Abstract
Background/Aim: Carbon-ion radiotherapy (CIRT) for bone and soft tissue tumors (BSTs) has been reported to have favorable clinical outcomes. Intensity-modulated CIRT (IMCT) techniques have been developed to further reduce dose delivery to adjacent organs compared to conventional CIRT. We retrospectively analyzed the clinical results of IMCT for BSTs and investigated treatment efficacy and toxicity. Patients and Methods: This study included 9 consecutive BSTs patients who underwent IMCT at the Kanagawa Cancer Center from January 2016 to April 2021. IMCT was administered at a dose of 60.8-70.4 Gy (relative biological effect) in 16 fractions. The time to event was calculated from the initiation of IMCT. Toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. Results: The median age was 49 (range=16-71) years. The median observation period was 57.6 (range=7.0-77.8) months. There were 7 and 2 cases for IMCT because of proximity to the spinal cord and intestinal tract, respectively. There was one death during the observation period, which occurred 7.0 months after the initiation of treatment. Clinical recurrence occurred in 3 patients at 1.3, 17.8, and 22.4 months after the initiation of treatment, respectively. Acute toxicity of Grade 2 or higher was seen in 2 patients with Grade 2 pharyngeal mucositis. Late toxicities of Grade 2 or higher included 1 case each of Grade 2 neuralgia and peripheral neuropathy, as well as 1 case of Grade 3 fracture. Conclusion: IMCT for BSTs showed good local therapeutic efficacy and tolerable toxicity in patients with bone and soft tissue tumors.
Surgery plays a leading role in the definitive treatment of bone and soft tissue tumors (BSTs) (1, 2). The status of the resection margin affects the prognosis, and thus it is important to ensure adequate margins for resection (3). However, when tumors are located in close proximity to critical organs, it is difficult to achieve adequate surgical margins. Radiotherapy (RT) and/or chemotherapy are selected in the treatment of unresectable BSTs. However, BSTs are radioresistant and the therapeutic efficacy is inadequate (4).
Carbon-ion RT (CIRT) has physical and biological advantages over conventional X-ray therapy. In the physical aspect, CIRT delivers a high dose concentration to the target volume due to Bragg peaks and sharp penumbra (5, 6). Furthermore, the relative biological effect (RBE) of CIRT is approximately thrice more than that of X-rays (7). Because of these characteristics, CIRT reportedly has excellent results in the treatment of unresectable BST (8-12). However, even with CIRT, caution must be exercised in avoiding excessive doses to critical organs (e.g., spinal cord) when tumors are in close proximity to them. In a treatment planning comparison study for spinal sarcoma, CIRT achieved better dose distribution than proton therapy and intensity-modulated RT (13).
Scanning CIRT (sCIRT) is offered to all patients at our center (14). sCIRT can provide better dose distribution than conventional passive CIRT (15). Intensity-modulated CIRT (IMCT) was developed based on this sCIRT technology. Unlike single field uniform dose (SFUD) irradiation, which irradiates uniform doses with each beam, IMCT is an irradiation method in which the individual beams are irradiated at non-uniform doses and the total dose is equalized by the sum of the individual beams (16). Several dosimetric studies have reported that good dose distribution can be obtained with IMCT (17, 18). Furthermore, reports on the clinical application of IMCT are limited, and results of IMCT in head and neck cancer have been reported (19, 20). IMCT is expected to be useful for BSTs adjacent to critical organs such as the spinal cord, but there have been no reports to date. Therefore, we retrospectively analyzed the clinical outcomes of BSTs treated with IMCT to estimate the efficacy and safety of IMCT for BSTs.
Patients and Methods
Patients. The subjects were consecutive patients with BSTs who received IMCT at our center between January 2016 and April 2021. The eligibility of this study was as follows: (i) histopathologically diagnosed BSTs, (ii) the tumor can be measured grossly by computed tomography (CT) or magnetic resonance imaging (MRI), and (iii) a performance status of 0-2. Clinical data was collected in January 2023. Written informed consent was obtained from all patients. The hospital’s institutional review board approved this study (approval number: 2022-146).
