In our systematic review, BSs patients, including patients with chordomas, chondrosarcomas, and osteosarcomas, were treated with C-ion RT. The prescribed doses were 48 to 80 Gy RBE for BSs (Table 4). The 3-year and 5-year OS rates were 85% and 72.7%, respectively (Fig. 3), the 3-year and 5-year LC rates were 86% and 74.3% (Fig. 2), respectively [10,11,12,13,14,15,16,17,18,19,20,21]. According to previous clinical outcomes in X-ray RT, the 5-year OS and LC rates were 50–70% and 27–67%, respectively, and those in proton RT were 67–84% and 62–81%, respectively [5, 6, 22,23,24,25,26,27,28,29]. Therefore, compared with those in past clinical reports, the efficacy and safety of C-ion RT for bone sarcoma were comparable to those of proton RT but better than those of X-ray RT. Moreover, patients treated with C-ion RT had similar surgical outcomes despite being unsuitable for surgery [5, 30,31,32,33,34,35]. In this case, C-ion RT may be an important local treatment option for patients with such BSs.

In the four studies regarding chordoma with C-ion RT in our study (Additional file 1: Fig. S1 and Additional file 4: Fig. S4), the LC rates at 3, 5, and 10 years were 81.9%, 80.2%, and 54.1%, respectively; the OS rates at 3, 5, and 10 years were 94.8%, 84.2%, and 70.1%, respectively [13, 15, 16, 18], Due to the low possibility of metastasis, complete surgical resection or control of local tumor progression is a critical factor for long-term survival [36,37,38]. Both base skull and sacrococcygeal chordomas are often adjacent to important neuroaxes; therefore, complete resection is often difficult to achieve. According to the previous reports, the proportion of complete resection of the tumor was approximately 20–70%, LC rate of total resection was approximately 60–80%, and LC rate of subtotal resection was approximately 25–50% [39,40,41,42]. In terms of proton therapy alone, Chen et al. reported a study including 24 unresectable chordomas, with 19 sacral chordomas [43]. They irradiated the tumor with a median total dose of 77.4 Gy (RBE). The 5-year local progression-free survival and OS rates were 79.8% and 78.1%, respectively. In a systematic review by Amichetti et al. [44], the mean 5-year LC and OS rates after proton therapy were 69% and 80%, respectively. Overall, carbon ion therapy for chordoma had outcomes similar to those of surgical and proton radiotherapy. In addition, an adequate total dose is essential for the LC of chordomas with carbon ion therapy. Uhl et al. prescribed a total dose of 60.0 Gy (RBE), with LR and 5-year LC rates of 35.5% and 72%, respectively [18]. The clinical results were inferior to those of three studies from Japan [13, 15, 18]. Nevertheless, the LR rate was 6.3–35.5% with carbon ion therapy for chordoma in our four selected studies [13, 15, 18], which was still significantly lower than the LR rate of 35–50% after primary chordoma surgery [36,37,38].

Surgical treatment is the first choice of treatment for chondrosarcoma. However, chondrosarcomas located in the base skull or spine/paraspinal region are often difficult to completely resect, and even if resection can be performed, there is still a risk of recurrence. According to Bloch et al., the 5-year LR rate was 44% after surgery alone, 19% after radiotherapy alone, and 9% after surgery combined with adjuvant RT [45, 46]. In this case, RT may be an important therapeutic strategy for chondrosarcomas that are unresectable or residual after incomplete surgery. Owing to the radiation resistance of chondrosarcomas, a relatively high dose is required to achieve an adequate LC rate. Kano et al. used a Gamma knife to irradiate base skull chondrosarcomas. According to this report, the median target volume and margin dose were 8 cm3 and 15 Gy, respectively, and the LC rates at 3, 5, and 10 years were 88%, 85%, and 70%, respectively [47]. In terms of proton therapy, Munzenrider et al. prescribed a median dose of 72 Gy (RBE) to irradiate G1 chondrosarcomas, in a study including 225 patients, and reported that the LC rate at 5 and 10 years was 98% and 94%, respectively [48]. Feuvret reported that in 159 patients who received proton therapy alone or with a combination of protons and photons, with a median dose of 70.2 Gy (RBE), the LC rate at 5 and 10 years was 96.4% and 93.5%, respectively [49]. Hug et al. published a study of 25 patients after proton radiotherapy, wherein the 5-year LC rate was 92% [50]. Weber et al. reported a 7-year LC rate of 93.6% for patients with chondrosarcomas treated with proton therapy after surgery [51]. Our systematic evaluation included three studies regarding chondrosarcomas managed with carbon ion therapy. Mattke et al. published clinical results of carbon ion therapy alone for 79 patients with skull base chondrosarcomas, the LC rate at 1, 2, and 4 years was 98.6%, 97.2%, and 90.5%, respectively [17]. A study by Uhl et al. showed 79 patients after carbon ion therapy alone with a dose of 60 Gy (RBE); the LC rate at 3-, 5-, and 10-years were 95.9%, 88%, and 78.9%, respectively [19]. However, a study reporting a 5-year LC rate of 53% for 73 patients after C-ion RT alone with a dose of 64–73.6 Gy (RBE) was published by Imai et al. [12]. The efficacy of C-ion RT was worse than that of surgery. The most likely reason for this was that chondrosarcomas were present close to the spinal cord or sacral lesions. Another suggested reason was that these patients were older than those in the groups undergoing surgery [52,53,54].

