Literature review

We conducted a comprehensive search of the MEDLINE database, employing relevant MESH terms including ‘skull base’, ‘clival’, ‘chordoma’, ‘radiosurgery’, and ‘proton therapy’, as well as several related variations. The search results underwent a screening process to eliminate duplicates and filter for articles in English, specifically focussing on research involving human subjects. Details of the screening process are illustrated in Figure 1. Out of a total of 505 search results, 219 publications were screened for relevance to the overarching theme of this narrative review. Our focus centred on original research articles that provided comprehensive institutional experiences in the primary treatment of clival chordomas, specifically those involving moderately large patient cohorts. We included studies exploring various radiation modalities, including photon, proton, and/or carbon ion therapies. Excluded from our review were studies directly comparing surgical approaches and those addressing the treatment of recurrent disease. Of the 128 reports retrieved, 94 articles were reviewed in detail, and the most relevant were included in Table 1 for proton therapy and Table 2 for photon-based RT. The evidence for surgery in this cohort was examined as it relates to the primary topic of radiation therapy.

Review of evidence regarding surgical resection

Any optimal surgical plan requires considerations of three key factors: patient factors (age, co-morbidities, previous treatment), anatomical factors (dural invasion, major vessel encasement, location, and size), and surgeon factors (experience with complex skull base approaches).⁷ Ultimately, the surgical treatment's overall goal is safe maximal resection while minimising surgical morbidity and preserving quality of life. Rarely is en bloc resection (R0) achievable for any skull base chordoma due to the dense and eloquent nature of adjacent anatomy.²¹ Therefore, the role of adjuvant radiotherapy in treating tumour that cannot be safely resected and/or ensuring eradication of microscopic (R1) or macroscopic (R2) residual disease is imperative.

There are no randomised controlled trials comparing different surgical approaches, with evidence being limited to institutional case series.²² The management strategy for approaching these tumours has shifted from exclusively open microsurgical approaches to implementing a 360° approach to each tumour following the development of extended endoscopic approaches.²³ These newer techniques have improved the degree of resection.²¹ The degree of resection at the index operation is well established as an important predictor of outcome, with complete resection having the best outcomes.¹⁷ Passeri et al. (from Lariboisière Hospital) and Wang et al. are two of the largest contemporary single-institution case series published on skull base chordoma.^{10, 21} These centres reported 5-year overall survival and progression-free survival rates of 75.1% to 76% and 52.1% to 45%, respectively. Even at the Lariboisière Hospital, which is a globally recognised centre with special expertise in the management of skull base chordoma, a gross total resection was only achieved in 43.8% of patients, with a near total resection (>90% resection) being achieved in a further 34.3%. This series highlights the value of adjuvant radiotherapy, as their series demonstrated a significantly lower progression-free survival in patients who did not receive adjuvant radiotherapy compared with patients who received radiotherapy.²¹

Review of evidence regarding use of radiotherapy

Initial research demonstrated that conventional fractionated doses in a dose range of 25–60 Gy were insufficient to achieve a high probability of long-term control.²⁴ These patients had a median time to progression of 35 months and overall medial survival of 62 months. With the advent of radiosurgery, it was recognised that small skull base chordomas which had sufficient space between tumour and critical organs such as brainstem could be well controlled with single-fraction stereotactic radiosurgery (SRS).²⁵ Early series reported 2-year local control rates of up to 82%.^{5, 26-30} However, more recent series consistently show 5-year local control rates ranging between 45% and 73% (Table 2).^31-35 Of note, Shinya et al.³⁵ report 5-year local control rates of 63–73% only when treating larger volumes including the pre-operative tumour volume with margins to margin doses of 18–20 Gy. Irradiating only the gross tumour residual/recurrences led to unacceptably high local recurrence rates, even when irradiating to high marginal doses, as recurrences occurred in the surrounding surgical cavity.

