluded that this combined technique represents a promising treatment option in selected cases. The robotic technology combined with the experience of highly qualified staff can improve surgical results by minimizing complications. However, longer follow-up is needed to confirm the long-term effects of this approach in terms of recurrence and survival. [34]

Results of an in vitro and in vivo investigation of the effects of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) on chordoma cells reveal that the SMARCB1/ATG5 axis is a promising therapeutic target for chordoma, and autophagy inhibitors may be effective agents for chordoma treatment. [35]

Chen and colleagues examined the role of glycogen synthase kinase 3 beta (GSK-3β) in the development of chordoma. Through methods that consisted of immunohistochemistry, Western blotting, immunofluorescence, real-time quantitative reverse transcription (qRT)-polymerase chain reaction (PCR), CCK-8 assay, and colony formation analysis, among others, they concluded that the GSK-3β-P21 axis may be an important signaling pathway for the occurrence and development of chordoma, providing a new therapeutic target for clinical treatment of patients with this disorder. [36]

For the present, the mainstay of therapy for chordoma remains primary surgical excision, with radiation therapy added for incompletely resected tumors. The near future will likely see the confirmation of potential therapeutic targets, such as signaling molecules in the pathways mentioned above. Inhibitors of these pathways may then be used to arrest the progression of disease, especially for patients with incomplete resection or recurrent/metastatic disease. [37]

Although these molecular studies continue to explore new treatment modalities for chordoma, the most significant dilemma remains the choice between a radical surgical procedure with the potential for serious morbidity and a subtotal resection with increased potential for recurrence. The general health of the patient should be considered during planning for the surgical procedure. With explanations of the risks and benefits provided to the patient, an informed decision regarding therapy can be reached.

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