Carbon-ion radiotherapy for clear cell odontogenic carcinomas.

BACKGROUND: Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic malignant tumor. The standard treatment for CCOC is surgical resection and adjuvant radiotherapy (RT). Radiotherapy is generally considered in inoperable cases. However, there are no reports on definitive RT for CCOC, and the role of RT in patients with inoperable CCOC remains unknown. Therefore, in this report, we present two cases of carbon-ion (C-ion) RT for CCOC. CASE PRESENTATION: In case 1, a 73-year-old man with mandibular CCOC presented with recurrence in the inferior temporal fossa after two tumor resections. The tumor was considered inoperable, and C-ion RT (57.6 Gy in 16 fractions) was administered. The tumor remained controlled even after 20 months of C-ion RT; however, the patient died of other causes. In case 2, a 34-year-old man with maxillary CCOC presented with recurrence in the left sinonasal region after two tumor resections. The tumor was considered inoperable, and C-ion RT (64 Gy in 16 fractions) was administered. However, recurrence was observed in the irradiated field 19 months after the treatment. Subsequently, C-ion RT (64 Gy in 16 fractions) was repeated for the recurrent tumors. Seven years and 6 months after the initial irradiation, the tumor remains controlled, and the patient is alive without any unexpected serious adverse events. CONCLUSION: C-ion RT may be an effective treatment option for patients with inoperable CCOC.

Carbon Ion Radiotherapy for Locally Recurrent Rectal Cancer of Patients with Prior Pelvic Irradiation.

BACKGROUND: This study aimed to assess the safety and efficacy of carbon-ion radiotherapy (CIRT) for salvage of previously X-ray-irradiated (XRT) locally recurrent rectal cancer (LRRC). METHODS: Between September 2005 and December 2017, 77 patients with LRRC were treated with CIRT re-irradiation. All the patients had received prior XRT with a median dose of 50.0 Gy (range 20-74 Gy), principally for neoadjuvant or adjuvant recurrence prophylaxis in 34 patients and for recurrence in 43 patients. The total CIRT dose of 70.4 Gy (RBE) (gray relative biologic effectiveness) was administered in 16 fixed fractions during 4 weeks (4.4 Gy [RBE] per fraction). RESULTS: All the patients completed the scheduled treatment course. None of the patients received resection after CIRT. Acute grade 3 toxicities occurred for eight patients (10 %), including five grade 3 pelvic infections (2 involving pain and 1 involving neuropathy). Late grade 3 toxicities occurred for 16 patients (21 %): 13 with late grade 3 pelvic infections, 9 with gastrointestinal toxicity, 1 with skin toxicity, 2 with pain, and 4 with neuropathy. No grade 4+ toxicity was noted. The overall local control rates (infield + out-of-field recurrence) were 69 % at 3 years and 62 % at 5 years. In the planning target volume (PTV), the infield recurrence rates were 90 % and 87 % respectively. The control rates for regional recurrence were 85 % at 3 years and 81 % at 5 years. The median overall survival time was 47 months. The survival rates were 61 % at 3 years and 38 % at 5 years. CONCLUSION: Carbon-ion re-irradiation of previously X-ray-irradiated locally recurrent rectal cancer appears to be safe and effective, providing good local control and survival advantage without unacceptable morbidity.

Long-term outcomes of octogenarian pancreatic cancer patients treated with carbon ion radiotherapy.

