Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients

Chordoma is a rare, low-grade, primary malignant bone tumour arising from primitive notochord remnants of the axial skeleton. It accounts for 1-4% of all primary skeletal tumors and its incidence rate is inferior to 0.1 per 100,000 inhabitants per year [1, 2].

Due to its ectodermal origin, chordoma is not properly a sarcoma even if it has clinically retained and classified as such being a primary tumor of bone [3]. The sacrum represents the more common anatomical site of origin accounting for 50-60% of all cases followed by the skull base region (spheno-occipital/nasal) (25-35% of cases), the cervical vertebrae (approximately 10% of cases), and the thoracolumbar vertebrae (approximately 5% of cases) [4]. Chordoma biological behaviour is characterized by a generally slow aggressive local growth with a low to late tendency in metastatizing to distant sites including the lung, bone, soft tissue, lymph nodes, liver, and skin [4]. Although it is considered to be of low metastatic potential, up to 40-60% of patients are, however, reported to develop distant metastases over the course of their disease [5–7].

Adequate wide surgery still remains the cornerstone of chordoma treatment even though safe margins are often hard to obtain because of its anatomical sites of origin. The achievement of negative surgical margins favourably correlates with the rate of local relapse and survival [8–10].

Conventional radiotherapy with high-energy photons is poorly active and need, moreover, to be delivered in doses as high as 60-65 Gy [11]. It may offer some temporary benefit in disease control in patients with inadequate surgery (i.e. close or positive margins) or, as exclusive treatment, in patients with unresectable/inoperable disease. Proton radiotherapy may succeed in offering better tumour control and fewer side effects even if it still not readily available in comparison to external-beam radiotherapy [12].

Sensitivity to chemotherapy is very low and generally reported in the small subgroup of patients with high-grade dedifferentiated chordomas with agents active in high-grade sarcomas [13]. Chordoma overexpresses platelet-derived growth factor receptor (PDGFR)-β and its phosphorylated form, denoting constitutive activation [14]. A phase II trial with tyrosine kinase inhibitor imatinib meyslate (IM) at 800 mg daily dose in 55 patients with unresectable or metastatic chordomas, showed a clinical benefit rate (complete response plus partial response plus stable disease ≥ 6 months) of 73% with a 38% of patients free from progression at 1 year [15]. Subjective pain relief was reported by 64% of 39 symptomatic patients. Other molecularly target agents (cetuximab, gefitinib) and antiangiogenic therapy with thalidomide were tested in single cases of chordomas with interesting results [16, 17].

In this report, we present an analysis of the clinical characteristics, multidisciplinary treatment and prognosis of 25 consecutive patients with chordoma observed at our cancer centre from February 2004 until December 2008.

Chordomas account for less than 5% of all bone tumours and its histological assessment is often delayed due to non-typical signs and symptoms of disease with a frequent clinical diagnosis of pelvic or vertebral and irradiated pain due to discogenic or aspecific pathology.

The slow modality of biologic growth, associated to a relatively low incidence of metastatic spread makes surgery the primary treatment of this rare bone tumour. Although potentially curative, a margin-free "en bloc" resection is often very hard to obtain due to the anatomical sites of origin of chordoma, i.e. skull base, spine, and sacrum. Moreover, surgery is often performed in not referred centres, sometimes without a pre-surgical specific histological diagnosis and without having any technical expertise to perform a wide resection. The extension of margins is, in fact, a very important prognostic factor being correlated with the incidence of local relapses and overall survival.

In the experience of Maggiore Hospital of Bologna (Italy) on 52 patients treated over a period of fifty years until 2002, only 20% of patients operated on with safe margins had a local recurrence with a relapse-free-survival of 56-94 months [8]. This percentage has grown up to 100% of patients who underwent radiotherapy alone or inadequate surgery with ILM with the detection of a local recurrence within 17-20 months from primary surgery.

The central role of adequate radical surgery to assure long term disease control has been, moreover, shown by Tzortzidis et al in a recent series of 74 patients with primary or recurrent cranial base chordomas [9]. Recurrence-free survival at 10 years was 31% for the whole group of patients, but was 42% for the primarily operated patients with aggressive microsurgical resection and 26% for the reoperation cases (p = .0001).

In the retrospective analysis of Bergh et al on 39 patients with chordoma of the sacrum and mobile spine, only 4 out of 23 patients (17%) in whom WM could be obtained, developed local relapse in contrast with 13 out of 16 patients (81%) with inadequate surgery [20]. Local recurrence was significantly associated with an increased risk of metastasis and tumour-related death (p < .001). The adequacy of the final surgical resection was, however, not found to be related to the rate of metastases being essentially the same (approximately 30%) for those patients with WM as for those with intralesional or marginal excision. In the multivariate analysis, the Cox forward step wise model revealed that the performance of an invasive diagnostic procedure outside the tumour centre was an independent prognostic factor for local recurrence and metastasis while inadequate surgical margins was an independent adverse prognostic factor for local recurrence and tumour-related death. Other independent adverse prognostic factors were microscopic tumour necrosis for local recurrence, ki-67>5% for metastases and larger tumour size for tumour-related death, respectively.

