Biological dose optimization incorporating intra-tumoural cellular radiosensitivity heterogeneity in ion-beam therapy treatment planning.

OBJECTIVE: Treatment plans of charged-particle therapy have been made under an assumption that all cancer cells within a tumour equally respond to a given radiation. However, an intra-tumoural cellular radiosensitivity heterogeneity clearly exists, and it may lead to an overestimation of therapeutic effects of the radiation. The purpose of this study was to develop a biological model that can incorporate the radiosensitivity heterogeneity into biological optimization for charged-particle therapy treatment planning. Approach. The radiosensitivity heterogeneity was modeled as the variability of a cell-line specific parameter in the microdosimetric kinetic model following the gamma distribution. To validate the developed intra-tumoural-radiosensitivity-heterogeneity-incorporated microdosimetric kinetic (HMK) model, a treatment plan with H-ion beams was made for a chordoma case assuming a radiosensitivity heterogeneous region within the tumour. To investigate the effects of the radiosensitivity heterogeneity on the biological effectiveness of H-, He-, C-, O-, and Ne-ion beams, the relative biological effectiveness (RBE)-weighted dose distributions were planned to a cuboid target with the stated ion beams without considering the heterogeneity. The planned dose distributions were then recalculated by taking the heterogeneity into account. Main results: The cell survival fraction and corresponding RBE weighted dose w- ere formulated basedon the HMK model. The first derivative of the RBE-weighted dose distribution was also derived,which is needed for fast biological optimization. For the patient plan, the biological optimization increasedthe dose to the radiosensitivity heterogeneous region to compensate for the heterogeneity-inducedreduction in biological effectiveness of the H-ion beams. The reduction in biological effectiveness dueto the heterogeneity waspronouncedfor low-LET beams but moderate for high-LET beams. The RBE-weighted dose in the cuboid target decreased by 7.6% for the H-ion beam, while it decreased by just 1.4% for the Ne-ion beam. Significance. The optimal treatment plans that consider the intra-tumoural cellular radiosensitivity heterogeneity can be devised using the HMK model. .

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.

High-Linear Energy Transfer Irradiation in Clinical Carbon-Ion Beam With the Linear Energy Transfer Painting Technique for Patients With Head and Neck Cancer.

Purpose: Dose-averaged linear energy transfer (LETd) is one of the important factors in determining clinical outcomes for carbon-ion radiation therapy. Innovative LET painting (LP) has been developed as an advanced form of conventional intensity modulated carbon-ion radiation therapy (IMIT) at the QST Hospital. The study had 2 motivations: to increase the minimum LETd (LETdmin) and to improve uniformity of the LETd distribution within the gross tumor volume (GTV) by using LP treatment plans for patients with head and neck cancer while maintaining the relative biologic effectiveness (RBE)-weighted dose coverage within the planning tumor volume (PTV) the same as in the conventional IMIT plan. Methods and Materials: The LP treatment plans were designed with the in-house treatment planning system. For the plans, LETd constraints and LETdmin, goal-LETd, and maximum-LETd (LETdmax) constraints for the GTV were added to the conventional dose constraints in the IMIT prescription. For 13 patients with head and neck cancer, the RBE-weighted dose to 90% (D90) and 50% (D50) of the PTV and the LETdmin, mean (LETdmean), and LETdmax values within the GTV in the LP plans were evaluated by comparing them with those in the conventional IMIT plans. Results: The LP for 13 patients with head and neck cancer could keep D90s and D50s for the PTV within 1.0% of those by the conventional IMIT. Among the 13 patients, the mean LETdmin of the LP plans for the GTV was 59.2 ± 7.9 keV/µm, whereas that of the IMIT plans was 45.9 ± 6.0 keV/µm. The LP increased the LETdmin to 8 to 24 keV/µm for the GTV compared with IMIT. Conclusions: While maintaining the dose coverage to the PTV as comparable to that for IMIT, the LP increased the mean LETdmin to 13.2 keV/µm for the GTV. For a GTV up to 170 cm3, LETd > 44 keV/µm could be achieved using LP, which according to previous studies was associated with lower recurrence. In addition, the LP method delivered more uniform LETd distributions compared with IMIT.

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.

Carbon Ion Radiotherapy: An Evidence-Based Review and Summary Recommendations of Clinical Outcomes for Skull-Base Chordomas and Chondrosarcomas.

