Chordoma Treatment & Management

A multicenter phase II clinical trial has confirmed the clinical efficacy of imatinib mesylate in the treatment of chordoma.^[10] Treatment with imatinib was successful in stabilizing tumor growth (84%) or shrinking tumor size (16%) in a cohort of patients with progressing, advanced chordoma. Imatinib is a tyrosine kinase inhibitor targeting several enzymes including platelet-derived growth factor receptor – β (PDGFRB), which can be expressed in chordomas. However, research is ongoing, and surgery remains the standard treatment for chordomas. Adjuvant radiation therapy is used in cases in which incomplete resection is suspected. Traditional chemotherapy has not been shown to be effective.

Surgery is the preferred treatment for chordomas. Success often depends on the extent and location of the tumor. In general, a more complete removal with wide excision delays the time interval between surgery and eventual recurrence. The natural history and the effectiveness of different kinds of therapy are not well understood in chordomas because of their rare incidence and slow-growing nature.

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

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

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

The evaluation of tumor margins is essential to assess the status of the resection as the resection proceeds. Knowledge of the completeness of the tumor resection helps predict patient outcome in terms of the length of the disease-free interval and assists in determination of the need for adjunctive therapy such as radiation.

General postoperative complications relevant to this or any surgery include wound infection or 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 possibilities 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 surgeries, if damage has occurred to the spinal cord and depending on the level of presurgical functioning.

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

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 scans, depends on the completeness of the resection. Because residual tumor drastically shortens the recurrence time, patients with known or suspected residual tumor need to be evaluated more frequently.

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

Morbidity from surgery can be either very mild or severe following tumor resection. With the resection of sacrococcygeal chordomas, bowel and bladder dysfunction are the most frequent complications.

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 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.

The 5-year survival rate is estimated to be 51%, and the 10-year survival is estimated to be 35%. Factors that may improve prognosis are young age, complete resection, and the addition of radiation therapy in incompletely resected tumors.

Several research groups are pursuing the identification of biomarkers of chordoma that may serve as prognostic indicators as well as potential therapeutic targets. A British research group has demonstrated the activation of the mTOR-signaling pathway in about 65% of chordomas, suggesting that mTOR inhibitors such as rapamycin and its analogues might be effective.^[11] Preliminary confirmation of this has come from an Italian group that treated progressive advanced chordoma with a combination of imatinib and sirolimus (a rapamycin analogue), inducing one partial response as well as stabilizing the disease in 7 patients.^[12] Only one patient showed continued progression over the 9-month treatment period.

A Harvard research group has demonstrated that the signaling molecule Stat3 (signal transducers and activators of transcription 3) expression correlated with survival and severity of disease in 70 chordoma samples.^[13] Furthermore, 3 chordoma cell lines exposed to SD-1029, an inhibitor of Stat3 activation, demonstrated inhibition of in vitro phosphorylation and cellular proliferation. This inhibition was enhanced when SD-1029 was combined with chemotherapeutic agents.

For the present, the mainstay of therapy for chordoma remains primary surgical excision, with the addition of radiation therapy 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 in patients with incomplete resections or recurrent/metastatic disease.

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 an 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.