Chordoma: The Quest for Better Treatment Options

Chordoma is an extremely rare cancer, with an incidence of about one case per million persons per year in the USA (about 300 cases per year) [1]. Chordoma has been called “bone cancer” [2], but this designation is debatable based on histologic features, which are more consistent with its presumed tumor of origin, namely, the residual embryonic notochord tissue [3, 4]. Designating chordoma as a “bone tumor” appears to be a holdover from the initial description of the disease by Virchow [5], but it was called into question soon thereafter by Ribbert [6], who coined the name “chordoma” based on its similarity to notochord tissue [7]. The relationship of chordoma to the notochord was strengthened by the finding that brachyury, a transcription factor found in notochord tissue and essential for embryonic development, is overexpressed in chordoma [3, 8]. Regardless of its historical designation, chordoma has unique histologic, radiographic, and clinical characteristics that call for chordoma-specific research to improve outcomes for patients with the disease. In this review, I briefly review the previously published natural history of the disease, including tumor characteristics, standard treatment paradigms, clinical management issues, and results of systemic treatment trials to date, to provide context for potential therapeutic targets and possible future treatment options.

Chordoma is most commonly diagnosed between ages 50 and 60, and it is more common in men than women, and rare in children [1]. Primary tumors develop along the axial spine, with approximately one-third of cases presenting in the clivus, mobile spine, and sacrum, respectively [1]. Disease presentation depends on tumor location and is related to the structures near which the tumor is growing. For example, patients with clival chordomas may present with headache, diplopia, or impairment of other cranial nerves, while those with sacral chordomas may present with low back or buttocks pain, neuropathy, and/or gait disturbance [7]. Patients may be diagnosed with large tumor masses in the sacrum due to the slow-growing nature of the disease, non-specific symptom profile, and a relatively large space for tumors to occupy before causing significant focal symptoms. Imaging findings that would point to chordoma include a mass along the axial spine, likely invading surrounding bone, which has a similar intensity to surrounding tissue on T1-weighted images, but appears hyperintense on T2-weighted images [9, 10]. Unfortunately, due to the slow-growing nature of chordoma, which results in insidious, non-specific symptoms, diagnosis may be delayed for months or years. The median overall survival (OS) from time of diagnosis has been estimated at around 6 to 7 years [1], but the range of outcomes is very wide and may be related to prognostic markers, including treatment options at the time of diagnosis [11‐13], as detailed below.

After surgical resection or initial biopsy, the diagnosis of chordoma is confirmed based on the classical (conventional) appearance of “sheets and cords of round to polygonal” tumor cells filled with occasionally large mucin-filled eosinophilic cytoplasm called physaliphorous cells [14]. Two less common chordoma variants are chondroid chordoma and dedifferentiated chordoma. Features of chondroid chordoma include the presence of “cartilaginous differentiation, not present in classical chordoma” [14]. Dedifferentiated chordoma occurs in a small subset of patients (<5%); it has an aggressive course and its features are consistent with those of spindle cell (sarcomatoid) carcinoma under histologic review [15, 16]. In cases where the diagnosis is not clear, staining for nuclear expression of brachyury distinguishes chordoma from tumors with similar morphologic features [8, 17, 18].

In 2015, the Chordoma Foundation and its advisors published a global consensus based on the input of world experts from the fields of medical oncology, radiation oncology, neurosurgery, and orthopedic surgery during the 2013 European Society for Medical Oncology annual meeting [19]. Practicing clinicians should use these guidelines when initially seeing a patient with chordoma, but the importance of patients being seen by a dedicated multidisciplinary team with experience in this rare disease cannot be overstated.

Surgery is the mainstay of treatment for primary and/or recurrent chordoma when feasible, and the outcome of surgery is closely related to the expected outcome for a given patient. Surgical techniques are specific to tumor site, but in general, the goal is to achieve a local excision with clear margins. The surgical management of chordoma has been discussed in detail in other recent reviews [2, 7, 20] and thus will not be a focus of this review. However, multiple retrospective analyses have demonstrated the impact of surgery on prognosis [21‐23]. In clival chordoma, though, there is evidence that aggressive resection may actually be the more cautious approach [13] because wide local excision is commonly not an option [22].

