Efficacy and safety of carbon ion radiotherapy for chordomas: a systematic review and meta-analysis

Objective Carbon ion radiotherapy (C-ion RT) for chordomas has been gradually performed in several research centres. This study aimed to systematically review the results of clinical reports from these institutions and to evaluate the safety and efficacy of C-ion RT. Methods In accordance with the PRISMA guidelines and set search strategies, we searched four databases for articles from their inception to February 11, 2023. These articles were screened, and data were extracted independently by two researchers. STATA 14.0 was used for statistical analysis of survival results. Results A total of 942 related articles were retrieved, 11 of which were included. Regarding lesion location, 57% (n = 552) originated in the sacral region, 41% (n = 398) in the skull base, and 2% (n = 19) in the spine (upper cervical). The local control (LC) rates at 1, 2, 3, 5, 9, and 10 years in these studies were 96%, 93%, 83%, 76%, 71%, and 54%, respectively. The overall survival (OS) rates at 1, 2, 3, 5, 9, and 10 years in these studies were 99%, 100%, 93%, 85%, 76%, and 69%, respectively. Acute and late toxicities were acceptable, acute toxicities were mainly grade 1 to grade 2 and late toxicities were mainly grade 1 to grade 3. Conclusion C-ion RT has attractive clinical application prospects and is an important local treatment strategy for chordomas. Encouraging results were observed in terms of LC and OS. Meanwhile, the acute and late toxicities were acceptable. PROSPERO registration number: CRD42023398792. Supplementary Information The online version contains supplementary material available at 10.1186/s13014-023-02337-x.


Introduction
Chordomas are locally aggressive malignant bone tumours with a low incidence that arise from cells of notochord remnants.Thus, chordomas are often located in the midline from the skull base to the sacrococcygeal bone [1].Overall, chordomas have an incidence of 0.8-1 per million, with approximately 50-55% of cases located in the sacrococcygeal bone, followed by the clival region (30-35%) and mobile spine (10-20%) [2][3][4][5][6].Chordomas have a low potential for metastasis, and the preferred treatment strategy for them is complete surgical resection [7].Previous studies have reported that local control (LC) is a significant survival outcome [7].However, complete resection of some chordomas are often difficult in patients with adjacent to critical anatomical structures such as the brainstem, spinal cord, and optic pathways [8,9].Radiotherapy (RT) plays an irreplaceable role in the treatment of chordomas, especially those that are inoperable or have residual tumours after surgery [10].
Chordomas are known to have low radiosensitivity, requiring higher-dose irradiation (at least 70 Gy) to gain adequate LC [11].However, because of the proximity of some chordomas to critical risk organs, such as the brain stem, spinal cord, and optic nerve pathways, achieving high doses of tumour irradiation can be difficult with traditional photon therapy.In recent decades, particle radiotherapies, such as proton beam therapy (PBT) and carbon ion radiotherapy (C-ion RT), have emerged as RT techniques.A higher dose can be delivered to the tumour area (Bragg peak effect) compared to photons while protecting the organs at risk (OARs).Compared with PBT and photons, C-ion RT has better relative biological effectiveness (RBE).Considering the abovementioned technical advantages, C-ion RT can become a new treatment option for chordomas [12].
In recent years, C-ion RT for chordomas has been gradually performed in several research centres.This study aimed to systematically review the results of clinical reports from these institutions and to evaluate its safety and efficacy.

Literature identification
This study was registered in the International Prospective Register of Systematic reviews (PROSPERO) (Registration No. CRD42023398792).This systematic review and meta-analysis adhered to the PRISMA guidelines and recommendations [13].

Search strategy
Candidate articles were obtained by searching four databases (Cochrane Library, Embase, PubMed, and Web of Science) from their inception to 11 February 2023.Literature not written in English was excluded.The search terms were as follows: (("Chordoma OR Chordomas OR Chordoma*") AND ("Heavy Ion Radiotherapy OR Heavy Ion Radiotherapies OR Heavy Ion Therap* OR Heavy Ion Radiation Therapy OR Carbon Ion Radiotherapy OR Carbon Ion Therap* OR Carbon Ion Radiation Therapy OR C-ion therapy OR hadron OR particle OR charged particle")).In addition, we traced the relevant references and manually searched the abstracts of congress meetings.

Inclusion and exclusion criteria
These articles were screened, and data were extracted independently by two researchers (MD and QZ).The inclusion criteria were as follows: (a) all patients were pathologically diagnosed with chordoma; (b) patients received C-ion RT; and (c) reported incidence of toxicity and survival outcomes, including overall survival (OS) and LC from initial diagnosis.The exclusion criteria were as follows:

Statistical analysis
Baseline variables and incidence of toxicity were analysed using descriptive statistics.Data descriptions included frequencies and percentages for dichotomous data, and means with standard deviations or medians with interquartile ranges for continuous data.We used a random effects model to provide an overall pooled estimate for the case series studies.We computed proportions with 95% confidence intervals (CIs) to estimate the effect sizes for continuous outcomes.All the analyses were performed using STATA version 14.0 (StataCorp, College Station, Texas, USA).

