Dose Distribution Degradation of Carbon-ion Radiotherapy Caused by Tumor Cell-specific Relative Biological Effectiveness of Osteosarcoma: A Simulation Study Using In Vitro Experimental Results.

BACKGROUND/AIM: Dose distributions of carbon-ion radiotherapy (C-ion RT) have been created with the relative biological effectiveness (RBE) of human salivary gland cells (HSG). However, no dose distributions have been created using various tumor cell-specific RBE values. Hence, we conducted in vitro experiments to determine the RBE of human osteosarcoma cells (U2OS) and used this RBE value (RBEU2OS) to calculate the dose distribution for C-ion RT. MATERIALS AND METHODS: To obtain RBE values for various linear energy transfer (LET) levels, we exposed U2OS cells to different doses of X-rays and varying doses and LET levels of C-ion beams (13, 30, 50, and 70 keV/µm). Subsequently, we converted the RBE of HSG (RBEHSG) to RBEU2OS in the treatment planning system and reconstructed the dose distribution for a typical osteosarcoma case. We performed a dose-volume histogram (DVH) analysis, evaluating the percentage of the minimum dose that covered 98%, 50%, and 2% (D98%, D50%, and D2%, respectively), as well as the homogeneity index [HI; calculated as (D2%-D98%)/D50%]. RESULTS: The RBEU2OS values for C-ion beams with LET of 13, 30, 50, and 70 keV/µm were 1.77, 2.25, 2.72, and 4.50, respectively. When comparing DVH parameters with the planning target volume, we observed the following values: D98%, D50%, D2%, and HI for RBEHSG were 64.1, 70.1, 72.4 Gy (RBE), and 0.12, respectively. For RBEU2OS, these values were 86.2, 95.0, 107.9 Gy (RBE), and 0.23, respectively. CONCLUSION: We utilized RBEU2OS to calculate the dose distribution of carbon ion radiotherapy, revealing potential degradation in dose distribution and particularly worsening of the HI.

Particle radiotherapy for breast cancer.

Breast cancer is the most common malignant tumor in female patients. Along with surgery, radiotherapy is one of the most commonly prescribed treatments for breast cancer. Over the past few decades, breast cancer radiotherapy technology has significantly improved. Nevertheless, related posttherapy complications should not be overlooked. Common complications include dose-related coronary toxicity, radiation pneumonia, and the risk of second primary cancer of the contralateral breast. Particle radiotherapy with protons or carbon ions is widely attracting interest as a potential competitor to conventional photon radiotherapy because of its superior physical and biological characteristics. This article summarizes the results of clinical research on proton and carbon-ion radiotherapy for treating breast cancer.

Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

Carbon-Ion Radiotherapy Combined with Concurrent Chemotherapy for Locally Advanced Pancreatic Cancer: A Retrospective Case Series Analysis.

Systemic chemotherapy has significantly improved in recent years. In this study. the clinical impact of carbon-ion radiotherapy (CIRT) with concurrent chemotherapy for locally advanced unresectable pancreatic cancer (URPC) was evaluated. METHODS: Patients with URPC who were treated with CIRT between January 2016 and December 2020 were prospectively registered and analyzed. The major criteria for registration were (1) diagnosed as URPC on imaging; (2) pathologically diagnosed adenocarcinoma; (3) no distant metastasis; (4) Eastern Cooperative Oncology Group performance status of 0-2; (5) tumors without gastrointestinal tract invasion; and (6) available for concurrent chemotherapy. Patients who received neoadjuvant chemotherapy (NAC) for more than one year prior to CIRT were excluded. RESULTS: Forty-four patients met the inclusion criteria, and thirty-seven received NAC before CIRT. The median follow-up period of living patients was 26.0 (6.0-68.6) months after CIRT. The estimated two-year overall survival, local control, and progression-free survival rates after CIRT were 56.6%, 76.1%, and 29.0%, respectively. The median survival time of all patients was 29.6 months after CIRT and 34.5 months after the initial NAC. CONCLUSION: CIRT showed survival benefits for URPC even in the multiagent chemotherapy era.

Robust Beam Selection Based on Water Equivalent Thickness Analysis in Passive Scattering Carbon-Ion Radiotherapy for Pancreatic Cancer.

