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.

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.

Comparing Oncologic Outcomes and Toxicity for Combined Modality Therapy vs. Carbon-Ion Radiotherapy for Previously Irradiated Locally Recurrent Rectal Cancer.

No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan-Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed.

Particle beam therapy for pelvic recurrence of colorectal cancer: a registry data analysis in Japan and a systematic review.

The aim of this study was to investigate the efficacy and safety of particle beam therapy (PBT) with proton or carbon ion beam for pelvic recurrence of colorectal cancer (PRCC) by comparing the clinical outcomes of a dataset of prospectively enrolled patients for PBT with those from the literature, which were collected by a systematic review of external X-ray radiotherapy (XRT) and PBT. Patients with PRCC treated at 14 domestic facilities between May 2016 and June 2019 and entered the database for prospective observational follow-up were analyzed. The registry data analyzed included 159 PRCC patients treated with PBT of whom 126 (79%) were treated with carbon ion radiation therapy (CIRT). The 3-year overall survival and local control rate were 81.8 and 76.4%, respectively. Among these PRCC patients, 5.7% had Grade 3 or higher toxicity. Systematic search of PubMed and Cochrane databases published from January 2000 to September 2020 resulted in 409 abstracts for the primary selection. Twelve studies fulfilled the inclusion criteria. With one additional publication, 13 studies were selected for qualitative analysis, including 9 on XRT and 4 on PBT. There were nine XRT studies, which included six on 3D conformal radiotherapy and three on stereotactic body radiation therapy, and four PBT studies included three on CIRT and one on proton therapy. A pilot meta-analysis using literatures with median survival time extractable over a 20-month observation period suggested that PBT, especially CIRT, may be a promising treatment option for PRCC not amenable to curative 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.

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.

Brown slits for colorectal adenoma crypts on conventional magnifying endoscopy with narrow band imaging using the X1 system.

BACKGROUND: Accurate diagnosis of colorectal premalignant polyps, including adenomas, is vital in clinical practice. AIM: To investigate the diagnostic yields of novel findings of brown slits for adenomas. METHODS: Patients who underwent colonoscopy at the Toyoshima Endoscopy Clinic were enrolled. Polyps sized ≥ 5 mm suspected of adenomas or clinically significant serrated polyps were included in the study. We defined the surface structures of colorectal polyps, which were brown curves inside and along the tubular glands identified using a combination of a new X1 system (Olympus Corporation) and a conventional magnifying colonoscope with non-staining narrow band imaging (NBI), as brown slits. The brown slits corresponded to slit-like lumens on endocytoscopy and histological crypt openings of an adenoma. We evaluated the diagnostic performance of brown slits for adenoma. RESULTS: A total of 108 Lesions from 62 patients were eligible. The average age was 60.4 years and 41.9% were male. The mean polyp size was 7.45 ± 2.83 mm. Fifty-seven lesions were positive for brown slits. Histopathological diagnosis comprised 59 low-grade tubular adenomas, 16 sessile serrated lesions, and 33 hyperplastic polyps. Among 59 adenomas, 56 (94.9%) were positive for brown slits. Among 16 sessile serrated lesions, 0 (0%) was positive for brown slits. Among 33 hyperplastic polyps, 1 (3.0%) was positive for brown slits. The sensitivity, specificity, and accuracy of brown slits for adenoma were 94.9%, 98.0%, and 96.3%, respectively. The positive predictive value and negative predictive value of brown slits for adenoma were also excellent for 98.2%, and 94.1%, respectively. CONCLUSION: Brown slits on conventional magnifying endoscopy with non-staining NBI using the X1 system were useful for diagnosing colorectal adenoma. The new endoscopy system could be examined using new standards.

Long-term outcomes of high dose carbon-ion radiation therapy for unresectable upper cervical (C1-2) chordoma.