In our series of 25 patients, 22 were submitted to surgery on primary lesion between 1995 and 2008 (4 patients in our cancer centre from 2004). Initial WM surgery were obtained in 5 patients while ILM were a result in the remaining 17 patients. One out of the 5 patients with wide resection margins is still without evidence of disease at 20 months while two patients died without evidence of disease after 3 and 36 months from surgery. The remaining two patients developed a distant metastatic disease without local recurrence after 90 months and a local and distant relapse of disease at 6 months from surgery, respectively. At a median follow up time of 48 months, almost all patients (16 out of 17, 94%) with not safe surgery (ILM) underwent first local progression of disease after a median time of 18 months. Only one patient with intralesional resection is currently without radiological and clinical evidence of local progression but the post-surgical follow up is still short (7 months). Taking into account all surgically treated patients, the median time to first evidence of local recurrence/local progression of disease was 26 months with a 2-year local progression-free survival of 53%. The median number of total local relapses per patient was 1 (range:1-3) and surgery was the treatment of choice in all cases except for three, the ones treated exclusively with radiotherapy.

Conventional photon beam radiation therapy is scarcely active and needs, moreover, to be delivered in high and often relatively toxic doses (60-65 Gy) to obtain a curative effect [21]. It may have a role as a complementary treatment in patients with close or intralesional margins or as definitive therapy in unresectable patients, even if a local control at 5 years can be obtained in much less than 50% of patients [6, 22, 23]. More recently, the introduction of new techniques such as intensity modulated radiation therapy (IMRT) and stereo-tactic radio-surgery has led to the possibility to deliver high photons doses with sparing surrounding tissue resulting in improving treatment tolerability [24, 25]. With the intent to offer better tumour control and fewer side effects, hadrons such as protons or charged particles (carbon ions, helium or neon) were employed with interesting clinical results [26, 27]. In particular, published series of high-dose protons radiotherapy showed a 5-year control rate of 50-60% even if this approach is still poorly available respect to external-beam radiotherapy [28, 29].

Only three out of 22 operated patients of our series were treated with "complementary" radiotherapy (protons for two patients and conventional radiotherapy for one patient) after primary surgery. All three patients had ILM and underwent a subsequent progression of disease (two local and one at distance).

In our survey, seven patients (28%) developed a metastatic disease at a median time from first diagnosis of 81 months. Five out of these seven patients obtained ILM at first surgery and all of them developed metastatic disease after local relapse. One of the remaining two patients with WM developed exclusive metastatic disease and the other one metastatic disease after local relapse. The lung, bone and soft tissues were the most frequent distant localizations. Patients with unresectable disease (or resectable disease but through highly mutilating surgery) as well as patients with metastatic spreading can be offered poor therapeutic chance of cure or, at least, of tumour growth control. As for other low-grade neoplasms, sensitivity to chemotherapy is very low and generally reported in the very small subgroup of patients with high-grade dedifferentiated chordomas with agents active in sarcomas [13]. A prospective phase II trial with topoisomerase I inhibitor 9-nitro-camptothecin was conducted by Chugh et al with only one (7%) objective response in 15 chordoma patients and a median progression-free survival of 47% and 33% at 3 and 6 months, respectively [30]. Single case experiences of responses to vinka alkaloids and alkylating agents have been reported as well as to thalidomide, an antiangiogenetic agent [17, 31, 32].

The advent of target therapy era has opened new perspectives for this rare and chemo-resistant disease. IM at a daily dose of 800 mg was employed in 6 patients with a prevalent non-dimensional tissue response (as evidenced by characteristics CT and RMN pictures) but a symptomatic improvement and a cytological evidence of regressive type alterations and apoptotic figures [33]. Successively, in a molecular/biochemical analyses of the three receptors targeted by IM (PDGFRB, PDGFRA, and KIT) in a series of 31 chordoma patients, it was proven that PDGFRB was highly expressed and phosphorilated whereas PDGFRA and KIT were less expressed but equally activated [14]. These results, together with the absence of gain-of-function mutations and the presence of cognate ligands, strongly supported the hypothesis that the activation mechanism is the autocrine/paracrine loop.

The clinical activity of IM at 800 mg daily dose was explored in a recent multicenter phase II prospective trial on 55 (7 of whom included in the present series) patients with locally advanced or metastatic chordomas with biomolecular or immunohistochemical evidence of PDGFRβ activation and/or presence of PDGFB [15]. A clinical benefit rate (complete response plus partial response plus stable disease ≥ 6 months) was obtained in 71% of 44 evaluable patients. The median progression-free survival was 39 weeks and 35% of patients were free from progression at 1 year. Interestingly, a subjective pain relief was reported by 64% of 39 symptomatic patients. A synergy between IM and cisplatin was, furthermore, assumed by the evidence of a restoration of response to the tyrosine-kinase inhibitor with adding a low dose of the cytotoxic agent [34].

Also, in the present case series, over 50% of patients experienced symptomatologic pain improvement with reducting the use of analgesics during IM treatment. The full dose of 800 mg daily was poorly tolerated for long periods and the majority of patients underwent a dose reduction to 400-600 mg daily.

To conclude, despite the progress of current surgical techniques and some encouraging results with the use of targeted therapy, disease control and long-term patients prognosis are still poor and chordoma results, generally, in a long-lasting life-affecting disease. Nevertheless, specific experience of the multidisciplinary team (surgeons, medical oncologists, radiotherapists, pathologists, radiologists) is a very important pre-requisite in succeeding to improve patients' quality of life and, hopefully, outcome.