In this study, we document a series of 12 chordoma cases through a single institution’s experience in Greece. Undoubtedly the common practice in many medical centers deviates from the ideal due to deficits in resources, use of outdated technology, or lack of surgical experience. The major objective of the analysis was to provide insight into the treatment of the disease and a framework for better practice in the future after an overview of the clinical and paraclinical characteristics of our patients and their therapeutic outcomes.
Due to the inherent biology of the tumor, chordomas’ clinical management has been traditionally dependent upon operative control. Boriani claimed aptly that “treatment of spinal chordoma is a 1-shot surgery” to accent the importance of the first surgery and the futility of reoperations in the long term [24]. Clarke reached a similar conclusion emphasizing the beneficial effect of maximal excisions of tumors not previously violated and proposed to include even the biopsy needle tract in the surgery plan to avoid recurrence [25]. Enneking in his surgical staging system for musculoskeletal sarcomas described operative margins as radical, wide, marginal, or intralesional [26]. However, due to the relentless progression of chordomas and their proximity to critical structures, gross total resection with free “wide” margins seems elusive even in the case of en bloc sacrectomy procedures [25], and this is the reason we only refer to intralesional excisions in this study. Particularly, when it comes to cervical chordomas, unless they are restricted within the vertebral body, striving for ample margins can irreversibly harm the patient [27].
Balancing between operative radicality and postoperative functional neurological status under the threat of recurrence and the inevitable fatal termination is challenging. Equally difficult is the decision to cease re-operating, an issue born out in our series and others [28] that necessitate good judgement on the surgeon’s side. The 82% rate of recurrence cited herein is daunting and credited largely to incomplete surgeries not outweighed by modern radiotherapy. In hindsight, it could have been more beneficial for our patients to carry out more radical operations, decrease the surgical stages, and select more suitable approaches in the context of a personalized treatment plan.
The dura, until breached, impedes early tumor expansion; hence, the worth of an epidural route has emerged from the literature [29, 30]. Sen failed to evince superiority among an assortment of either lateral or midline anterior or combined approaches to the skull base in a total of 80 operations but accentuated the positives of the recent wide application of endoscopic endonasal approach (EEA) [30], which seems to gain momentum according to many studies [31,32,33,34]. In a series of 54 patients harboring skull base chordomas managed exclusively with EEA, Chibbaro recorded a gross-total resection rate of 65% and underlined the method’s shortcoming in repairing the base’s defect [32]. Gui, having experience with 161 cases, separated cranial chordomas into anterior skull base type, superior clivus type, superior-middle clivus type, middle-inferior clivus type, inferior clivus type, total clivus type, and extensive type (tumor in the median and paramedian regions) to direct the surgical corridor through the EEA and suggested a subsequent phase II open approach or just even a single craniotomy to facilitate resection of those too far laterally, superiorly, or inferiorly located tumors [33].
The advent of particle therapy paired with the evolution of molecular-targeted drugs and the tremendous advancements in terms of surgical approaches, reconstruction, and microsurgical techniques have reinvigorated the inception of a potent cure against an infiltrative radioresistant tumor that poorly responds to cytotoxic chemotherapy. Refinements in the field of neuroimaging, neuroanesthesia, neurointensive medicine and the widespread adoption of intraoperative neuronavigation and electrophysiological monitoring also played a contributory role. This paradigm of multimodal treatment, in the concept of maximally safe cytoreductive surgery, has many proponents [35, 36], but still in this series due to the small number of patients, selection bias, and diversity of radiation modalities; no definitive conclusions on the benefits from adjuvant treatment regimens could be drawn.
The adjuvant treatment mostly advocated in the literature, albeit with the pertinent discrepancies, is proton beam radiotherapy, which is capable of delivering high-energy particles to the tumor bed with precision, ergo lessening the dose to tissues in close vicinity [22, 37]. Rotondo studied the preoperative administration of proton-based radiotherapy (RT) to 44 primary and 16 recurrent spinal chordomas followed by a boost postoperative RT and deduced 5-year overall survival (OS) rates of 85% for the primary chordomas and 71% for the recurrent ones [38]. Likewise, 91 skull base chordomas attained good outcomes when given mixed proton–photon irradiation with the prescribed dose adjusted to postoperative tumor volume, a value of which less than 25 ml conferred higher local control rates (LC) [39]. Imai surveyed the efficacy of carbon ion radiotherapy for 95 unresectable sacral chordomas and observed a 5-year overall survival rate at 86% [40], which is in keeping with the favorable results shown by Uhl in 56 similar cases irradiated either solely with carbon ions or in combination with photon IMRT [41]. Uhl et al. also accumulated the results of 155 skull base chordomas treated with carbon ions, yielding at 5 years an OS rate of 85% and a corresponding LC rate of 72% [42]. Nowadays, a phase III trial is ongoing by Uhl’s associates with the purpose of sorting out whether the higher relative biological effectiveness of carbon ions reflects a therapeutic advantage over protons [43].