Carbon-ion radiotherapy (CIRT) is one of the most effective radiotherapeutic modalities. This study aimed to select robust-beam configurations (BC) by water equivalent thickness (WET) analysis in passive CIRT for pancreatic cancer. The study analyzed 110 computed tomography (CT) images and 600 dose distributions of eight patients with pancreatic cancer. The robustness in the beam range was evaluated using both planning and daily CT images, and two robust BCs for the rotating gantry and fixed port were selected. The planned, daily, and accumulated doses were calculated and compared after bone matching (BM) and tumor matching (TM). The dose-volume parameters for the target and organs at risk (OARs) were evaluated. Posterior oblique beams (120-240°) in the supine position and anteroposterior beams (0° and 180°) in the prone position were the most robust to WET changes. The mean CTV V95% reductions with TM were -3.8% and -5.2% with the BC for gantry and the BC for fixed ports, respectively. Despite ensuring robustness, the dose to the OARs increased slightly with WET-based BCs but remained below the dose constraint. The robustness of dose distribution can be improved by BCs that are robust to ΔWET. Robust BC with TM improves the accuracy of passive CIRT for pancreatic cancer.

Repeated Carbon-Ion Radiation Therapy for Intrahepatic Recurrent Hepatocellular Carcinoma.

PURPOSE: This retrospective study aimed to evaluate the safety and efficacy of repeated carbon-ion radiation therapy (CIRT) in patients with intrahepatic recurrent hepatocellular carcinoma (HCC). METHODS AND MATERIALS: We reviewed patients who underwent repeated CIRT for intrahepatic recurrent HCC between 2010 and 2020. RESULTS: Forty-one patients received multiple CIRT courses for HCC. During the second course, 17 (41.5%) and 24 (58.5%) of 41 patients underwent CIRT for local recurrence (LR) and intrahepatic recurrence after the first irradiation, respectively. The median age at the first course was 76 years, and the median tumor size in all the courses was 25 mm. Throughout all CIRT courses, the prescribed dose was 52.8 to 60.0 Gy (relative biological effectiveness), which was delivered in 4 to 12 fractions. The median follow-up period after the first and second CIRT was 40 and 21 months. Median overall survival (OS) after the first and second CIRT were 80 and 27 months, respectively. The 2- and 5-year OS after the first CIRT were 87.8% and 50.1%, and the 2-year OS rate after the second CIRT was 56.0%. The 1- and 2-year local control (LC) after the second CIRT was 93.4% and 83.0%, respectively. The median progression-free survival (PFS) after the second CIRT was 11 months. There were no significant differences in the LC and PFS between patients with LR and out-of-field recurrence (P = .83; 0.28, respectively). The albumin-bilirubin scores at 3 and 6 months after the second CIRT were not significantly different from those before irradiation. According to the Common Terminology Criteria for Adverse Events version 4.0, grade 4 or greater toxicities were not observed. CONCLUSIONS: Repeated CIRT for intrahepatic recurrent HCC was safe and effective, including reirradiation for LR. OS, LC, and PFS were satisfactory, and liver function was preserved. Repeated CIRT could be considered a treatment option for intrahepatic recurrent HCC.

Complications and Functional Outcome Differences in Carbon Ion Radiotherapy and Surgery for Malignant Bone Tumors of the Pelvis: A Multicenter, Cohort Study.

BACKGROUND: Carbon ion radiotherapy (CIRT) is an evolving treatment option for malignant pelvic tumors in patients with poor surgical indications. However, the difference in complications and functional outcomes between CIRT and surgery is poorly understood. This study compares the complications and functional outcomes of CIRT and surgery to facilitate treatment selection. METHODS: A total of 28 patients who underwent CIRT for pelvic bone tumors while theoretically meeting the surgical resection criteria were included. Sixty-nine patients who underwent surgery for pelvic bone tumors were included as controls. Major complication rates and functional outcomes (ambulatory, pain, urination, constipation) were evaluated and compared at several time points (pretreatment, discharge, and final follow-up) between the groups. RESULTS: Early (within 90 days) major complications were not observed in the CIRT group but occurred in 30% of the surgery group, which was statistically significant (P < 0.001). In contrast, late (after 90 days) major complications occurred more often in the CIRT group than in the surgery group (18% and 4%, respectively; P = 0.042). From pretreatment until discharge, all functional outcomes in the surgery group deteriorated (P < 0.001 for all) but did not change in the CIRT group (P = 0.77-1.00). At the final follow-up, all functional outcomes showed no significant intergroup difference (P = 0.28-0.92) due to the recovery trend in the surgery group and the deterioration trend in the CIRT group. CONCLUSIONS: Compared with surgery, CIRT may have favorable safety and stable functional outcomes in the short-term but more late complications. Mid-term functional outcomes were similar between the groups.

Visualizing Bioabsorbable Spacer Effectiveness by Confirming the Distal-Tail of Carbon-Ion Beams: First-In-Human Report.