Skull-base chordoma and chondrosarcoma are rare radioresistant tumors treated with surgical resection and/or radiotherapy. Because of the established dosimetric and biological benefits of heavy particle therapy, we performed a systematic and evidence-based review of the clinical outcomes of patients with skull-base chordoma and chondrosarcoma treated with carbon ion radiotherapy (CIRT). A literature review was performed using a MEDLINE search of all articles to date. We identified 227 studies as appropriate for review, and 24 were ultimately included. The published data illustrate that CIRT provides benchmark disease control outcomes for skull-base chordoma and chondrosarcoma, respectively, with acceptable toxicity. CIRT is an advanced treatment technique that may provide not only dosimetric benefits over conventional photon therapy but also biologic intensification to overcome mechanisms of radioresistance. Ongoing research is needed to define the magnitude of benefit, patient selection, and cost-effectiveness of CIRT compared to other forms of radiotherapy.

Shortening image registration time using a deep neural network for patient positional verification in radiotherapy.

We sought to accelerate 2D/3D image registration computation time using image synthesis with a deep neural network (DNN) to generate digitally reconstructed radiographic (DRR) images from X-ray flat panel detector (FPD) images. And we explored the feasibility of using our DNN in the patient setup verification application. Images of the prostate and of the head and neck (H&N) regions were acquired by two oblique X-ray fluoroscopic units and the treatment planning CT. DNN was designed to generate DRR images from the FPD image data. We evaluated the quality of the synthesized DRR images to compare the ground-truth DRR images using the peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM). Image registration accuracy and computation time were evaluated by comparing the 2D-3D image registration algorithm using DRR and FPD image data with DRR and synthesized DRR images. Mean PSNR values were 23.4 ± 3.7 dB and 24.1 ± 3.9 dB for the pelvic and H&N regions, respectively. Mean SSIM values for both cases were also similar (= 0.90). Image registration accuracy was degraded by a mean of 0.43 mm and 0.30°, it was clinically acceptable. Computation time was accelerated by a factor of 0.69. Our DNN successfully generated DRR images from FPD image data, and improved 2D-3D image registration computation time up to 37% in average.

A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

Simulation study of comparative dosimetric analysis of coplanar horizontal-port scanned carbon-ion beam therapy in the head and neck.

OBJECTIVE: Carbon-ion radiotherapy (CIRT) has demonstrated success in treating radioresistant disease within the head and neck, owing to its unique physical and radiobiological properties. Construction cost remains prohibitive; a center offering only a horizontal port may bridge this difficulty, but removal of the vertical port may prohibit treatment of disease near critical organs-at-risk. Building a center only containing a horizontal treatment port has been proposed as one method for cost savings. METHODS: 20 complex cases of head and neck cancer previously treated with conventional CIRT were retrospectively planned using horizontal-port-only treatment incorporating non-coplanar treatment angles to achieve greater degrees of freedom. These were dosimetrically compared with the previous plans. RESULTS: Comparable D95 coverage of both planning target volume and gross tumor volume with ability to meet organ-at-risk constraints were feasible with horizontal-port-only treatment. Collectively differences were noted in PTV D95, brain stem Dmax, contralateral eye Dmax and V10 Gy (RBE); further qualitative differences were noted on a plan-by-plan basis dependent on disease location. CONCLUSION: Horizontal-port-only treatment employing non-coplanar angles was feasible for complicated head and neck disease typically treated with CIRT, though careful consideration is necessary on a plan-by-plan basis. ADVANCES IN KNOWLEDGE: It is worth noting that non-coplanar approaches are not typically used with the current treatment gantry and may extend further the difference between horizontal port planning and a gantry-based gold-standard.

Deep neural network-based synthetic image digital fluoroscopy using digitally reconstructed tomography.

