Abstract
Background/Aim: The aging population is expected to increase the occurrences of bone sarcoma (BS) and soft tissue sarcoma (STS). Carbon ion radiotherapy (CIRT) is reported to be effective for BS and several STSs. However, the effect of CIRT on clinical outcomes, functional prognoses, and quality of life (QOL) in older patients who underwent CIRT has not been reported. Therefore, we aimed to evaluate the effect of CIRT on clinical outcomes, functional prognoses and QOL in older patients with BS or STS. Patients and Methods: This retrospective cohort study included 235 patients aged >70 years with BS or STS who underwent CIRT. Overall survival (OS), cancer-specific survival (CSS), and local control (LC) were evaluated in chordoma and non-chordoma patients. Furthermore, factors associated with post-CIRT Toronto Extremity Salvage Score (TESS) and EuroQoL 5-dimension 5-level (EQ-5D-5L) index were assessed. Results: The overall 5-year LC, OS, and CSS rates were 81%, 62%, and 76%, respectively. In the chordoma and non-chordoma groups, the 5-year LC, OS, and CSS rates were 84%, 72%, and 87%; and 77%, 47%, and 60%, respectively. The mean post-CIRT TESS and EQ-5D-5L index were 75% and 0.71, respectively. The TESSs and EQ-5D-5L indices tended to be better among males, younger patients (<76 years old), patients with small tumor volumes, and patients with chordoma. Conclusion: CIRT is effective for older patients with BS, especially with chordoma, and STS with good LC and survival rates. Furthermore, post-treatment limb function and QOL were comparable with those of the other treatments and age groups.
Bone sarcomas (BS) and soft tissue sarcomas (STS) are rare tumors that account for more than 50 different histologic subtypes and occur in children and older individuals (1, 2). In Japan, of the 702 BS cases registered in the National Bone Tumor Registry in 2019, older patients aged ≥65 years accounted for 39% (3, 4). In contrast, in Japan, 1,975 STS cases were registered in the National Soft Tissue Tumor Registry in 2019. Of these, 1,158 (59%) were older patients (5). With an aging population, the number of older patients with BS and STS is expected to increase (6); therefore, effective and appropriate treatment for patients with BS and STS is necessary.
The mainstay of management for patients with high-grade BS and STS of the extremities and trunk is extensive resection, adjuvant perioperative chemotherapy, and radiotherapy (7). In Japan, carbon ion radiotherapy (CIRT) was introduced for unresectable sarcomas in 1996 (8). We previously reported that CIRT is useful for unresectable sarcomas (9-11). Similarly, Yolcu et al. suggested the CIRT was satisfactory for patients with sacral chordoma for whom resection was technically or medically inadvisable, or for those who preferred not to undergo the procedure when they compared oncologic outcomes and treatment-related toxicity of CIRT and en bloc resection for sacral chordoma (12). Additionally, the effectiveness of CIRT has been reported for other types of sarcomas (13).
Recently, the importance of functional prognosis and quality of life (QOL) after multidisciplinary treatment in patients with sarcoma has been reported (14). The Toronto Extremity Salvage Score (TESS) and EuroQoL 5-dimension 5-level (EQ-5D-5L) questionnaires are useful for evaluating post-treatment limb function and QOL in patients with sarcoma, respectively (15, 16). However, no thorough evaluations of the clinical outcomes, functional prognosis, or QOL of older patients with BS and STS who underwent CIRT have been reported.
Therefore, this study aimed to evaluate the clinical outcomes, limb function, and QOL of older patients with BS or STS treated with CIRT.
Patients and Methods
Study design and patients. This study was approved by the local Ethics Review Board (Approval number: N22-004). Between 2000 and 2020, 235 patients aged >70 years with axial bone or soft tissue sarcomas were treated with CIRT at a single institute. Among the 235 patients, 60 surviving and disease-free patients were given the TESS and EQ-5D-5L questionnaires. Of them, 47 returned the completed questionnaires. Informed consent was obtained from all 47 patients.