BACKGROUND: Pancreatic cancer is a disease of the elderly; patients >65 years are 60% of the cases. Due to multiple comorbidities, treating these patients is challenging. We report the efficacy and safety of carbon ion radiotherapy (C-ion RT) in octogenarians. METHODS: We retrospectively analyzed the cases of 46 pancreatic cancer patients aged ≥80 years (median 83, range 80-97) treated with definitive C-ion RT in 2007-2018 at our institute. RESULTS: Twenty-five patients (54%) had resectable or borderline-resectable disease; none underwent surgery (because of medical reasons, e.g., age, multiple comorbidities). C-ion RT was delivered with a median dose of 55.2 Gy (RBE) in 12 fractions. The survivors' median follow-up period was 43 (range 19-76) months. The entire cohort's median overall survival (OS) was 15 (95%CI: 14-22) months with a 3-year OS of 20% (95%CI: 11%-35%). On both univariate and multivariate analyses, baseline CA19-9 remained the significant independent OS prognostic factor (p = 0.032). The 3-year local control rate for all patients was 34% (95%CI: 19%-53%). Local failure (n = 25, 54%) was as common as distant relapse (n = 26, 57%); 33% of the patients experienced both local and systemic failure. About 15% underwent re-C-ion RT for infield recurrence; they achieved a median 22-month OS. No patients exhibited grade ≥3 severe acute or late toxicities (including those who received re-C-ion RT). CONCLUSIONS: C-ion RT in octogenarians with pancreatic cancer showed promising outcomes with acceptable acute and late toxicities and can be considered a reasonable alternative to radical surgery.

[A Case of Initially Locally Advanced Pancreatic Cancer Curatively Resected after Carbon-Ion Radiotherapy with Gemcitabine].

BACKGROUND: The neoadjuvant therapy against locally advanced pancreatic cancer(LAPC)have been developed by combining radiation with chemotherapy. We experienced a case of LAPC performed R0 resection and obtained high histopathological effect by carbon-ion radiotherapy with gemcitabine(GEM). CASE PRESENTATION: A 65-year-old male with epigastric and back pain was suspected as pancreas cancer by FDG-PET/CT scan, and was referred to our hospital. CT scan revealed a tumor in pancreatic body with poor contrast effect and with invasion to celiac artery, common hepatic artery and portal vein, and diagnosed as pancreatic adenocarcinoma by endoscopic ultrasound-fine needle aspiration(EUS-FNA). Therefore we diagnosed the tumor as pancreatic body cancer, cT4, cN1a, cM0, cStage Ⅲ, UR-LA. GEM plus nab-paclitaxel(GnP)were administered for 4 months followed by carbon-ion radiotherapy with GEM at other hospital. Distal pancreatectomy with en bloc celiac axis resection(DP-CAR)was performed 3 months after irradiation. High therapeutic effect was obtained histopathologically( Evans grade Ⅲ), and lesions outside the pancreas disappeared except for metastasis to one lymph node (ypT1c, ypN1a, ycM0, ypStage ⅡB), and R0 resection was performed. CONCLUSION: Carbon-ion radiotherapy with chemotherapy for LAPC may improve curative resection rate.

Carbon-ion radiotherapy for lymph node oligo-recurrence: a multi-institutional study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS).

BACKGROUND: The efficacy of carbon-ion radiotherapy (C-ion RT) for lymph node (LN) oligo-recurrence has only been evaluated in limited single-center studies. We aimed to investigate the benefit of C-ion RT for LN oligo-recurrence in a large multi-center study. METHODS: Patients who received C-ion RT between December 1996 and December 2015 at 4 participating facilities and who met the following eligibility criteria were included: (i) histological or clinical diagnosis of LN recurrence; (ii) controlled primary lesion; (iii) no recurrence other than LN; (iv) LN recurrence involved in a single lymphatic site; and (v) age ≥ 20 years. RESULTS: A total of 323 patients were enrolled. Median follow-up period was 34 months for surviving patients. The most common dose fractionation of C-ion RT was 48.0 Gy (relative biological effectiveness) in 12 fractions. Forty-seven patients had a history of RT at the recurrent site. The 2-year local control (LC) and overall survival (OS) rates after C-ion RT were 85% and 63%, respectively. Only 1 patient developed grade-3 toxicity. Factors such as LN diameter, histology, and history of previous RT did not correlate with LC. Smaller diameters (< 30 mm) and numbers (≤ 3) of LN metastases as well as longer disease-free intervals post-primary therapy (≥ 16 months) were associated with significantly better OS. CONCLUSIONS: C-ion RT for LN oligo-recurrence appeared to be effective and safe. C-ion RT may provide a survival benefit to patients with LN oligo-recurrence, particularly to those with few LN metastases, smaller LN diameters, and longer disease-free intervals.

Particle Radiation Therapy for Gastrointestinal Cancers.