Table 1 Assessment of risk of bias in included studies
(a) Were there clear criteria for inclusion in the case series?;(b) Was the condition measured in a standard, reliable way for all participants included in the case series?; (c) Were valid methods used for identification of the condition for all participants included in the case series?;(d) Did the case series have consecutive inclusion of participants?; (e) Did the case series have complete inclusion of participants?; (f ) Was there clear reporting of the demographics of the participants in the study?; (g) Was there clear reporting of clinical information of the participants?;(h) Were the outcomes or follow-up results of cases clearly reported?;(i) Was there clear reporting of the presenting sites'/clinics' demographic information?; (j) Was statistical analysis appropriate?

Prognostic factors of C-ion RT effectiveness
The following factors were evaluated in nine studies: age, sex, Karnofsky performance status, gross target volume, planning target volume, tumour volume, level of proximal invasion, total irradiated dose, tumour status, eye symptoms, prior treatment, tumour-gastrointestinal distance, chemotherapy, spinal cord infiltration, and histology.

Discussion
Chordomas often occur adjacent to critical neuroaxes, such as the brainstem, spinal cord, and optic pathways [8,9].Therefore, complete resection of some chordomas is often difficult.A previous study has reported that the total resection rate of chordomas is approximately 20-70%, with an LC rate of 60-80% [26][27][28][29].However, the LC rate in patients with subtotal resection is approximately 25-50% [26][27][28][29].According to the practical guide from the Spine Oncology Society, RT plays an important role, especially PBT and C-ion RT, for some chordomas [30].To the best of our knowledge, this is the first systematic review and meta-analysis of C-ion RT for chordomas, including the skull base, sacral, and mobile spine.
Achieving high doses of tumour irradiation is difficult with traditional photon therapy because of chordomas adjacent to the critical neuroaxis OAR.Performing photon irradiation therapy in patients postoperatively has also been reported.After five years, LC reached only 39% [31].Satisfactory LC may be equally difficult to achieve with stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS).Debus et al. have reported the results of SBRT in the treatment of chordomas, with a 5-year LC rate of only 50% [32].Similarly, in a study of 93 patients with intracranial chordomas treated with SRS, the LC rate was 54.7% after 5 years [33].However, C-ion RT demonstrated an impressive LC rate compared to photon therapy in our study, with pooled LC rates of 76% and 54% at 5 years and 10 years, respectively (Fig. 2).
C-ion RT and PBT have similar physical advantages (Bragg peaks).Moreover, the C ion has a better RBE than PBT.However, whether C-ion RT or PBT is more favourable for chordoma treatment remains a long-term challenge in the field of charged-particle therapy.A systematic review of RT for chordoma included 2 prospective and 21 retrospective studies of PBT published by    Redmond et al. [30].The median LC and OS after 5 years among the reported studies were 73.3% and 81.3%, respectively [30].In our meta-analysis, the pooled incidence of LC and OS at 5 years were 76% and 85%, respectively (Figs. 2 and 3).Unfortunately, survival outcomes at follow-up times of ≥ 10 years could not be compared in the two studies.Using only prospective data, Iannalfi et al. have reported on PBT and C-ion RT for skull base chordomas [23].They observed a 5-year LC rate of 84% in the PBT group and 71% in the C-ion RT group, although they stated that patients with poor prognosis were specifically assigned to the C-ion RT group [23].
An imbalance in the baseline of patients was observed, and comparing survival outcomes between the two techniques was not appropriate.The Heidelberg Ion Therapy Center has published a retrospective study of PBT and C-ion RT for skull base chordomas [25].The 1-, 3-, and 5-year LC rates of the PBT group were 97%, 80%, and 61%, respectively, whereas those in the C-ion group were 96%, 80%, and 65%, respectively [25].The corresponding 1-, 3-, and 5-year OS rates were 100%, 92%, and 92% for the PBT group and 99%, 91%, and 83% for the C-ion RT group [25].Outcomes of C-ion RT and PBT treatment of skull base chordomas may be similar in terms of tumour control, survival, and toxicity [25].Therefore, the advantages of different charged particle RT techniques for chordomas need to be determined in more prospective studies, especially randomised controlled clinical trials.Of the 11 included articles, five were on skull base chordomas, five were on sacral chordomas, and one was regarding a mobile spine chordoma (Table 2).As reported in Additional files 1-4, the pooled LC and OS rates at 5 years and 10 years were very similar for the skull base and sacral chordomas, which indicates that C-ion RT may have similar tumour control and survival in different sites of chordomas [15][16][17][18][19][20][21][22][23][24][25].Chordomas have various pathological subtypes (classic, chondroid, and dedifferentiated subtypes), among which the prognosis of the chondroid type and dedifferentiated subtypes is very different.A model of individualised C-ion RT for chordomas requires further investigation.To the best of our knowledge, no reports on particle therapy (C-ion or PBT) for the different pathological subtypes of chordoma have been published.
Regarding toxicity, the most frequent toxicity was skin reaction [15-17, 19, 20, 22], and the incidences of grade 3 acute and grade 4 late skin toxicity were 3.2% and 1.1-2.1%,respectively [16,17,19].Kamada et al. have suggested that 73.6 Gy (RBE) may be the maximum tolerated dose for patients without subcutaneous tumours in order to reduce the incidence of skin toxicity [34].For patients with subcutaneous tumour involvement, the maximum dose may not exceed 70.4 Gy (RBE) [34].Koto et al. have reported on a one case with a recurrent skull base chordoma that developed grade 5 late toxicity (fatal bleeding from the nasopharynx) at 9 years and 3 months after C-ion RT [18].This patient had undergone transsphenoidal approach surgery 3 years before C-ion RT, and received a second surgery through the transpetrosal approach 1 year prior to C-ion RT [18].Late neuropathy (grade 3) and optic nerve injury toxicity (grade 4) had an incidence of 0.9-3.2% and 5.9%, respectively [17][18][19].According to a review on RT for chordomas published by Redmond et al., the median follow-up time for photon RT was 10-50 months [30].However, the median follow-up time in our included studies was longer, ranging from 23.3 to 108 months (Table 2).Therefore, directly comparing the toxicity between photon RT and C-ion RT is difficult.
This meta-analysis has several limitations.First, only 11 of 61 relevant full-text articles met the inclusion criteria, and grey literature was ignored, which may have a higher risk of publication bias.Second, the metadata were from different regions: Japan (64%), Italy (18%), and Germany (18%); only four studies were prospective or phase I/II or II trials.Therefore, the metadata were mainly obtained from small retrospective studies, and there could be patients lost to follow-up, selection biases, and reporting biases.Finally, chordomas are generally slow-growing; Scampa et al. have reported a median OS of approximately 10 years [35], although four studies had a followup period of > 10 years in our study.
Further, C-ion RT has some limitations as a therapeutic strategy for chordomas.Chordomas have various pathological subtypes (classic, chondroid, and dedifferentiated subtypes), among which the chondroid subtype has the best prognosis, and the dedifferentiated subtype has the worst prognosis [36][37][38].Therefore, it is interesting to hypothesise whether the dose is sufficient for pathological types with poor prognosis.In addition, clinical observations have demonstrated the metastatic potential of chordomas, with 5-40% of patients developing distant metastases during the course of the disease [39].Moreover, systemic therapies, including chemotherapy and targeted therapy, may be occasionally necessary, although