Radiotherapy also plays a key role in the management of patients with localized chordoma, particularly in the adjuvant setting after full resection or subtotal resection and as the primary treatment in unresectable disease. One series from Choy et al. indicated that the use of adjuvant radiotherapy was the most important variable influencing time to progression [13]. A research group from Massachusetts General Hospital demonstrated excellent disease control with adjuvant high-dose radiotherapy after surgery in primary tumors after resection, but poor outcomes in recurrent disease [12]. This group went on to show reasonable tumor control with high-dose proton or photon radiotherapy in patients with primary, unresected chordoma, with 5-year OS and local progression-free survival (PFS) of 78.1% and 79.8%, respectively [24]. The same group demonstrated very low recurrence rates in patients with localized spinal chordoma treated with high-dose radiotherapy, with the exception of locally recurrent chordomas, which had a 5-year recurrence rate of 50% [25]. Because proton-beam therapy is capable of delivering high doses of radiotherapy to focal targets, it has advantages over photon therapy. However, it is not clear that, at equivalent doses, proton therapy has any advantage over photon therapy in terms of disease control or the likelihood of symptom control.

Surgery, when feasible, should aim for margin-negative resection without penetration of the capsule, with adjuvant high-dose radiotherapy for optimal local tumor control [19]. Because this outcome is not possible for most patients, prediction of clinical outcome is very difficult for a given patient at the time of initial management. Patients with residual disease after surgery or unresectable disease at the time of diagnosis should consider high-dose radiotherapy at a center with expertise in delivering such doses for chordoma. An important surgical aspect of the tumor is related to its histology. These tumors contain gelatinous material that can spill into the resection cavity even with careful planning, and recurrence often occurs at the margins of the resected tumor. These characteristics of chordoma reinforce the importance of consulting an experienced, multidisciplinary team for initial treatment. In fact, a recent retrospective analysis suggested that preoperative radiation may reduce the risk of surgical-field contamination [26]. Patients should be encouraged to seek the assistance of advocacy groups, such as the Chordoma Foundation (http://​www.​chordomafoundati​on.​org/​), for recommendations of treatment centers for their specific situation.

Chordoma is often considered to be a slow-growing disease with low metastatic potential, but this description may give the wrong impression of its disease course in the advanced setting. Chambers et al. reported that 30% of patients developed metastatic disease, with a predominance of lesions occurring in patients with non-clival chordoma [27]. Kishimoto et al. described a similar incidence of metastatic disease in a group of 198 patients [9]. Other studies have described a wide range of observed metastatic disease. However, it is possible that these retrospective analyses underrepresent the true incidence of metastatic chordoma. Sites of metastatic disease are widely variable and include subcutaneous tissue, liver, lung, lymph nodes, and bone [22, 27] (Fig. 1). Because some sites of metastatic chordoma may not be well visualized by an imaging modality that can easily detect other sites of metastasis (Fig. 1), or because clinical evaluation commonly focuses on local recurrence, sites of metastatic disease can easily be missed. However, this may not be an issue of great significance in most cases because local recurrence is still the major cause of morbidity and mortality [22]. In older series, OS in patients with metastatic disease has been reported as approximately 1 year [28], but more recent series have indicated a median OS closer to 3 years [22, 29]. This apparent shift in survival from the time of detection of metastatic disease may be due to detection bias, in which metastatic lesions are identified earlier with improved imaging modalities and more thorough evaluation. Alternatively, the difference could be due to improved treatment methods over time.

To date, there has been no randomized, controlled trial of a therapeutic agent in locally advanced and/or metastatic chordoma. Perhaps owing to the lack of clear historical control data in this population, there also has not been a study that has clearly defined treatment benefit for patients with advanced chordoma. The combination of the rarity of the disease and the diversity of upfront clinical management practice makes clinical trial design and enrollment difficult. Table 1 summarizes data from clinical trials of systemic treatment. Imatinib is the most thoroughly evaluated therapeutic agent in chordoma, based on the expression of platelet-derived growth factor beta (PDGFB) or its receptor (PDGFRB). Imatinib, which is best known as an inhibitor of the BCR-ABL gene fusion product, which is a constitutively active tyrosine kinase, has off-target effects, including the inhibition of PDGFRB [30, 31]. In a single-arm phase II study, Stacchiotti et al. observed a radiographic response rate of only 1 of 50 patients (2%) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST; 30% decrease in sum of longest diameters), despite stable disease in 35 of 50 patients (70%). The median PFS in the study was 9 months [32], but it is not clear how this would compare with no treatment in a similar cohort. In a separate retrospective analysis, 17 of 17 patients with advanced disease and PDGFR expression experienced stable disease, but no radiographic responses were observed [33]. Imatinib, though commonly used in clinical practice [34], is not approved by the U.S. Food and Drug Administration (FDA), or by any other regulatory agency, for the treatment of chordoma.