IMCT. Gross tumor volume (GTV) was delineated using CT, MRI, and positron emission tomography (PET)-CT. The clinical target volume (CTV) was GTV plus 0.5-1 cm and it was excluded for areas with low potential for invasion. PTV was CTV plus 0.5-1 cm all around. The total dose was set at 70.4 Gy (RBE) in 16 fractions, with 64.0 Gy (RBE) or 60.8 Gy (RBE) in 16 fractions for cases in close proximity to the spinal cord; the total dose was reduced to 67.2 Gy (RBE) for cases with 70.4 Gy (RBE) in 16 fractions that did not meet dose constraints for the risk organs. The treatment plan was designed so that 95% of the PTV volume was covered by 95% of the prescribed dose. If risk organ dose constraints could not be met, the PTV was shrunk, or the PTV dose was reduced to meet the constraints. Dose constraints for risk organs were as follows: Maximum dose (Dmax) <60 Gy (RBE) for skin, maximum dose covered 1 cc (D1cc) <40 Gy (RBE) for small and large intestine, Dmax < 60 Gy (RBE) for bladder, Dmax <30 Gy (RBE) for the spinal cord, and D10cc <67.2 Gy (RBE) for sciatic nerve. IMCT was performed in all patients.
Follow-up. After completion of IMCT, patients were followed up every 1-3 months by a radiation oncologist and a musculoskeletal tumor surgeon, with imaging studies using CT and MRI performed. If necessary, PET-CT was added to diagnose recurrence or distant metastasis. The diagnosis of recurrence or distant metastasis was made by both the radiation oncologist and the musculoskeletal tumor surgeon. The period of observation and time to the events were calculated from the date of the initiation of IMCT treatment. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 5.0. Toxicities occurring less than 3 months after the initiation of IMCT were considered acute toxicities, and toxicities occurring after 3 months were considered late toxicities. The worst toxicity grade was used as the final grade of toxicity.
Results
Patient characteristics. Table I summarizes the patient characteristics. Representative dose distributions are shown in Figure 1. The number of patients included in the analysis was 9. The median follow-up period was 57.6 (range=7.0-77.8) months. The study included 5 males and 4 females with a median age of 49 (range=16-71) years. The median maximum diameter of the tumor was 6.5 (range=2.8-18.6) cm. The pathological diagnoses were osteosarcoma (n=2), chondrosarcoma (n=2), chordoma (n=2), liposarcoma (n=1), meningioma (n=1), and solitary fibrous tumor (n=1). IMCT was selected because of spinal cord proximity and intestinal proximity in 7 and 2 cases, respectively. There were 3 fresh cases; 6 cases had been treated prior to IMCT, of which 2 had a history of RT, one recurrent lesion after X-ray RT (patient #2), and one recurrent lesion after CIRT (patient #8).
Patient characteristics.
Representative dose distribution of intensity-modulated carbon-ion radiotherapy (IMCT). This is a case of chondrosarcoma of the thoracic spine treated with 64.0 Gy (relative biological effect) in 16 fractions using IMCT (patient #5). The patient was irradiated using posterior and lateral beams in two directions with non-uniform dose distributions. The lower figure shows the sum of the dose distribution; a uniform dose distribution was obtained as the sum of the two beams.
Survival and recurrence. There was one death during the observation period, which occurred 7.0 months after the initiation of IMCT due to the primary disease (patient #6). Clinical recurrence was observed at 1.3, 17.8, and 22.4 months after the initiation of IMCT, and the first recurrence site was lung metastasis (patient #6), lymph node metastasis (patient #4), and local recurrence (patient #7). There were two cases of local recurrence during the observation period. The time to local recurrence was 3.7 (patient #6) and 22.4 (patient #7) months.
Toxicity. Acute toxicity included Grade 1 dermatitis in 6 cases and Grade 2 mucositis in 2 patients; no acute toxicity of Grade 3 or higher was observed. One case of Grade 1 dermatitis was observed as late toxicity. Peripheral nerve-related late toxicity included Grades 1 and 2 peripheral neuropathy in one patient each and Grade 2 neuralgia in one patient. Fractures were observed in 2 patients (Grade 1 n=1, Grade 3 n=1). The Grade 3 fracture (patient #4) was treated with cervical posterior decompression fusion 20 months after IMCT for numbness in the upper extremity, which occurred 17 months after IMCT of the cervical spine, and his symptoms improved after surgery.