Clinical characteristics and parameters for investigation. We investigated the following variables in all patients (235 patients): sex, age at CIRT, follow-up period after CIRT, tumor volume and location, histology, local recurrence, and distant metastasis (Table I). Additionally, the overall survival (OS), cancer-specific survival (CSS), and local control (LC) of all cases, and those of chordoma cases and non-chordoma cases were evaluated (Figure 1 and Figure 2). For the 47 patients who completed the TESS and EQ-5D-5L questionnaires the following were evaluated: sex, age at CIRT, follow-up period after CIRT, tumor volume and location, histology, local recurrence, and distant metastasis (Table II). Subjective QOL and limb function after CIRT were evaluated using the EQ-5D-5L and TESS questionnaires at the final follow-up. The descriptive system of EQ-5D-5L for QOL evaluation comprises five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each graded on five levels: no problems, slight problems, moderate problems, severe problems, and extreme problems (17). TESS, a self-administered questionnaire, is widely used for the functional assessment of patients after surgery for musculoskeletal tumors (15, 18). Furthermore, factors associated with post-CIRT TESS and EQ-5D-5L, including sex, age at CIRT, tumor volume, and chordoma were evaluated.
Patient demographics and disease characteristics.
Kaplan–Meier survival curves demonstrating (A) local control (LC), (B) overall survival (OS), and (C) cancer-specific survival (CSS) in 235 patients. In all 235 patients, the 5-year LC, OS, and CSS rates were 81%, 62%, and 76%, respectively. The 10-year LC, OS, and CSS rates were 69%, 30%, and 57%, respectively.
Kaplan–Meier survival curves demonstrating (A) local control (LC), (B) overall survival (OS), and (C) cancer-specific survival (CSS) of the chordoma group (124 patients) and non-chordoma group (111 patients). In the chordoma group, the 5-year LC, OS, and CSS were 84%, 72%, and 87%, respectively. In the non-chordoma group, the 5-year LC, OS, and CSS were 77%, 47%, and 60%, respectively. There were significant differences in OS and CSS between the chordoma and non-chordoma groups.
Patient demographics and disease characteristics for evaluation of limb function and quality of life.
Carbon ion radiotherapy. CIRT was administered using the Heavy Ion Medical Accelerator in Chiba (HIMAC), which the world’s first heavy-ion accelerator complex dedicated to medical use in a hospital environment (8). The patients were positioned in customized cradles (Moldcare; Alcare, Tokyo, Japan) and immobilized with a low-temperature thermoplastic shell (Shellfitter; Kuraray Co., Ltd., Osaka, Japan). A set of 2-mm-thick computed tomography (CT) images was referred to formulate treatment using the immobilization devices. Respiratory gating was performed for both CT acquisition and therapy. Three-dimensional (3D) treatment planning was performed using an in-house HIPLAN (National Institute of Radiological Sciences, Chiba, Japan). Since 2010, Xio-N (ELEKTA, Stockholm, Sweden; Mitsubishi Electric, Tokyo, Japan) planning software has been used at our institution. CIRT was administered once daily for four days a week (Tuesday to Friday): fixed 16 fractions over four weeks. The dose was set at 52.8 to 73.6 Gy (RBE) [3.3 to 4.6 Gy (RBE) per fraction] as derived from the phase 1 trial of CIRT for BS and tissue sarcoma. In a phase 2 dose-escalation study, 70.4 and 73.6 Gy (RBE) were used. In this study, 64 Gy (RBE) was used for tumors close to the spinal cord, 67.2 Gy (RBE) for sacral chordoma, and 70.4 Gy (RBE) for other sarcomas. More than three irregularly shaped ports delivered from various directions were used for CIRT treatment. The target volume was defined based on contrast-enhanced CT, magnetic resonance imaging (MRI), and positron emission tomography (PET) imaging. The gross tumor volume (GTV) was defined as the macroscopic tumor visible on imaging, and the clinical target volume (CTV) was determined by adding a 0.5-2 cm margin to the GTV, depending on the structure, tumor grade, and histology. To calculate the planning target volume (PTV), 1-5 mm added around the CTV, considering the shape and location of the irradiated field. The dose constraint for the D2cc of the intestine was set to 50 Gy (RBE).
Follow-up and statistical analyses. The follow-up period was estimated from the start of the initial CIRT treatment. Patients were monitored through physical examination, CT, and MRI using a contrast medium. Initial follow-up imaging examinations were usually performed after the completion of all CIRT sessions and follow-up examinations were conducted every 3-6 months. If the patients were unable to travel to our hospital, their latest medical reports and CT and/or MRI images were sent to us by their local hospital. LC was defined as no increase in tumor volume on two consecutive MRI or CT scans. Local recurrence was defined as the enlargement of the tumor inside the irradiation field or the appearance of new tumors connected to the irradiated field, suggesting failure of the CTV evaluation.
