Proton and carbon ion radiotherapy in skull base chordomas: a prospective study based on a dual particle and a patient-customized treatment strategy

Abstract

Background The aim of this study is to evaluate results in terms of local control (LC), overall survival (OS), and toxicity profile and to better identify factors influencing clinical outcome of skull base chordoma treated with proton therapy (PT) and carbon ion radiotherapy (CIRT). Methods We prospectively collected and analyzed data of 135 patients treated between November 2011 and December 2018. Total prescription dose in the PT group (70 patients) and CIRT group (65 patients) was 74 Gy relative biological effectiveness (RBE) delivered in 37 fractions and 70.4 Gy(RBE) delivered in 16 fractions, respectively (CIRT in unfavorable patients). LC and OS were evaluated using the Kaplan–Meier method. Univariate and multivariate analyses were performed, to identify prognostic factors on clinical outcomes. Results After a median follow-up of 44 (range, 6–87) months, 14 (21%) and 8 (11%) local failures were observed in CIRT and PT group, respectively. Five-year LC rate was 71% in CIRT cohort and 84% in PT cohort. The estimated 5-year OS rate in the CIRT and PT group was 82% and 83%, respectively. On multivariate analysis, gross tumor volume (GTV), optic pathways, and/or brainstem compression and dose coverage are independent prognostic factors of local failure risk. High rate toxicity grade ≥3 was reported in 11% of patients. Conclusions Particle radiotherapy is an effective treatment for skull base chordoma with acceptable late toxicity. GTV, optic pathways, and/or brainstem compression and target coverage were independent prognostic factors for LC. Key Points • Proton and carbon ion therapy are effective and safe in skull base chordoma. • Prognostic factors are GTV, organs at risk compression, and dose coverage. • Dual particle therapy and customized strategy was adopted.

Chordoma—Current Understanding and Modern Treatment Paradigms

“…Cyclin D-dependent kinases (CDK4 and CDK6) are another target for chordoma molecular therapy. These oncoproteins regulate cell cycle progression through the G1 phase into the S phase and have been shown to be overexpressed in chordoma cell lines and tissue samples due to loss of the CDKN2A gene and its protein product, p16INK4a [ 100 ]. Palbociclib, a CDK4/6 inhibitor, has been demonstrated to have in vitro [ 99 , 100 ] efficacy against chordoma cells and is part of a Phase II trial for advanced chordoma and other tumors (NCT03110744, accessed on 31 January 2021) ( Figure 4 ).…”

Brainstem NTCP and Dose Constraints for Carbon Ion RT—Application and Translation From Japanese to European RBE-Weighted Dose

“…In a recent publication on skull base chordomas treated at CNAO, Iannalfi et al. found that 92% of the local recurrences were attributable to suboptimal target dose in regions close to the brainstem or optic pathways ( 19 ). The estimated 5-year local control (LC) rate was 71%.…”

A Review of Particle Therapy for Skull Base Tumors: Modern Considerations and Future Directions

“…In the large majority of particle therapy series, gross tumor volume correlated with local control, and patients with small residual disease had a better outcome [ 22 , 24 , 26 – 29 , 36 , 37 ]. Moreover, several series demonstrated a correlation between compression of brainstem and/or optic pathways and outcome [ 26 , 29 , 34 ]. Finally, target coverage emerged as another factor strongly predictive of outcome [ 23 , 27 , 29 , 37 ].…”

“…Moreover, several series demonstrated a correlation between compression of brainstem and/or optic pathways and outcome [ 26 , 29 , 34 ]. Finally, target coverage emerged as another factor strongly predictive of outcome [ 23 , 27 , 29 , 37 ].…”

“…None of the three approaches is, however, at present based on adequate evidence. In a recent article from the Italian center Centro Nazionale di Adroterapia Oncologica [ 29 ], proton therapy with 2 GyRBE per fraction was used in favorable cases (small residual gross tumor volume) and carbon ions with a high dose per fraction (4.4 GyRBE) was instead prescribed to patients deemed at higher risk. This selection was done according to clinical judgement.…”