Particle irradiation of cancerous disease has gained great traction in recent years. The ability for particle therapy centers to deliver radiation with a highly conformal dose distribution while maintaining minimal exit or excess dose delivered to normal tissue, coupled with various biological advantages particularly found with heavy-ion beams, enables treatment of diseases inapproachable with conventional radiotherapy. Here, we present a review of the current status of particle therapy with regard to cancers of the gastrointestinal tract, including esophagus, liver, pancreas, and recurrent rectal cancer.

Stereotactic body radiation therapy for primary lung cancers clinically diagnosed without pathological confirmation: a single-institution experience.

BACKGROUND: Pathological diagnosis of small lung lesions is sometimes difficult in medically inoperable patients. The purpose of this study was to evaluate the adverse events and the outcomes of stereotactic body radiation therapy (SBRT) for lung lesions which were clinically diagnosed as primary lung cancer without pathological confirmation. METHODS: Between April 2003 and April 2011, 88 patients with small lung lesions which were clinically diagnosed as primary lung cancer were treated with SBRT. The median tumor size was 19 mm (range 8-40 mm). The radiation dose was 48 Gy in four fractions in all patients. The median follow-up was 23 months (range 6-91 months). RESULTS: Recurrence was observed in 13 patients. The local control rate, progression-free survival rate, and overall survival rate at 3 years were 90, 67, and 80 %, respectively. Two patients (2.3 %) had Grade 2 radiation pneumonitis, and six patients (6.8 %) had Grade 2 rib fractures. There were no adverse events of Grade 3 or greater. CONCLUSIONS: SBRT appears to be a safe and effective treatment option for small lung lesions that are clinically diagnosed as primary lung cancer without pathological confirmation.

Clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy for lung tumors.

BACKGOUND: We retrospectively investigated the clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy (SBRT) for lung tumors. METHODS: Between April 2003 and July 2012, 473 patients with lung tumors were treated with SBRT. We identified 12 patients (2.5 %) with pneumothorax caused by SBRT, and evaluated the clinical features of pneumothorax. RESULTS: All of the tumors were primary lung cancers. The severity of radiation pneumonitis was grade 1 in 10 patients and grade 2 in two patients. Nine patients had emphysema. The planning target volume and pleura overlapped in 11 patients, and the tumors were attached to the pleura in 7 patients. Rib fractures were observed in three patients before or at the same time as the diagnosis of pneumothorax. The median time to onset of pneumothorax after SBRT was 18.5 months (4-84 months). The severity of pneumothorax was grade 1 in 11 patients and grade 3 in one patient. CONCLUSION: Although pneumothorax was a relatively rare late adverse effect after SBRT, some patients demonstrated pneumothorax after SBRT for peripheral lung tumors. Although most pneumothorax was generally tolerable and self-limiting, careful follow-up is needed.

In Silico Study of Simultaneous Integrated Boost Carbon-Ion Radiotherapy for Locally Advanced Pancreatic Cancer.

BACKGROUND/AIM: Carbon-ion radiotherapy (CiRT) has been used for the treatment of locally advanced pancreatic cancer (LAPC) with uniform dose plan. The aim of the present study is to investigate the effectiveness of a simultaneous integrated boost (SIB) technique with scanned CiRT against LAPC. MATERIALS AND METHODS: Data of 21 patients with LAPC were used to compare two treatment planning approaches: a conventional uniform dose approach and a SIB approach. A relative biological effectiveness (RBE)-weighted dose (DRBE) of 55.2 Gy (RBE) in 12 fractions was prescribed to the planning target volume (PTV) in the conventional approach. In the SIB approach, DRBE of 67.2 Gy (RBE) and 43.2 Gy (RBE) in 12 fractions were prescribed to a high-risk PTV (HR-PTV) and low-risk PTV (LR-PTV), respectively. The DRBE and dose-averaged linear energy transfer (LETd) of targets and gastrointestinal tracts as organs at risk (OARs) were evaluated. RESULTS: The HR-PTV D90% and LR-PTV D90% were 64.4±0.6 and 42.5±0.1 Gy (RBE) in SIB approach compared to the PTV D90% of 54.1±0.4 Gy (RBE) in the conventional approach. All SIB plans achieved the D2cc lower than 46 Gy (RBE) and V30 lower than 4 cm3 within OARs. The SIB approach increased the minimum LETd within the GTV to 44 keV/µm or higher for 20 out of 21 patients as compared to 16 out of 21 patients in the conventional approach. CONCLUSION: The SIB approach effectively increased the RBE-weighted dose and LETd within the HR-PTV and GTV by accumulating the high-LET stopping carbon-ions into the HR-PTV in addition to the decreased RBE-weighted dose to OARs.