LC, OS, and CSS were determined by Kaplan–Meier analysis. All data with rejected normality were evaluated using the Mann–Whitney U-test. Differences were considered statistically significant when p-values were less than 0.05. All analyses were performed using the SAS software, version 14.2 (SAS Institute, Inc., Cary, NC, USA).
Results
Patient characteristics. The characteristics of the 235 patients are summarized in Table I. Of them, 136 patients were males and 99 patients were females. The median age at CIRT and follow-up period after CIRT were 76 years (range=70-90 years) and 63 months (range=0.5-248 months), respectively. The median tumor volume was 382 ml (range=12-2,522 ml). The tumor locations were the sacrum (133 patients), pelvis (31 patients), retroperitoneum (16 patients), and other sites (25 patients). The histological tumor subtypes included chordoma (124 patients), chondrosarcoma (28 patients), myxofibrosarcoma (MFS)/undifferentiated pleomorphic sarcoma (UPS) (22 patients), osteosarcoma (18 patients), and others (43 patients). Local recurrence and distant metastasis were observed in 39 and 74 patients, respectively.
Local control and survival. In all 235 patients, the 5-year LC, OS, and CSS rates were 81%, 62%, and 76%, respectively. The 10-year LC, OS, and CSS rates were 69%, 30%, and 57%, respectively (Figure 1A-C). We further divided the 235 patients into two groups: the chordoma (124 patients) and non-chordoma group (111 patients). In the chordoma group, the 5-year LC, OS, and CSS rates were 84%, 72%, and 87%, respectively. In the non-chordoma group, the 5-year LC, OS, and CSS rates were 77%, 47%, and 60%, respectively (Figure 2A-C). There were significant differences in the OS and CSS between the chordoma and non-chordoma groups.
Functional outcomes and quality of life. Data regarding the patient and tumor characteristics of the 47 patients, including criteria for functional outcomes and QOL, are shown in Table II. Thirty-one patients were males, and 16 were females. The median age at CIRT and the follow-up period after CIRT were 76 years (range=70-90 years) and 66 months (range=21-195 months), respectively. The median tumor volume was 371 ml (range=98-2,522 ml). The tumor locations were the sacrum (29 patients), pelvis (7 patients), retroperitoneum (4 patients), and others (7 patients). The histological tumor subtypes were chordoma (29 patients), chondrosarcoma (5 patients), MFS/UPS (4 patients), dedifferentiated liposarcoma (3 patients), and others (6 patients). None of the patients experienced local recurrences or distant metastases.
The post-CIRT mean TESS and EQ-5D-5L index were 75% (range=20.6-100%) and 0.71 (range=0.07-1), respectively (Table III). Although there were no significant differences, the TESS and EQ-5D-5L indices tended to be better among males, younger patients (<76 years old), patients with small volume tumor, and patients with chordoma.
Factors associated with the post-CIRT TESS and EQ-5D-5L index.
Discussion
In the current study, we demonstrated that CIRT had positive LC and survival rates in older patients with BS and STS, especially in patients with chordoma, thus concluding its effectiveness. Furthermore, mean post-CIRT TESS and EQ-5D-5L index indicated that the patients of this study had good limb functionality and decent QOL.
Oncologic outcomes of CIRT have been reported in several sarcomas, including osteosarcomas, chondrosarcomas, STSs, and chordomas (9, 10, 11, 19). Mohamad et al. reported that CIRT was safe and effective for inoperable pediatric osteosarcoma, with improved LC and OS compared with conventional treatments. In addition, Imai et al. suggested that CIRT may be an option for unresectable chordomas and axial STSs, such as UPS, malignant peripheral nerve sheath tumors, and liposarcomas.
Several studies have investigated the effectiveness of CIRT for chordomas (9, 12). Yolcu et al. compared oncological outcomes and treatment-related toxicities of CIRT and en bloc resection for sacral chordomas in 911 patients. This study found a higher rate and severity of peripheral motor neuropathy in patients who underwent en bloc resection. Therefore, concluding that CIRT can be a viable option for older patients with a high performance status and sacral chordoma, especially when surgery is not preferred. The prognosis for chordoma is sometimes poor, with 5-year survival rates ranging from 50% to 68% and 10-year survival rates ranging from 28% to 40% (20). Additionally, older patients may develop a more aggressive form of chordoma, while younger patients have a higher survival rate (21). The current study demonstrated a 5-year OS of 72% and CSS of 87% in older patients with chordoma, which can be considered satisfactory.