We developed a deep neural network (DNN) to generate X-ray flat panel detector (FPD) images from digitally reconstructed radiographic (DRR) images. FPD and treatment planning CT images were acquired from patients with prostate and head and neck (H&N) malignancies. The DNN parameters were optimized for FPD image synthesis. The synthetic FPD images' features were evaluated to compare to the corresponding ground-truth FPD images using mean absolute error (MAE), peak signal-to-noise ratio (PSNR), and structural similarity index measure (SSIM). The image quality of the synthetic FPD image was also compared with that of the DRR image to understand the performance of our DNN. For the prostate cases, the MAE of the synthetic FPD image was improved (= 0.12 ± 0.02) from that of the input DRR image (= 0.35 ± 0.08). The synthetic FPD image showed higher PSNRs (= 16.81 ± 1.54 dB) than those of the DRR image (= 8.74 ± 1.56 dB), while SSIMs for both images (= 0.69) were almost the same. All metrics for the synthetic FPD images of the H&N cases were improved (MAE 0.08 ± 0.03, PSNR 19.40 ± 2.83 dB, and SSIM 0.80 ± 0.04) compared to those for the DRR image (MAE 0.48 ± 0.11, PSNR 5.74 ± 1.63 dB, and SSIM 0.52 ± 0.09). Our DNN successfully generated FPD images from DRR images. This technique would be useful to increase throughput when images from two different modalities are compared by visual inspection.

Basic and translational research on carbon-ion radiobiology.

Carbon-ion beam irradiation (IR) has evident advantages over the conventional photon beams in treating tumors. It releases enormous amount of energy in a well-defined range with insignificant scatter in surrounding tissues based on well-localized energy deposition. Over the past 28 years, more than 14,000 patients with various types of cancer have been treated by carbon ion radiotherapy (CIRT) with promising results at QST. I have provided an overview of the basic and translational research on carbon-ion radiobiology including mechanisms underlying high linear energy transfer (LET) carbon-ion IR-induced cell death (apoptosis, autophagy, senescence, mitotic catastrophe etc.) and high radiocurability produced by carbon-ion beams in combination with DNA damaging drugs or with molecular-targeted drugs, micro-RNA therapeutics and immunotherapy. Additionally, I have focused on the application of these treatment in human cancer cells, especially cancer stem cells (CSCs). Finally, I have summarized the current studies on the application of basic carbon-ion beam IR according to the cancer types and clinical outcomes.

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.

Effects of dose and dose-averaged linear energy transfer on pelvic insufficiency fractures after carbon-ion radiotherapy for uterine carcinoma.

BACKGROUND AND PURPOSE: The correlation between dose-averaged linear energy transfer (LETd) and its therapeutic or adverse effects, especially in carbon-ion radiotherapy (CIRT), remains controversial. This study aimed to investigate the effects of LETd and dose on pelvic insufficiency fractures after CIRT. MATERIAL AND METHODS: Among patients who underwent CIRT for uterine carcinoma, 101 who were followed up for > 6 months without any other therapy were retrospectively analyzed. The sacrum insufficiency fractures (SIFs) were graded according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. The correlations between the relative biological effectiveness (RBE)-weighted dose, LETd, physical dose, clinical factors, and SIFs were evaluated. In addition, we analyzed the association of SIF with LETd, physical dose, and clinical factors in cases where the sacrum D50% RBE-weighted dose was above the median dose. RESULTS: At the last follow-up, 19 patients developed SIFs. Receiver operating characteristic curve analysis revealed that the sacrum D50% RBE-weighted dose was a valuable predictor of SIF. Univariate analyses suggested that LETd V10 keV/µm, physical dose V5 Gy, and smoking status were associated with SIF. Cox regression analysis in patients over 50 years of age validated that current smoking habit was the sole risk factor for SIF. Therefore, LETd or physical dose parameters were not associated with SIF prediction. CONCLUSION: The sacrum D50% RBE-weighted dose was identified as a risk factor for SIF. Additionally, neither LETd nor physical dose parameters were associated with SIF prediction.

Emerging Role of Carbon Ion Radiotherapy in Reirradiation of Recurrent Head and Neck Cancers: What Have We Achieved So Far?

