High-dose carbon-ion based radiotherapy of primary and recurrent sacrococcygeal chordomas: Long-term clinical results of a single particle therapy center.
Authors: Bostel Tilman , Mattke Matthias , Nicolay Nils Henrik , Welzel Thomas , Wollschläger Daniel , Akbaba Sati , Mayer Arnulf , Sprave Tanja , Debus Jürgen , Uhl Matthias 
Published: May 2020

Abstract
BackgroundThis study aimed to analyze the oncological long-term results and late toxicity of carbon ion-based radiotherapy (RT) of patients with sacral chordoma and to identify potential prognostic factors for local control (LC) and overall survival (OS). MethodsA total of 68 patients with sacral chordoma (median age 61 years, range 34 - 84 years) treated at the Heidelberg Ion Beam Therapy Center were included in this study. Of these 52 patients (77%) received a primary RT and 16 patients (23%) received a RT in a recurrent situation. All patients were treated with carbon ion RT, either in combination with photons or as a monotherapy, with a median radiation dose of 66 Gy RBE (range 60 - 74 Gy). In 40 patients (59%), RT was performed in the postoperative situation. Postoperative care included regular MRI scans, which were performed in 3-month intervals in the first year and in 6-month intervals in the following years. Local progression was defined as an enlargement of the maximum tumor diameter by 10% or a new tumor growth within the planning target volume (PTV). LC and OS were determined using the Kaplan-Meier method. Furthermore, the relevance of various prognostic factors for LC and OS was assessed by univariate and multivariate analysis.Results:The median follow-up period was 60 months (range 1 - 96 months). The 5-year rates for LC, metastasis-free and disease-free survival and OS were 43%, 82%, 44% and 82%, respectively. Local recurrence was observed in 31 patients (46%), occurring after a median follow-up time of 24 months (range 2 – 72 months). Only 10% of local recurrences occurred later than 5 years after RT. The univariate analysis showed a statistical significance for the initial macroscopic tumor volume (GTV) and a strong trend for the therapy situation (primary vs. recurrence situation) to predict a local tumor recurrence. In the log-rank test and univariate analysis, the age of patients, size of the GTV and PTV were identified as strong predictors of OS after RT of sacral chordoma. In the multivariate testing, borderline significance was evident for the therapeutic situation (primary vs. recurrence situation) to predict local tumor recurrence, while none of the tested factors were significant for the prediction of OS after RT.The incidence of late toxicity ≥ III° according to CTCAE v5.0 was 21%. Sacral insufficiency fractures occurred in 49% of patients (maximum III°: 16%) and were thus by far the most frequent late side effect in our analysis. Radiogenic damage to the peripheral nerves, intestinal tract and skin was observed in only 9% (≥ III°: 5%), 3% (all II°) and 9% (all I°) of patients.Conclusion Our analysis showed only moderate long-term local control rates after carbon ion-based RT, with sacral chordomas having a particularly poor prognosis in the recurrent situation. A recent study (ISAC) evaluates the safety and effectiveness of further dose escalation and hypofractionation of proton and carbon ion therapy in sacral chordoma. Here, the potential benefits of dose escalation must be weighed against the possible side effects.