BACKGROUND: Chordoma is a rare, locally invasive neoplasm of the axial skeleton. Complete resection is often difficult, especially for the upper-cervical (C1-2) spine. We evaluated the efficacy and safety of carbon-ion radiotherapy (CIRT) for unresectable C1-2 chordoma. METHODS: Patients with C1-2 chordoma treated with definitive CIRT (60.8 Gy [RBE] in 16 fractions) were retrospectively analyzed. We evaluated OS, LC, PFS, and toxicity. RESULTS: Nineteen eligible patients all completed the planned course of CIRT. With the median follow-up 68 months (range: 29-144), median OS was 126 months (range: 36-NA). Five-year OS, LC, and PFS were 68.4% (95% CI, 42.8%-84.4%), 75.2% (46.1%-90.0%), and 64.1% (36.3%-82.3%), respectively. Regarding acute toxicity of grade ≥3, there was only one grade 3 mucositis. Late toxicity included radiation-induced myelitis (grade 3 in 1 patient; 5.3%), and compression fractures (n = 5; 26.3%). CONCLUSIONS: High-dose CIRT is a promising treatment option for unresectable upper cervical chordoma.

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.

Accurate Delineation of Mucosal Lesions in Treatment-Planning Computed Tomography Using Iodine Paste Markers for Oral Mucosal Melanoma.

This technical report introduces the utility of iodine paste markers using endodontic materials for the accurate contouring of mucosal lesions of oral mucosal melanoma, which are difficult to delineate on imaging during the planning of carbon-ion radiation therapy (CIRT). The patient had a primary oral mucosal melanoma located in the palatal mucosa without palatal or maxillary bone invasion. A dental root canal filling material, which is a calcium hydroxide/iodoform nonhardenable paste, was used as a marker. We first performed treatment-planning computed tomography (CT) without an iodine paste marker for mucosal lesions. Subsequently, we placed an iodine paste marker on the palatal mucosal lesion to accurately delineate the mucosal lesions of the palate. Finally, we obtained a reference CT image with an iodine paste marker. Computed tomography without the marker was fused to the reference CT with markers during treatment planning, and the gross tumor volume was contoured. Thereafter, CIRT was delivered without markers. During CIRT, expected acute mucositis was observed in the area of the planning target volume, including melanosis, in accordance with the dose distribution. The use of iodine paste markers for localized mucosal lesions, which are difficult to delineate on CT and magnetic resonance imaging, may be useful for accurately contouring gross tumor volumes on treatment-planning CT.

Comparison of clinical outcomes between carbon ion radiotherapy and X-ray radiotherapy for reirradiation in locoregional recurrence of rectal cancer.

Carbon ion radiotherapy (CIRT) has garnered interest for the treatment of locoregional rectal cancer recurrence. No study has compared CIRT and X-ray radiotherapy (XRT) for reirradiation (reRT) in such cases. We analyzed and compared the clinical outcomes such as local control, overall survival, and late toxicity rate between CIRT and XRT, for treating locoregional rectal cancer recurrence. Patients with rectal cancer who received reRT to the pelvis by CIRT or XRT from March 2005 to July 2019 were included. The CIRT treatment schedule was 70.4 Gy (relative biological effectiveness) in 16 fractions. For the XRT group, the median reRT dose was 50 Gy (range 25-62.5 Gy) with a median of 25 fractions (range 3-33). Thirty-five and 31 patients received CIRT and XRT, respectively. Tumour and treatment characteristics such as recurrence location and chemotherapy treatment differed between the two groups. CIRT showed better control of local recurrence (adjusted hazard ratio [HR] 0.17; p = 0.002), better overall survival (HR 0.30; p = 0.004), and lower severe late toxicity rate (HR 0.15; p = 0.015) than XRT. CIRT was effective for treating locoregional rectal cancer recurrence, with high rates of local control and survival, and a low late severe toxicity rate.

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.

Stopping-power ratio of mouthpiece materials for charged-particle therapy in head and neck cancer.