Discussion
The clinical outcome of IMCT for BSTs was investigated, with 1 mortality, and 2 local recurrences out of 9 patients during the observation period. There were few serious adverse events in both the acute and late phases, with only one Grade 3 toxicity, a fracture. To the best of our knowledge, this is the first report of the clinical results of IMCT for BSTs not located at the head and neck.
Intensity-modulated particle therapy has been used mainly in proton therapy, and several studies have been reported as intensity-modulated proton therapy (IMPT). Similar to IMCT, IMPT does not use SFUD irradiation, which irradiates uniform doses with each beam, but rather the sum of each non-uniform beam forms the desired dose distribution (21). IMPT is an advanced irradiation technique in proton therapy, useful for irradiating large or irregularly shaped volumes and for administering multiple prescribed doses (22). Several dosimetric studies have shown that IMPT can reduce dose delivery to risk organs in the treatment of various sites (23-26). Moreover, several clinical outcomes of IMPT, including head and neck cancer, thoracic esophageal cancer, and BSTs, have demonstrated that favorable dose distribution using IMPT reduced adverse events (27-31).
Studies on IMCT remain limited. Chi et al. compared the dose distribution of IMCT, IMPT, and volumetric modulated arc therapy in thoracic radiotherapy (17). They found no significant difference in PTV coverage between the three modalities, and IMCT was able to reduce low-dose areas in the lungs. Moreover, a comparison between IMCT and IMPT showed that major blood vessels were significantly lower with IMCT. Wang et al. also performed a dosimetric study of IMCT versus IMPT in patients with locally recurrent nasopharyngeal carcinoma (18). That study showed no significant difference in target-volume coverage between the two irradiation methods, but dose parameters in various risk organs such as the brainstem, spinal cord, and optic chiasm were significantly reduced with IMCT. These reports suggest that IMCT may be useful for dose reduction in these risk organs. In our study, IMCT was performed in cases with adjacent critical organs such as the spinal cord and intestinal tract, and no adverse events to these risk organs have been observed so far.
There are few reports on the clinical outcomes of IMCT. Mattke et al. performed IMCT in 79 patients with skull base chondrosarcoma, reporting promising efficacy with 4-year local control and overall survival rates of 90.5% and 100%, respectively (19). On the other hand, Huang et al. performed IMCT in 47 patients with major salivary gland cancer with 2-year progression-free survival and overall survival rates of 78.6% and 91.6%, respectively (20). In our study with a relatively long median follow-up period, there was 1 death and 2 local recurrences out of 9 cases during the follow-up period. Although the number of patients was small, the results were comparable to previous reports of IMCT.
Study limitations. This was a single-center retrospective study with a small number of cases. The patients in this study presented with different patient characteristics, including various histopathological diagnoses and treatments prior to IMCT. Furthermore, the robustness of IMCT was not assessed in this study. In addition, studies related to IMCT are still limited, and the appropriate treatment is still unknown. Further studies are needed to examine the clinical outcome of IMCT for BSTs.
Conclusion
In this study, IMCT showed good therapeutic efficacy and tolerable toxicity for BSTs. IMCT, which was used to reduce the dose to the spinal cord and intestinal tract in close proximity to the tumor, showed no toxicity to these critical organs. Our results suggest that IMCT may be a promising treatment option in cases wherein tumors are in close proximity to critical organs such as the spinal cord and intestine.
Footnotes
Authors’ Contributions
YT collected and analyzed the data and drafted the manuscript. H Katoh, DY, and TK analyzed the data and contributed to the final draft of the manuscript. H Koge, KK and SS collected and analyzed the clinical data. KT and NM aided in writing the manuscript and contributed to the final draft of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
Hiroyuki Katoh and Daisaku Yoshida received research funding from Toshiba Energy Systems and Solutions Corporation (Kanagawa, Japan).
- Received March 2, 2023.
- Revision received March 27, 2023.
- Accepted March 30, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