Conclusion
C-ion RT has attractive clinical application prospects and is an important local treatment strategy for chordomas.Encouraging results were observed in terms of LC and OS.Meanwhile, the acute and late toxicities were acceptable.
(a) studies on patients receiving other RT techniques, including photons, PBT, brachytherapy, and other charged particles; (b) duplicate publications; (c) overlapping cohorts (only the most complete studies were included); (d) re-irradiation studies; (e) sample size of < 10 patients; (f ) lack of detailed data; and (g) other irrelevant studies (case reports, reviews, and protocols).Data extraction Data extraction was performed independently by two reviewers (RL and QZ), and the results were verified by a third reviewer (DW).The following data were extracted: (a) research institution, study period, and study design; (b) baseline patient characteristics; (c) clinical features and treatment regimens; (d) survival and toxicity data; and (e) evaluation indicators of quality and bias.

Fig. 1
Fig. 1 Search results per the PRISMA guidelines

Fig. 2 Fig. 3
Fig.2The pooled incidences of LC after C-ion RT for chordoma

Table 2
Baseline characteristics of included studies *HIBMC, QST, SAGA-HIMAT, GHMC † Only carbon ion data is included § Only chordoma data is included NIRS National Institute of Radiological Sciences, HIBMC Hyogo Ion Beam Medical Center, QST National Institutes for Quantum Science and Technology, SAGA-HIMAT SAGA Heavy Ion Medical Accelerator in Tosu, GHMC Gunma University Heavy Ion Medical Center, CNAO Clinical Department, National Center for Oncological Hadrontherapy, HIT Heidelberg Ion-Beam Therapy Center

Table 3
Clinical features and treatment regimens main results of all included studies NR no reported, P/R/M primary/recurrent/metastasis, RBE relative biological effectiveness †

Table 4
Survival outcomes, toxicity incidence and prognostic factors on patients of all included studies Bold indicates statistically significant difference NR no reported, KPS Karnofsky performance status, GTV gross target volume, PTV plan target volume, GI: gastrointestinal † Only carbon ion data is included § Only chordoma data is included Study Local

Table 4
(continued)no recommended consensus or treatment guidelines have been established.