Administering reirradiation for the treatment of recurrent head and neck cancers is extremely challenging. These tumors are hypoxic and radioresistant and require escalated radiation doses for adequate control. The obstacle to delivering this escalated dose of radiation to the target is its proximity to critical organs at risk (OARs) and possible development of consequent severe late toxicities. With the emergence of highly sophisticated technologies, intensity-modulated radiotherapy (IMRT) and stereotactic body radiotherapy have shown promising outcomes. Proton beam radiotherapy has been used for locally recurrent head and neck cancers because of its excellent physical dose distribution, exploring sharp Bragg peak properties with negligible entrance and exit doses. To further improve these results, carbon ion radiotherapy (CIRT) has been explored in several countries across Europe and Asia because of its favorable physical properties with minimal entrance and exit doses, sharper lateral penumbra, and much higher and variable relative biological efficacy, which cannot be currently achieved with any other form of radiation. Few studies have described the role of CIRT in recurrent head and neck cancers. In this article, we have discussed the different aspects of carbon ions in reirradiation of recurrent head and neck cancers, including European and Asian experiences, different dose schedules, dose constraints of OARs, outcomes, and toxicities, and a brief comparison with proton beam radiotherapy and IMRT.

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.

Multicenter study of re-irradiation using carbon-ions for head and neck malignancies after photon radiotherapy.

PURPOSE: The goal of this multicenter retrospective study of patients with head and neck malignancies was to evaluate the efficacy and safety of carbon-ion (C-ion) radiotherapy (RT) after photon RT. METHODS: We enrolled 56 patients with head and neck malignancies who underwent re-irradiation (re-RT) using C-ions between November 2003 and March 2019, treated previously with photon RT. The tumors at re-RT were located in the sinonasal cavities (n = 20, 35.7%), skull base (n = 12, 21.4%), and orbit (n = 7, 12.5%). The tumors at the initial RT were located in the sinonasal cavities (n = 13, 23.2%), skull base (n = 9, 16.1%), and orbit (n = 9, 16.1%). The median period between the initial RT and re-RT was 41 (4-568) months. The most common histology of re-RT was squamous cell carcinoma (n = 11, 19.6%). The most commonly used protocol was 57.6 Gy (relative biological effectiveness) in 16 fractions (n = 23, 41.1%). Surgery preceded re-RT in three patients (5.4%). One patient with malignant melanoma received concurrent chemotherapy. RESULTS: The 2-year local control, progression-free survival, and overall survival rates were 66.5%, 36.9%, and 67.9%, respectively. The median follow-up time was 28 months. Two patients (3.6%) developed grade ≥ 3 acute toxicities, and 14 (25.0%) developed grade ≥ 3 late toxicities. A single patient had confirmed grade 5 dermatitis with infection. CONCLUSION: Re-RT using C-ions for head and neck malignancies after photon RT is an effective treatment with tolerable toxicity.

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.

Carbon-ion beam irradiation in combination with cisplatin effectively suppresses xenografted malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer. This study investigated the growth-inhibitory effects of the combination of carbon ion beam irradiation (IR) and cisplatin (CDDP) on MPM xenografts. Carbon-ion beam IR at 15 Gy effectively inhibited tumor growth and decreased the tumor volume more than 90% after 9 weeks. However, tumor regrowth was observed after 17 weeks. The combination of carbon-ion beam IR (15 Gy) and CDDP significantly suppressed tumor growth after 9 weeks, with tumor regression being observed for more than 18 weeks. In contrast, X-ray IR (30 Gy) alone or in combination with CDDP effectively suppressed tumor growth and decreased the tumor volume after 11 weeks, but tumor growth was observed after 15 weeks. Carbon-ion beam IR at 25 Gy resulted in complete tumor regression without tumor regrowth in the 20-week follow-up period. Histopathological analysis revealed that combination of carbon-ion beam IR and CDDP exerted effective cytotoxic effects on MPM xenograft tumor cells and significantly promoted tumor cell necrosis, cavitation, and fibrosis when compared with individual treatment with carbon-ion beam, X-ray IR, or CDDP. Immunohistochemical analysis revealed that the expression levels of tumor cell migration and invasion-related proteins such as CXCL12, MMP2 and MMP9 were not significantly affected upon low dose (15 Gy) carbon-ion beam IR alone or in combination with CDDP but were markedly upregulated upon treatment with CDDP alone relative to control. However, IR with a high dose (25 Gy) carbon-ion beam inhibited tumor growth without upregulating these proteins. In conclusion, the combination of IR with a low dose (15 Gy) carbon ion beam and CDDP effectively suppressed MPM tumor in vivo without significantly upregulating CXCL12, MMP2 and MMP9, suggesting that combination therapy of carbon ion beam IR and chemotherapy is a promising therapeutic strategy for MPM.

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.