In particle therapy, bioabsorbable polyglycolic acid (PGA) spacer was developed to reduce the healthy organ irradiation dose, especially in the gastrointestinal tract. The PGA spacer is safe and effective; however, there are no reports that have confirmed whether the PGA spacer which inserted in the body actually stops the carbon-ion (C-ion) beams. Here, we visualized and confirmed that the PGA spacer stops the C-ion beams in the body based on the dose distribution using auto-activation positron emission tomography (AAPET). A 59-year-old dedifferentiated retroperitoneal liposarcoma patient underwent C-ion radiotherapy (C-ion RT) on referral. A month before C-ion RT initiation, the patient underwent PGA spacer placement. Postoperatively, the patient received 4.4 Gy (RBE) per fraction of C-ion RT, followed by AAPET. AAPET revealed lower positron emitter concentrations at the distal tissue ventral to the PGA spacer than in the planning target volume. In observing the efficacy of the PGA spacer, the AAPET images and the average count per second of the positron emitter suggested that the PGA spacer stopped the C-ion beams in the body in accordance with the dose distribution. Therefore, AAPET was useful in confirming the PGA spacer's effectiveness in this study, and the PGA spacer stopped the C-ion beams.

Safety and Efficacy of Re-irradiation With Carbon-ion Radiotherapy for Pelvic Recurrence of Rectal Cancer After Preoperative Chemoradiotherapy: A Retrospective Analysis.

BACKGROUND/AIM: Previous evaluation of the safety and clinical efficacy of re-irradiation for pelvic recurrence of rectal cancer after preoperative chemoradiotherapy (PCRT) and rectal surgery is insufficient. We evaluated the safety and efficacy of re-irradiation with carbon-ion radiotherapy (C-ion RT) for pelvic recurrence of rectal cancer after PCRT. PATIENTS AND METHODS: We reviewed the medical records of patients treated with C-ion RT between August 2011 and December 2021 and analyzed the data of seven consecutive patients. The probabilities of overall survival (OS), local control (LC), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Toxicities were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.0). RESULTS: The median follow-up duration after C-ion RT initiation was 30.9 months. Five patients received 73.6 Gy [relative biological effectiveness (RBE)] in 16 fractions, and two patients received 57.6 Gy (RBE) in 12 fractions. All patients completed C-ion RT as scheduled. Two-year estimated OS, LC, and PFS rates after C-ion RT initiation were 100%, 83.3%, and 28.6%, respectively. No patients developed grade ≥3 acute toxicity. Regarding late toxicities, one patient who received Gore-Tex sheets as a spacer before C-ion RT developed grade 3 colon perforation, and then developed a grade 3 urinary tract disorder. One patient developed grade 2 peripheral neuropathy. CONCLUSION: C-Ion RT showed favorable local efficacy with minimal toxicity. C-Ion RT might be an effective treatment option for pelvic recurrence of rectal cancer after PCRT even when re-irradiation of the pelvis is required.

Long-term survivor of hepatocellular carcinoma treated with repeated carbon ion radiotherapy and transarterial chemoembolization: a case report.

Hepatocellular carcinoma (HCC) often recurs in the liver and requires multiple rounds of treatment. Thus, less-invasive multidisciplinary approaches are essential for preserving liver function, especially in elderly patients. Here, we report a case of an 86 year-old Japanese male patient with HCC who was successfully treated with repeated carbon ion radiotherapy (C-ion RT) and transarterial chemoembolization (TACE). The patient had alcoholic liver cirrhosis with a 60 mm HCC lesion and a satellite lesion in segment 6. The patient underwent initial C-ion RT but developed primary tumor recurrence (segment 6) and a new lesion (segment 2) 24 months later. The patient received TACE for each lesion, followed by an increased dose of C-ion RT for the recurrent primary tumor. Although the primary tumor lesion was well controlled, the patient subsequently developed new lesions, and TACE was repeated. The patient died of bacterial pneumonia 88 months after the initial treatment. His general condition and liver function were well preserved, and no severe adverse events were observed throughout the course of treatment. These results suggest that a less-invasive multidisciplinary approach involving repeated C-ion RT combined with TACE enables preservation of liver function, which may contribute to long-term survival in elderly patients with HCC.

Long-term survival of two patients with inoperable post-irradiation osteosarcoma treated with carbon-ion radiotherapy: a case report.