In this study, the stopping-power ratios (SPRs) of mouthpiece materials were measured and the errors in the predicted SPRs based on conversion table values were further investigated. The SPRs of the five mouthpiece materials were predicted from their computed tomography (CT) numbers using a calibrated conversion table. Independently, the SPRs of the materials were measured from the Bragg peak shift of a carbon-ion beam passing through the materials. The errors in the SPRs of the materials were determined as the difference between the predicted and measured values. The measured SPRs (errors) of the Nipoflex 710™ and Bioplast™ ethylene-vinyl acetate copolymers (EVAs) were 0.997 (0.023) and 0.982 (0.007), respectively. The SPRs of the vinyl silicon impression material, light-curable resin, and bis-acrylic resin were 1.517 (0.134), 1.161 (0.068), and 1.26 (0.101), respectively. Among the five tested materials, the EVAs had the lowest SPR errors, indicating the highest human-tissue equivalency.

Carbon-ion Radiotherapy for Colorectal Cancer.

Heavy-ion radiotherapy (RT) is a kind of particle RT, and carbon-ion beam constitutes the primary delivery method of heavy-ion RT. Unlike the conventional photon modalities, particle RT, in particular carbon-ion radiotherapy (CIRT), offers unique physical and biological advantages. Particle therapy allows for substantial dose delivery to tumors with minimal surrounding tissue damage. In addition, CIRT in particular possesses biological advantages such as inducing increased double-strand breaks in DNA structures, causing irreversible cell damage independently of cell cycle or oxygenation, more so than proton or photon. It can be expected that CIRT is effective on radioresistant cancers such as colorectal cancers (CRCs). We introduced the results of CIRT for local recurrent rectal cancer, lung metastasis, liver metastasis, and lymph node metastasis.

Efficacy and feasibility of re-irradiation using carbon ions for pancreatic cancer that recurs after carbon-ion radiotherapy.

BACKGROUND AND PURPOSE: Patients who receive carbon-ion radiotherapy (C-ion RT) for primary pancreatic cancer may experience locoregional recurrence; however, the treatment options for such patients are limited. We aimed to investigate the feasibility and efficacy of carbon-ion re-irradiation for patients with pancreatic cancer who experienced recurrence after initial C-ion RT. MATERIALS AND METHODS: Twenty-one patients with recurrent pancreatic cancer who underwent repeat C-ion RT between December 2010 and November 2016 at our institute were retrospectively evaluated. The sites of post-initial C-ion RT failure were in-field central in 16 patients (76.2%) and marginal in 5 (23.8%). The median doses of initial and repeat C-ion RT were both 52.8 Gy (relative biological effectiveness [RBE]). Thirteen patients (61.9%) received concurrent chemotherapy with re-irradiation, while 11 (52.4%) received adjuvant chemotherapy. RESULTS: The median follow-up period after re-irradiation was 11 months. The 1-year local control, progression-free survival, and overall survival rates were 53.5%, 24.5%, and 48.7%, respectively. Toxicity data was obtained from the patients' charts. Only 1 patient (4.8%) developed grade 3 acute toxicities and none developed grade ≥3 late toxicities. Univariate analysis indicated that patients who received adjuvant chemotherapy had significantly improved local control rates compared with those who did not; the 1-year local control rates were 80.0% and 0.0%, respectively (P = 0.0469). CONCLUSION: Repeating C-ion RT may be a reasonable option with tolerable toxicity for patients with recurrent pancreatic cancers. Adjuvant chemotherapy appears to improve the local control rate. This is the first study to examine re-irradiation using C-ion for recurrent pancreatic cancer after initial C-ion RT.

Heavy charged particles for gastrointestinal cancers.

Carbon ion beams constitute the primary delivery method of heavy ion radiotherapy. It offers improved dose distribution, and enables concentration of dose within target volumes with minimal extraneous exposure of normal tissue, while delivering superior biological effect in comparison with photon and proton technologies. Here, we review the application of this technology to various gastrointestinal cancers.

[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.