Carbon-Ion Radiation Therapy for Unresectable Locally Recurrent Colorectal Cancer: A Promising Curative Treatment for Both Radiation Therapy: Naïve Cases and Reirradiation Cases.

PURPOSE: It is difficult to effectively cure patients with unresectable locally recurrent colorectal cancers (LRCRCs) using conventional chemotherapy or chemoradiation therapy. Furthermore, treatment options vary depending on the patient's history of radiation therapy. Carbon-ion radiation therapy (CIRT) is a potentially curative treatment for these patients. Here, we compare the treatment outcomes of radiation therapy-naïve cases (nRT) and re-irradiation cases (reRT). METHODS AND MATERIALS: Patients with LRCRC treated with CIRT at QST Hospital between 2003 and 2019 were eligible. CIRT was administered daily 4 d/wk for 16 fractions. The total irradiated dose was set at 73.6 Gy (relative biologic effectiveness-weighted dose [RBE]) for nRT and 70.4 Gy (RBE) for reRT patients. RESULTS: We included 390 nRT cases and 83 reRT cases. The median follow-up period from the initiation of CIRT was 48 (5-208) months. The 3-year overall survival (OS) rates for nRT and reRT were 73% (95% CI, 68%-77%) and 76% (65%-84%), respectively. The 5-year OS rates were 50% (45%-55%) and 50% (38%-61%), respectively. These rates did not differ significantly (P = .55). The 3-year local control (LC) rates for nRT (73.6 Gy) and reRT (70.4 Gy) cases were 80% (75%-84%) and 80% (68%-88%), respectively. The 5-year LC rates were 72% (67%-78%) and 69% (55%-81%), respectively, without a significant difference (P = .56). CONCLUSIONS: Our results suggest that CIRT for LRCRC is a very effective and promising treatment for both nRT and reRT cases.

Clinical target volume design and dose in carbon-ion radiation therapy for sinonasal mucosal melanoma.

BACKGROUND AND PURPOSE: No guidelines exist for the clinical target volume (CTV) and radiotherapy dose in sinonasal mucosal melanoma (SNMM). Thus, we aimed to determine the carbon-ion radiotherapy (CIRT) CTV and dose for SNMM. MATERIALS AND METHODS: In total, 135 patients with SNMM who received CIRT were reviewed. The relative biological effectiveness-weighted dose was 57.6 or 64 Gy in 16 fractions. CTV was classified into small CTV, which included the gross tumor and visible melanosis with a certain margin, and extended CTV, which included the tumor site and adjacent anatomical structures. Local recurrence (LR) patterns were pattern I, II, and III, defined as recurrence over the gross tumor, visible melanosis and subclinical area, which would be covered if extended CTV was applied, and outside the extended CTV, respectively. RESULTS: The 5-year LR rate was 35.3 %. The prescribed dose was not a significant risk factor for pattern I LR; however, 57.6 Gy for a large tumor was insufficient for local control. Using an extended CTV was significantly associated with a lower risk of pattern II LR, and these recurrences did not occur in regions that received > 40 Gy. The 5-year pattern III LR rate was 6.4 %. CONCLUSION: Utilizing an extended CTV in CIRT for SNMM is appropriate even for small tumors. Using a smaller CTV after an extended CTV of at least 40 Gy is recommended to reduce adverse events. Although the optimal dose for gross tumors remains unclear, the latest technology with 64 Gy showed good outcomes.