BACKGROUND: Curative treatment of inoperable post-irradiation sarcoma is often challenging, especially using radiotherapy, wherein curative dose administration is difficult because the organs around the tumor have already been irradiated during the first cancer treatment. Carbon-ion radiotherapy (C-ion RT) might be useful in the treatment of post-irradiation sarcomas because it allows re-irradiation with high-dose localization properties and also demonstrates higher cytotoxic effects on radioresistant tumors compared with X-rays. This study presents the long-term survival of two patients with inoperable post-irradiation pelvic osteosarcoma treated with C-ion RT after uterine cervical cancer treatment. CASE PRESENTATION: The durations from prior radiotherapy to the diagnosis of post-irradiation osteosarcoma were 112.8 and 172.2 months, respectively. Both patients received 70.4 Gy (relative biological effectiveness) in 16 fractions of C-ion RT, and chemotherapy was performed before and after C-ion RT. Both patients achieved a complete response 1 year after the initiation of C-ion RT. However, one patient developed single lung metastasis 12.6 months after the initiation of C-ion RT and underwent thoracoscopic lobectomy. After 63.7 and 89.0 months from the initiation of C-ion RT, respectively, the patients were alive with no evidence of local recurrence, other distant metastasis, or fatal toxicities. CONCLUSIONS: The study findings suggest that C-ion RT is a suitable treatment option for inoperable post-irradiation osteosarcoma.

An adaptive planning strategy in carbon ion therapy of pancreatic cancer involving beam angle selection.

BACKGROUND AND PURPOSE: In carbon-ion radiotherapy for pancreatic cancer, altered dose distributions due to changes in the gastrointestinal gas volume and anatomy during irradiation are an unresolved therapeutic issue. We developed and investigated an adaptive strategy involving beam angle selection to improve dose distributions in pancreatic cancer. MATERIALS AND METHODS: In the adaptive strategy, multiple beams were prepared with angles similar to those of the conventional strategy, and the beam that best reproduces the dose distribution of the treatment plan was used. The dose distributions of the adaptive strategy were compared with those of the conventional strategy for five patients. Patients underwent computed tomography (CT) before every irradiation. The adaptive strategy was evaluated using the same irradiation schedule as that of the conventional method and an adjusted method based on anatomical changes per fraction. Dose distributions on the pre-treatment CT and accumulated dose distributions on the treatment planning CT were evaluated using the volume receiving ≥95% of the prescription dose (V95) from the clinical target volume (CTV) between strategies. RESULTS: There were significant differences in the CTV V95 values for the pre-treatment CT between all strategies. The median (range) CTV V95 for the conventional strategy was 92.7% (87.1-96.1%), for the proposed adaptive strategy without adjusted schedules was 96.9% (95.1-97.8%), and for the proposed strategy with adjusted schedules was 97.8% (96.5-99.2%). CONCLUSIONS: The adaptive strategy can improve target coverage for the pre-treatment CT and accumulated dose distributions for the treatment planning CT without increasing the dose to critical organs.

Efficacy and Safety of 4 Fractions of Carbon-Ion Radiation Therapy for Hepatocellular Carcinoma: A Prospective Study.

INTRODUCTION: Prospective evidence supporting the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) remains lacking. This prospective study aimed to evaluate the safety and efficacy of hypofractionated C-ion RT in patients with HCC. METHODS: The inclusion criteria were as follows: (1) pathologically or clinically diagnosed HCC; (2) measurable tumor and tumor size ≤10 cm; (3) absence of major vascular invasion; (4) no extrahepatic metastasis; (5) the alimentary tract was not adjacent to the target lesion (>1 cm); (6) not suitable for or refusal to undergo surgery or local ablative therapies; (7) an interval ≥4 weeks from previous therapy; (8) no other intrahepatic lesion or at least 2 years after the previous curative therapy; (9) performance status score, 0-2; and (10) Child-Pugh score, 5-9. The prescribed C-ion RT dose was 52.8 Gy (relative biological effectiveness [RBE]) or 60.0 Gy (RBE) in 4 fractions. RESULTS: In total, 35 patients with HCC were enrolled between October 2010 and May 2016. The median follow-up durations in the survivor group (n = 23) and in the whole cohort were 55.1 and 49.0 months, respectively. The 2-, 3-, and 4-year overall survival rates were 82.8%, 76.7%, and 69.4%, respectively. The 2-, 3-, and 4-year local control (LC) rates were 92.6%, 76.5%, and 76.5%, respectively. The median time-to-progression was 25.6 months (95% confidence interval, 13.7-37.5 months). Grade 4 or 5 toxicities were not observed. Grade 3 acute and late toxicities were observed in 2 patients. There was no significant deterioration in serum albumin, bilirubin, prothrombin time-international normalized ratio, platelet count, or Child-Pugh score after C-ion RT. CONCLUSION: Four fractions of C-ion RT for HCC did not yield serious adverse events and showed promising LC, thus making it a safe and effective modality for this type of malignancy.