According to the Cooperative Osteosarcoma Study report, which included 67 patients with pelvic osteosarcoma, the LC and OS rates at 5 years were 30% and 27%, respectively. However, the LC and OS rates at 5 years were 6% and 0%, respectively, which are unsuitable for surgery patients [30]. Osteosarcoma is relatively radiation-resistant to conventional radiotherapy. Especially in patients with pelvic and axial osteosarcoma, it is difficult to administer high-dose radiation to the tumor because it is adjacent to the intestinal tract and spinal cord. However, particle radiotherapy, especially carbon ion therapy, has unique physical and biological advantages [55, 56]. We included two studies regarding osteosarcoma that utilized carbon ion therapy: the LC incidence at 2, 3, and 5 years was 73.1%, 69.2%, and 61.5%, respectively (Additional file 3: Fig. S3); the OS rates at 2, 3, and 5 years were 57.7%, 50%, and 35.4%, respectively (Additional file 6: Fig. S6); and the LR incidence was 7.7% to 26.9% (Table 5) [11,12,13,14]. Regarding proton therapy, a study by DeLaney et al. reported unresectable or incompletely resected truncal osteosarcomas. Patients who received proton radiotherapy have a lower risk of recurrence after incomplete resection [57]. In another report, a proton or mixed proton/photon radiotherapy was performed for osteosarcomas of the trunk; the LC and OS rates at 5-years were 72% and 67%, respectively [27]. This survival rate appears to be superior to that of carbon ion radiotherapy. The most likely reason for this was that the baseline characteristics (stage, resectability, site, grade, and size) in this study were more favorable. In terms of the LC rate, carbon ion therapy for pelvic or truncal osteosarcoma showed similar proton outcomes but was superior in terms of surgical outcomes despite including patients who had more unfavorable baseline characteristics. It is well known that distant metastasis is the major factor affecting the OS rate of osteosarcoma. Because of the great differences in systemic treatment in different studies, the reported OS rates are significantly different.

Regarding toxicity, the incidence of acute and late toxicity was mainly grade 1 to grade 2 and grade 1 to grade 3, respectively. Regarding the acute toxicity, grade 3 was observed in two studies, with an incidence of 3.2–3.8% [14, 15]. The most common event was an acute skin reaction [10, 11, 14,15,16,17, 20], and a grade 3 skin acute reaction was observed in six patients [14, 15]. No grade 4 or higher skin and mucosal acute reactions were observed in any of the studies. Kamada et al. considered that the maximum tolerated dose for patients with no subcutaneous tumor and subcutaneous tumor involvement may be 73.6 Gy (RBE) and 70.4 Gy (RBE) or less [58]. In terms of the late toxicity, grade 4 was observed in five articles, with an incidence of 1.1% to 8% [11,12,13,14,15]. The BSs of the skull base not observed at more than grade 2 early and late toxicities [16,17,18,19,20]. The two studies of sacral sarcoma discovered grade 4 late toxicity of the skin and sciatic nerve neuropathy; however, the incidence was 1.1–2.1% [13, 15]. In a study by Yanagi et al., the area of skin irradiated with > 60 Gy (RBE) (S60 > 20 cm2) was the most important factor for grade 4 skin late toxicity development [59]. Imai et al. indicated that the risk factors for sciatic nerve injury in sacral chordoma may be the length (> 10 cm) and dose (> 70 Gy (RBE)) of irradiation [15]. Regarding sarcoma located in the pelvis, axis, and spinal or paraspinal area, three studies observed grade 4 late toxicity of vertebral body compression fractures, fracture, and bone necrosis, with an incidence of 2.6–6.8% [11, 12, 14]. Although the toxicity of carbon ion therapy was low and acceptable, late toxicity required larger samples and long-term follow-up.

In our systematic review, there were 10 studies that reported the prognostic factors of C-ion RT effectiveness (Table 5) [10,11,12,13,14, 16,17,18,19, 21]. The following factors were evaluated: age, sex, performance status, pathology, histological grading, tumor status, tumor location, target volume, chemotherapy, and total dose. Prognostic factors varied widely among the selected studies. Overall, most studies have shown that the target volume is a common significant prognostic factor for BSs. Furthermore, younger age, better performance status, and a higher total dose were significantly associated with better LC and OS.

This systematic review and meta-analysis had several limitations. First, gray literature was not included, and there may be publication bias. Second, the results of our search showed that 58% of the literature on C-ion RT for BSs was from Japan, 33% of the literature was from Germany, and one study was from China. Therefore, there could be a reporting bias. In addition, all the studies were case series reports without randomized controlled studies and included small sample sizes, which would affect the reliability of the conclusions of this systematic review. However, all study designs were reasonable, the missed follow-up rates were low, and the strength of the endpoints was high, with all studies evaluating the OS and LC as specific outcomes.

As an advanced radiotherapy technique, carbon ion therapy has shown promising efficacy and acceptable toxicity in BSs. However, there are still some areas of insufficient carbon ion radiotherapy for BSs. First, previous studies on carbon ion therapy have often involved various types of BSs. Different pathological types of BSs may have inconsistent optimal dose patterns, and individualized carbon ion radiotherapy still requires further study. Second, although carbon ion therapy for BSs has achieved a good LC rate, integrated treatment modalities, including chemotherapy, antiangiogenic therapy, and immunotherapy, require further study. Third, the number of patients treated with carbon ions for BSs was too small, although a potential role of carbon ions in improving LC at low toxicity was found. Finally, whether carbon ion radiotherapy is superior to other radiotherapy technologies needs to be determined in high-quality prospective, randomized controlled clinical trials in bone sarcoma patients.