Reduced Risk of Severe Radiation-Induced Lymphopenia in Carbon Ion Radiation Therapy for Locally Advanced Pancreatic Cancer: A Comparative Analysis of Carbon Versus Photon Therapy.

PURPOSE: Radiation-induced lymphopenia (RIL) is associated with poor prognosis in patients with locally advanced pancreatic cancers. However, there are no reports comparing the effects of carbon ion radiation therapy (CIRT) and photon beam radiation therapy (RT) on the development of RIL. Differences in RIL after CIRT or photon beam RT and predictive factors for RIL in patients with locally advanced pancreatic cancer were investigated. MATERIALS AND METHODS: This retrospective study cohort included 834 patients who received concurrent chemoradiotherapy (CCRT) in 2 separate institutions: 337 and 497 in the CIRT and photon beam RT groups, respectively. Severe RIL was defined as an absolute lymphocyte count (ALC) <0.5 × 109 cells/L. A 1:1 propensity score-matching analysis was performed between the CIRT and photon beam RT groups. Patients were categorized into 3 groups according to the development of recovery from severe RIL: no severe RIL (Group A), recovery from severe RIL (Group B), and no recovery from severe RIL (Group C). Logistic regression analysis was performed to identify the predictive value of severe RIL. The prognostic factors of overall survival (OS) were determined using Cox regression analysis. RESULTS: After propensity score matching, the baseline ALC and planning target volume of the CIRT and photon beam RT groups were comparable. During CCRT, the ALC of the entire cohort decreased and was significantly lower in the photon beam RT group than in the CIRT group (P < .001). Multivariate logistic regression analysis showed that CIRT reduced severe RIL more than photon beam RT. After adjusting for other factors, the RT modality and RIL were significantly associated with OS. Photon beam RT showed a significantly worse OS than CIRT, and Group C showed a significantly worse OS than Group A. CONCLUSIONS: CIRT seems to reduce the development of severe RIL. The RT modality and development/recovery from severe RIL were associated with OS in patients who received CCRT for locally advanced pancreatic cancer. The reduction of severe RIL through optimized RT may be essential for improving treatment outcomes.

Dose-averaged LET optimized carbon-ion radiotherapy for head and neck cancers.

This feasibility study confirmed the initial safety and efficacy of a novel carbon-ion radiotherapy (CIRT) using linear energy transfer (LET) painting for head and neck cancer. This study is the first step toward establishing CIRT with LET painting in clinical practice and making it a standard practice in the future.

Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer.

BACKGROUND: The authors evaluated the tolerance and efficacy of carbon-ion radiotherapy (CIRT) as a short-course, preoperative treatment and determined the recommended dose needed to reduce the risk of postoperative local recurrence without excess injury to normal tissue. METHODS: Patients radiographically defined with potentially resectable pancreatic cancer were eligible. A preoperative, short-course, dose-escalation study was performed with fixed 8 fractions in 2 weeks. The dose of irradiation was increased by 5% increments from 30 grays equivalents (GyE) to 36.8 GyE. Surgery was to be performed 2 to 4 weeks after the completion of CIRT. RESULTS: The study enrolled 26 patients. At the time of restaging after CIRT, disease progression with distant metastasis or refusal ruled out 5 patients from surgery. Twenty-one of 26 patients (81%) patients underwent surgery. The pattern of initial disease progression was distant metastasis in 17 patients (65%) and regional recurrence in 2 patients (8%). No patients experienced local recurrence. The 5-year survival rates for all 26 patients and for those who underwent surgery were 42% and 52%, respectively. CONCLUSIONS: Preoperative, short-course CIRT followed by surgery is feasible and tolerable without unacceptable morbidity.

Comparison of dosimetries of carbon-ion pencil beam scanning, proton pencil beam scanning and volumetric modulated arc therapy for locally recurrent rectal cancer.