Based on preclinical evidence of the role of epidermal growth factor receptor (EGFR) in chordoma pathogenesis [35], Stacchiotti et al. performed a single-arm phase II clinical trial evaluating lapatinib (a dual inhibitor of EGFR and Her2) in subjects with advanced EGFR-overexpressing chordomas. Eighteen patients were enrolled and treated, and six (33.3%) experienced a response based on the Choi radiographic criteria. Median PFS in this study was 6 months by the Choi criteria and 8 months by the RECIST guideline [36]. Further attempts to target EGFR in chordoma include a case report which described a radiographic partial response using erlotinib alone [37], and another case series which described stable disease in three patients when erlotinib was used in combination with bevacizumab [38]. EGFR has also been targeted via the combination of the monoclonal antibody cetuximab and gefitinib, a tyrosine kinase inhibitor of EGFR. In two separate case reports, individual patients achieved partial radiographically defined responses [39, 40].

Bompas et al. evaluated sorafenib, a multikinase inhibitor, in an open-label, multicenter, single-arm phase II clinical trial. Sorafenib targets a number of tyrosine kinases that are overexpressed in chordoma, including vascular endothelial growth factor (VEGF), PDGF, EGFR, and c-KIT [41]. The goal of the study was to determine the 9-month PFS, as well as to describe other clinical outcomes. After a median 8.7-month follow-up, the median PFS was not reached, median OS was not reached, and there was one partial radiographic response according to the RECIST 1.1 guideline. The 9-month PFS was 73%. Adverse events related to sorafenib were similar to those seen historically in other disease settings, which include grade 3 hand–foot syndrome (18.5%), diarrhea (18.5%), hypertension (18.5%), weight loss (14.8%), and fatigue (11.1%). Notably, there is no historical control for trials such as this one in advanced chordoma and due to the heterogeneity of the patient population in the advanced setting, it is difficult to interpret PFS in single-arm studies like this. It is even more difficult to interpret PFS in the setting of significant toxicities, such as those caused by sorafenib. In the opinion of this author, the radiographic response is interesting and deserves further study, but any future study should have an active comparator arm to determine the role of sorafenib, given its adverse-event profile.

A single-arm phase II study of 9-nitro-camptothecin, an oral topoisomerase I inhibitor, enrolled 15 patients with advanced chordoma. One of 15 patients (7%) had an objective radiographic response, and the median PFS was 9.9 months [43]. Thalidomide has also been reported to induce a radiographic response in one case report [44]. Despite intermittent reports of activity with various agents, there is no clear standard of treatment in the advanced disease setting.

It is unclear if the agents described herein have an impact on clinical outcomes in patients other than those who have responses, because there is no clear historical control or randomized control arm comparator for PFS in the single-arm studies performed to date. The heterogeneity of clinical outcomes in the advanced disease setting, paired with the rarity of the disease, makes the path to drug registration unclear unless an agent induces objective responses in a larger proportion of patients [45].

The initial management of chordoma is fairly well defined. Patients should have maximal tumor debulking and adjuvant high-dose radiotherapy when possible. When surgery is not possible, high-dose radiotherapy achieves reasonable disease control in most cases. However, the majority of patients are not eligible for optimal therapy, and most of these will have disease recurrence. In most cases, recurrent disease will lead to death along variable timelines. As a result, there is an urgent need for therapeutic options capable of controlling or shrinking tumors. To date, evaluations of systemic therapies have been limited to single-arm studies or case reports. Unfortunately, despite rational selection of agents based on potential therapeutic targets identified by extensive preclinical work, radiographic response rates have been very low. Thus, the impact of these agents cannot be fully assessed, which has precluded their approval for use in advanced chordoma by the FDA or other regulatory agencies. Additional therapeutic targets continue to emerge, including brachyury, survivin, and others not described here. The recent activity seen in other tumor types treated with immunotherapy suggests that therapeutic cancer vaccines, immune checkpoint inhibitors, or a combination of these agents may be potential therapeutic options for chordoma. Careful selection of patient populations and endpoints will be required to definitively demonstrate efficacy and increase the armamentarium for physicians treating this rare tumor.