A short time ago, we came across the dilemma of modifying the fixation system of a patient, suffering from gross residual disease of the thoracic spine, since questions had been raised as to whether the target volume could be delineated and covered sufficiently in the presence of metal-induced artifacts, leading to him being rejected from two proton therapy centers. Unfortunately, a few months later, he developed signs of impending paraplegia, and a thoracotomy was performed, the third overall, with the intent of anterior spinal cord decompression, leaving the instrumentation intact and followed by stereotactic radiosurgery (SRS). Staab et al. in a prior work implied that surgical stabilization (SS) could possibly compromise the outcome of extracranial chordomas, quoting a 100% actuarial LC rate at 5 years for 19 patients without SS, after actively scanned proton delivery. On the opposite to this cohort, the same radiation technique heralded a clearly worse 5-year LC rate of 30% when used on another subgroup of 21 patients who required titanium-based SS [44].
Considering small intracranial tumors, SRS is an effective alternative to particles correlated with fewer adverse radiation effects (AREs), as evidenced in a study embodying 71 cranial chordomas, out of whom 51 that had not received fractionated radiation therapy prior to SRS trended toward better 5-year survival rates contrary to the rest (93% vs 43%) [45]. In another series with a median follow-up time of 34 months, tumor control was the fact for 8/16 patients with cranial chordomas who had an operation in conjunction with SRS [46]. SRS for spinal chordomas is not that well-established but has clinical merits warranting evaluation in view of the absence of particle therapy facilities in countries that render the treatment cost prohibitive [47, 48].
The refractoriness of chordoma cells to cytotoxic chemotherapy and their rich expression of numerous tyrosine kinase receptors, such as PDGFR-α, PDGFR-β, EGFR, VEGFR, HER2, KIT, and MET prompted the appraisal of molecular inhibitors as novel therapeutics in chordomas. So far, imatinib, sunitinib, sorafenib and lapatinib have been tested in phase II trials with appreciable results on disease remission [49], which is in striking contrast with the unpleasant inferences made about our three eligible medicated patients.
Published records to date report a mean age at diagnosis of 47.5 for chordomas arising in the basiocciput [19], and 59.9 years for the extracranial lesions [20]. In our cohort, the mean age for cranial lesions was 46.9 and for extracranial was 49.4. In particular, the youngest patients in our series were one 22- and one 24-year-old males afflicted with spheno-occipital chordoma, which is in line with the reported age spectrum of the disease in regard with location [13].
The etiologic factors of the dismal survival outcomes in our series could be attributed to delayed presentation to physician, contaminated margins, and iatrogenic tumor seeding, portending primary site failure. Palliative conventionally fractionated radiotherapy appeared to relieve pain and restrain tumor regrowth only temporarily, an experience shared by others before the emergence of proton therapy [10, 13, 50,51,52]. The longest survivor is successfully salvaged at 7 years and harbors a cervical chordoma with cartilaginous differentiation, which concurs with Heffelfinger’s perspective on that pathology [14]. Only two cases of distant failures were discovered, but others could have been missed, owing to staging or follow-up procedures that did not encompass all risky sites.
Methodologic limitations and recommendations
Emphasis should also be put on the limitations of this study, given the rarity of this disease that precludes not only an individual clinician’s potential to expertise but also a center’s ability to output large series and offer a rationale for treatment. For its retrospective nature, the present analysis could be susceptible to bias, emanating from restrictions related to patient heterogeneity, individually tailored protocols, changes in surgical team, and improvements in practices over the last 27 years. Further, we relied on scant data on some patients, especially from the earlier era without omitting those who had a short follow-up. This article depicts the outcomes of 12 patients subjected to a non-subspecialized center and, despite not reaching statistical significance, they were indeed illustrative of all clinic-anatomical features of chordoma and could be examined on their concordance with other series.
Due to its peculiarities, this condition is not amenable to satisfactory treatment and still follows a set fatal course. The position paper of the Chordoma Global Consensus Group in January 2015 concludes that in order to optimize treatment outcomes, chordoma patients should be served in specialized centers with a high caseload and a multitude of disciplines involved [22]. On the basis of the second consensus group meeting on how to tackle locoregional recurrence of chordoma, convened in November 2015, when metal implants cannot be altered, extracted, or replaced with carbon fiber devices, photons, which generate less artifacts, can be delivered in lieu of charged particle radiotherapy [18]. In countries deprived of referral institutes, surgical hospitals of average size such as ours, that prefer to follow a safe rather than an aggressive treatment policy, are in imperative need of interdisciplinary communication with radiotherapists and oncologists of other domestic or even foreign institutions in order to prevent instrumentation-caused interference to radiotherapy plans and enable patient participation in coordinated experimental research programs.