A risk factor analysis for local recurrence of bone and soft tissue sarcoma treated with carbon ion radiotherapy: A retrospective cohort study at a single institution.

AIM: Carbon ion radiotherapy is well-recognized as an excellent radiation modality that is suitable for treating unresectable bone and soft-tissue sarcoma of the trunk, spine, and pelvis; however, further study is needed to improve the local control rate. The current study examined the risk factors of the local recurrence of sarcomas after carbon ion radiotherapy. METHODS: Patients with inoperable bone and soft-tissue sarcomas treated with carbon ion radiotherapy in our institute from 2010 to 2018 were retrospectively analyzed. Among them, 87 patients were eligible for this study. We divided the instances of local recurrence into two types, in-field and out-field recurrence, and evaluated the predictors for the risk of local recurrence such as the age at the treatment, sex, histopathological diagnosis, standard uptake value on fluorodeoxyglucose positron emission tomography, and the clinical target volume for each recurrence using a Cox proportional hazards model. RESULTS: A multivariate analysis revealed that the tumors with a post-treatment standard uptake value of more than 3.84 on positron emission tomography had a significantly high risk of in-field recurrence (hazard ratio, 3.42; p = .03). Furthermore, postoperative lesions were a risk factor for out-field recurrence (hazard ratio, 3.82; p < .01). CONCLUSION: The current study revealed that sarcomas maintaining a high glucose metabolic activity after carbon ion radiotherapy carried a risk of in-field recurrence, and the most significant risk factor of out-field recurrence was identified to be surgery before CIRT.

Deterioration of pancreatic exocrine function in carbon ion radiotherapy for pancreatic cancer.

BACKGROUND AND PURPOSE: In radiotherapy (RT) for pancreatic cancer, the pancreas is considered an important organ at risk. However, there are insufficient reports on pancreatic function deterioration after X-ray RT as organ at risk, and there are no reports on those after carbon ion (C-ion) RT. Here, we evaluated pancreatic exocrine insufficiency (PEI) after C-ion RT using dose-volume histogram (DVH) analysis. MATERIALS AND METHODS: Data were retrospectively collected from patients who had undergone C-ion RT for pancreatic cancer between July 2013 and June 2019. The prescribed C-ion doses were 55.2 Gy (relative biological effectiveness) in 12 fractions. Serum pancreatic amylase and lipase values were measured before and after C-ion RT. In DVH analysis, we assessed V5Gy-50Gy and V<5 Gy-50Gy of pancreatic volume and analyzed whether these DVH parameters involved PEI. RESULTS: Thirty-three patients were included in the analysis. The median follow-up duration after the initiation of C-ion RT in these patients was 15.8 months (range, 4.3-64.8). During and after treatment, 57.6% of patients developed PEI within 13.6 months, defined as pancreatic amylase and lipase deficiencies. In DVH analysis, V<5Gy was the most effective factor for the PEI, and the cutoff value for developing PEI in V<5Gy was 4.57 cm3. CONCLUSION: We showed that pancreatic exocrine function declined after C-ion RT for pancreatic cancer and that PEI was initiated early in the course of C-ion RT. Additionally, a low dose of DVH parameters, such as V<5Gy, was a prognostic factor of PEI.

Visualisation of Range Shortening in Carbon Ion Beams and Washout of Positron Emitter: First-in-Human Report.

BACKGROUND/AIM: Auto-activation positron emission tomography (AAPET) is one of the most promising methods to verify beam range in carbon ion radiotherapy (C-ion RT). We aimed to confirm this for the first time in a clinical setting by performing AAPET in a patient with pancreatic cancer previously receiving coil embolisation of hepatic artery pseudoaneurysm. MATERIALS AND METHODS: A 70-year-old pancreatic head cancer patient was treated with C-ion RT on a clinical dose of 4.6 Gy (RBE), followed by AAPET, to verify beam ranges in C-ion RT. RESULTS: Positron emission tomography (PET) revealed low positron emitter concentrations at the distal side of the internal metals and in the aorta compared to the dose distribution of the treatment plan, indicating range shortening by internal metals in C-ion beams and positron emitter transportation by biofluids. CONCLUSION: AAPET may detect range shortening by internal metals in the trajectory and washout of intravascular positron emitter compared to plan dose distribution.