Proton therapy was used in specialised centres for skull base chordomas to attempt dose escalation in this challenging anatomical site, initially with passive-scattered proton therapy, and later with pencil-beam scanning proton therapy techniques. The ability to provide durable control of the primary tumour is dependent on the amount of residual tumour post-resection and the ability to deliver very high radiation dose to the residual disease, as underdosing even a small part of the target volume has been associated with a reduced probability of local control.^{12, 36, 37} The importance of delivering high doses to the tumour to ensure local control is seen in the study by Kim et al. where delivery of 79 Cobalt Grey Equivalent (CGE) resulted in 90% tumour control rate at 5 years. However, a lower tumour dose of 62 CGE caused a precipitous drop in the control rate to only 50%, suggesting a steep dose–response relationship for local control.³⁸ Although radiosurgical treatment approaches can deliver similar equivalent high doses, it does so with minimal or zero GTV to CTV margin and in a heterogeneous manner (‘hotspots’ within the target volume), and most series demonstrate recurrences that are outside the prescription isodose envelope.³⁹

Contemporaneous proton therapy series show a local control rate ranging from 70 to 85% at 5 years, arguably better than that for comparable photon-based treatment approaches. As local recurrences inevitably cause severe morbidity and eventually death, the improvement in local control is also reflected in better overall survival rates of 62–88.3% (Table 1). Reported series from the Paul Scherrer Institute, Switzerland, the pioneers of pencil-beam scanning proton therapy, show excellent local control rates (5-year LC = 75.8% and 7-year LC = 70.9%) and long-term survival (5-year OS = 86.4% and 7-year OS = 80%).^{16, 40} The authors also emphasised the need for chordomas to receive a higher dose compared to chondrosarcomas and another mesenchymal malignant tumour seen in the skull base region. This series being one of the largest long-term outcomes of intensity-modulated proton therapy (IMPT) for chordomas of the skull base showed reduced toxicity profiles in patients treated with proton therapy compared to historical cohorts.¹⁶ The largest reported experience of paediatric base of skull chordomas was reported from the Massachusetts General Hospital (MGH), Boston, by Ioakeim-Ioannidou M et al.⁴¹ The group reported 10- and 20-year PFS of 69% and 64%, respectively, with median survivals of 26 years and very low toxicity rates from high-dose (median 76.7 Gy RBE) conventionally fractionated proton or combined proton–photon treatment approaches. It is of note that MGH transitioned from combined treatments to proton-only treatments with the advent of pencil-beam scanning technology. Several excellent reviews of the literature for proton therapy in skull base chordomas have been published recently including systematic reviews.^42-46 Other significant series are summarised in Table 1.^{15, 37, 47-49}

To date, there have been no randomised studies comparing proton therapy and photon therapy. In a meta-analysis spanning the years 1999 to 2010, Di Maio et al.⁵⁰ concluded that there was no significant difference in 5-year overall survival based on the adjuvant radiation modality, whether it be proton therapy, carbon ion therapy, Gamma knife radiosurgery, or fractionated photon radiation. However, it is noteworthy that the impact of the radiation dose delivered was not explored. Therefore, it remains unclear whether the absence of modality-related differences is attributable to the dose–response relationship. Interestingly, the analysis revealed a lower weighted mean 5-year progression-free survival (PFS) for patients treated with radiosurgical photon therapy when compared to carbon ion therapy (P = 0.042).

Carbon ion-based particle therapy presents an alternative therapeutic approach for chordomas, characterised by a sharp distal fall-off, with the added radiobiological benefit of higher radiobiological equivalent (RBE) doses of carbon ions. These RBE doses are generally considered to range from 1.5 to 6.7 at the distal edge.⁵¹ This may translate into further improving the therapeutic ratio by delivering a more biologically effective dose to this radio-resistant tumour. While long-term comparable data to PBT are missing, some encouraging early outcomes have been reported.^{49, 52} Currently, there is a single ongoing randomised controlled trial worldwide that compares the outcomes of skull base chordoma treatment using either proton or carbon ion radiation.⁵³