Dong et al. conducted a systematic evaluation and meta-analysis of the efficacy and safety of CIRT for the treatment of BS, which showed that the 5-year and 10-year LCs of CIRT are 74.3% and 64.7%, respectively, in all age groups (22). Moreover, various studies have reported that the 3-year LC rate of CIRT for STS across all age groups is between 72.9% and 79.1% (23, 24). The current study showed that the 5- and 10-year LCs were 81% and 69%, respectively, indicating that CIRT is effective, even in older patients with BS and STS.
As in previous studies (25), there was a discrepancy between OS and CSS in this study because of the higher number of non-cancer-specific deaths among older patients. However, studies have preferred CSS over OS when evaluating the prognosis of older patients (26). Takuwa et al. reported a difference between OS and CSS in older patients with breast cancer, suggesting the importance of CSS.
In the present study, the mean post-CIRT TESS and EQ-5D-5L index were 75% and 0.71, respectively. There are limited studies on post-treatment limb function and QOL for BS and STS using TESS and EQ-5D-5L evaluations. Table IV shows comparative data from other studies (16, 27-30). To our knowledge, only one study has investigated the TESS and EQ-5D-5L index following CIRT (27), which reported that the mean TESS and EQ-5D-5L score after CIRT for unresectable pelvic BS were 64% and 0.587, respectively, across all age groups. Another study demonstrated that the TESS of internal and external hemipelvectomy or flail hip in patients with sarcomas was 60.4%, suggesting that pelvic surgery tends to result in a relatively poor functional prognosis (28). Moreover, we have previously conducted a retrospective cohort study using the same inclusion criteria as in the current study involving 67 patients aged >70 years who underwent surgery for BS or STS at a single institution (16). This study included 52 limbs and 15 axial sarcomas. The postoperative mean TESS and EQ-5D-5L index of the older patients were 76.9% (range=23.1-100%) and 0.74 (range=0.04-1), respectively. Izawa et al. studied the psychological and physical states of older patients who underwent outpatient rehabilitation at a geriatric health service facility using the EQ-5D-5L. The mean EQ-5D-5L indices for males (mean age, 82.3 years) and females (mean age, 84.6) without cancer or who did not undergo surgery at a geriatric health services facility were 0.69 and 0.77, respectively (31). The TESS and EQ-5D-5L results for axial sarcoma of older participants in this study were similar to those of healthy older individuals. However, additional QOL assessments such as the 36-Item Short Form Survey (SF-36) require further evaluation using different methods for a more precise investigation.
Comparison of previously published studies.
Study limitations. First, this was a retrospective study, meaning that the data were collected from past cases. Second, the EQ-5D-5L indices and TESS were not assessed before treatment; therefore, it was not possible to determine the changes over time. Finally, only the surviving patients were included in the study, as the post-irradiated questions were based on the patients’ own reports.
Conclusion
In conclusion, our findings show that CIRT is effective for older patients with BS and STS, with good LC and survival rates, especially for patients with chordoma. Furthermore, post-treatment limb function and QOL were comparable to those of the other treatments and age groups.
Acknowledgements
The Authors thank all members of the Working Group for Carbon Ion Radiotherapy for Bone and Soft Tissue Sarcomas for their cooperation: Keisuke Ae (Department of Orthopedic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan), Shintaro Iwata (Department of Musculoskeletal Oncology and Rehabilitation, National Cancer Center Hospital, Tokyo, Japan), Toshifumi Ozaki (Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan), Hiroyuki Kawashima (Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan), Yoichi Naito (Department of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan), Yoshihiro Nishida (Department of Rehabilitation, Nagoya University Hospital, Aichi, Japan), Hiroaki Hiraga (Department of Musculoskeletal Oncology, National Hospital Organization Hokkaido Cancer Center, Hokkaido, Japan), Takehiko Yamaguchi (Department of Pathology, Nikko Medical Center, Dokkyo Medical University, Tochigi, Japan),
Footnotes
Authors’ Contributions
H. Kinoshita designed the research, analyzed the data, and wrote the article. R. Imai treated patients with CIRT and collected all data. T. Yonemoto and S. Yamada provided technical support and conceptual advice.
Conflicts of Interest
The Authors have no conflicts of interest relevant to the content of this article.
- Received January 26, 2024.
- Revision received February 13, 2024.
- Accepted February 15, 2024.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