We compared the dose distributions of carbon-ion pencil beam scanning (C-PBS), proton pencil beam scanning (P-PBS) and Volumetric Modulated Arc Therapy (VMAT) for locally recurrent rectal cancer. The C-PBS treatment planning computed tomography (CT) data sets of 10 locally recurrent rectal cancer cases were randomly selected. Three treatment plans were created using identical prescribed doses. The beam angles for C-PBS and P-PBS were identical. Dosimetry, including the dose received by 95% of the planning target volume (PTV) (D95%), dose to the 2 cc receiving the maximum dose (D2cc), organ at risk (OAR) volume receiving > 15Gy (V15) and > 30Gy (V30), was evaluated. Statistical significance was assessed using the Wilcoxon signed-rank test. Mean PTV-D95% values were > 95% of the volume for P-PBS and C-PBS, whereas that for VMAT was 94.3%. However, PTV-D95% values in P-PBS and VMAT were < 95% in five and two cases, respectively, due to the OAR dose reduction. V30 and V15 to the rectum/intestine for C-PBS (V30 = 4.2 ± 3.2 cc, V15 = 13.8 ± 10.6 cc) and P-PBS (V30 = 7.3 ± 5.6 cc, V15 = 21.3 ± 13.5 cc) were significantly lower than those for VMAT (V30 = 17.1 ± 10.6 cc, V15 = 55.2 ± 28.6 cc). Bladder-V30 values with P-PBS/C-PBS (3.9 ± 4.8 Gy(RBE)/3.0 ± 4.0 Gy(RBE)) were significantly lower than those with VMAT (7.9 ± 8.1 Gy). C-PBS provided superior dose conformation and lower OAR doses compared with P-PBS and VMAT. C-PBS may be the best choice for cases in which VMAT and P-PBS cannot satisfy dose constraints. C-PBS could be another choice for cases in which VMAT and P-PBS cannot satisfy dose constraints, thereby avoiding surgical resection.

Dosimetric Analysis for Otitis Media With Effusion Due to Eustachian Tube Dysfunction After Carbon-ion Radiation Therapy for Head and Neck Cancers.

Purpose: This study aimed to clarify the predictive factors for otitis media with effusion (OME) due to Eustachian tube dysfunction in patients treated with carbon-ion radiation therapy (CIRT) for head and neck cancers. Methods and Materials: We investigated patients with head and neck cancer whose Eustachian tube was irradiated by CIRT between October 2013 and December 2018 at our institution. OME severity was assessed by the proportion of mastoid cell opacification of magnetic resonance or computed tomography imaging (grade 0: <5% of volume of mastoid cell with opacification by fluid collection; grade 1: 6%-33%; grade 2: 34%-67%; and grade 3: 68%-100%). Clinical factors and dosimetric parameters affecting the development of grade 2 to 3 OME were analyzed using a log-rank test and Cox proportional hazards model. Results: In total, 141 patients were analyzed. The median follow-up period was 25.2 months. Grade 2 to 3 OME was observed in 65 patients, with a median incidence period of 6.5 months. According to the multivariate analysis, the mean dose of the cartilage part was a significant independent predictive parameter of grade 2 to 3 OME. The 2-year incidence rate of patients with a mean dose of the cartilage part of <40.59 Gy (relative biological effectiveness) and ≥40.59 Gy (relative biological effectiveness) was 24.2% (95% confidence interval, 15.1%-37.4%) and 66.4% (95% confidence interval, 54.5%-78.0%), respectively. Conclusions: Our findings may be useful to predict the risk of grade 2 to 3 OME due to Eustachian tube dysfunction before CIRT.

[Remote radiation planning support system].

We constructed a remote radiation planning support system between Kyushu University Hospital (KUH) in Fukuoka and Kyushu University Beppu Hospital (KBH) in Oita. Between two institutions, radiology information system for radiotherapy division (RT-RIS) and radiation planning system (RTPS) were connected by virtual private network (VPN). This system enables the radiation oncologists at KUH to perform radiotherapy planning for the patients at KBH. The detail of the remote radiation planning support system in our institutions is as follows: The radiation oncologist at KBH performs radiotherapy planning and the data of the patients are sent anonymously to the radiation oncologists at KUH. The radiation oncologists at KUH receive the patient's data, access to RTPS at KBH, verify or change the radiation planning at KBH: Radiation therapy is performed at KBH according to the confirmed plan by the radiation oncologists at KUH. Our remote radiation planning system is useful for providing radiation therapy with safety and accuracy.