Reasons for recurrence and the value of proton therapy

Local recurrence is the most common site of progression for skull base chordomas. Depending on the length of follow-up, recurrence rates for skull base chordoma vary between 40% and 60% at 10 years.^{21, 54} In cases where proton therapy is not available, clinicians may opt for stereotactic radiosurgery or fractionated stereotactic radiotherapy to extend the progression-free interval and reduce local recurrence, sometimes in combination with a second-look surgery. However, due to the necessity for exceptionally high radiation doses, as discussed earlier, this approach poses a substantial challenge in treatment planning. The clinical target volume, designed to encompass areas at risk of containing microscopic disease, often overlaps with critical neural and vascular structures that have been previously irradiated. Consequently, delivering such high radiation doses to adjacent normal tissues frequently leads to unacceptable levels of morbidity for the patient. Proton therapy, distinguished by its unique physical properties, offers a potential solution to both challenges. It enables dose escalation compared to conventional irradiation of the tumour while ensuring the safe delivery of doses to nearby sensitive structures. As demonstrated earlier, comparing patient series treated with radiosurgical approaches and proton therapy will always present challenges due to inherent selection biases, variations in treatment philosophy, and technical nuances. In the past, a radiosurgical approach may have been the only viable option when access to proton therapy was limited, primarily due to logistical and cost-related barriers associated with travel. However, with the establishment of a proton therapy centre in Australia, making this advanced treatment accessible to Australians with chordoma, the approach to management warrants reconsideration. This development is expected to bring about a significant improvement in patient care, aligning it more closely with international best practices. This also affords a unique opportunity to generate prospectively collected, proton therapy-related, long-term toxicity data in this rare tumour, which may be the most robust data in the absence of randomised comparisons with other techniques. The ASPIRE²⁰ aims to achieve this by establishing a survivorship plan for these patients and longitudinally following up in collaboration with the referring teams for delayed side effects of radiation, including visual, hearing, cognitive, endocrine, and growth-related side effects as well as second malignancies, further comparing with a cohort of patients treated with photon-based techniques.

There is uniform consensus among the global medical and patient community involved in the treatment of chordomas that local control and survival with proton therapy is superior when compared with conventional photon radiotherapy techniques.⁵⁵ If using radiosurgical techniques, the concern for dose uniformity across the target volume is also highlighted in this paper.

A summary of recommendations is presented in Table 3.

The multidisciplinary team approach

The value of the multidisciplinary team approach in management of skull base chordoma is highlighted by Freeman et al., who published their experience of MD Anderson Cancer Centre, where they examined the outcomes of patients referred to their unit for initial management compared to patients referred after failed management at a different unit.⁵⁶ They demonstrated that a comprehensive multidisciplinary team requires surgeons with expertise in complex open and endoscopic skull base surgery, radiotherapy teams that offer adjuvant therapy with protons and photons and have access to clinical trials for patients with progressive or metastatic disease to deliver superior patient outcomes.

Du et al. in 2022 published an article examining the influence of facility patient volume and outcome.⁵⁷ The study demonstrated that academic centres operating on at least seven patients a year with skull base chordoma had superior outcomes compared to units who operated on fewer patients per year. It has also been demonstrated that delivery of radiotherapy in rare tumours like sarcomas, and thus arguably chordomas, is best done at specialised treatment centres.⁵⁸ This an important concept to consider in Australia with a population of only 26.5 million people and an incidence of skull base chordoma of 0.033 per 100,000 population.⁵⁹ Extrapolating this to the introduction of proton therapy to the region, there needs to be a robust system of multidisciplinary communication between geographically distant specialists and systematic referrals to a nationally accessible proton centre. This is because implementation of this technology is not without its challenges. It requires an experienced multidisciplinary team, rigorous patient selection criteria, and attention to detail in terms of surgical techniques and robust optimisation and evaluation protocols.

With the development of the first proton therapy centre in Australia, it is important to establish a collaborative approach and an associated multidisciplinary team of skull base surgeons, radiologists, pathologists, radiation oncologists, and medical oncologists, each with expertise in the various aspects of treating this rare and complex tumour, to ensure the best patient care will be delivered, as the evidence supports superior patient outcomes when complex cases are concentrated to a handful of expert multidisciplinary skull base teams. This may be enhanced by efforts to generate awareness about the specific requirements for proton therapy and establishment of a robust referral mechanism and access to clinical trials at the proton therapy centre.