Interfractional robustness of scanning carbon ion radiotherapy for prostate cancer: An analysis based on dose distribution from daily in-room CT images.

PURPOSE: We analyzed interfractional robustness of scanning carbon ion radiotherapy (CIRT) for prostate cancer based on the dose distribution using daily in-room computed tomography (CT) images. MATERIALS AND METHODS: We analyzed 11 consecutive patients treated with scanning CIRT for localized prostate cancer in our hospital between December 2015 and January 2016. In-room CT images were taken under treatment conditions in every treatment session. The dose distribution on each in-room CT image was recalculated, while retaining the pencil beam arrangement of the initial treatment plan. Then, the dose-volume histogram (DVH) parameters including the percentage of the clinical target volume (CTV) with 95% and 90% of the prescribed dose area (V95% of CTV, V90% of CTV) and V80% of rectum were calculated. The acceptance criteria for the CTV and rectum were set at V95% of CTV ≥95%, V90% of CTV ≥98%, and V80% of rectum < 10 ml. RESULTS: V95% of CTV, V90% of CTV, and V80% of rectum for the reproduced plans were 98.8 ± 3.49%, 99.5 ± 2.15%, and 4.39 ± 3.96 ml, respectively. Acceptance of V95% of CTV, V90% of CTV, and V80% of rectum was obtained in 123 (94%), 125 (95%) and 117 sessions (89%), respectively. Acceptance of the mean dose of V95% of CTV, V90% of CTV, and V80% of rectum for each patient was obtained in 10 (91%), 10 (91%), and 11 patients (100%), respectively. CONCLUSIONS: We demonstrated acceptable interfractional robustness based on the dose distribution in scanning CIRT for prostate cancer.

Complication rate, functional outcomes, and risk factors associated with carbon ion radiotherapy for patients with unresectable pelvic bone sarcoma.

BACKGROUND: To the authors' knowledge, carbon ion radiotherapy (CIRT) is one of the few curative treatments for unresectable pelvic bone sarcoma. The current study investigated the complications, functional outcomes, and risk factors of CIRT. METHODS: Of 112 patients who were treated with CIRT for unresectable pelvic bone sarcoma, the authors enrolled 29 patients who were without local disease recurrence or distant metastasis. The mean follow-up was 93 months. Complications, functional outcomes, and quality of life scores were assessed. Risk factors were analyzed, including the dose-volume histogram of the femoral head. RESULTS: Femoral head necrosis occurred in approximately 37% of patients, pelvic fractures were reported in 48% of patients, and neurological deficits were noted in 52% of patients. Femoral head necrosis was found to be significantly more prevalent among patients with periacetabular tumors (P = .018). The dose-volume histogram of the femoral head indicated tolerable volume percentages of the femoral head to be <33% for 40 grays (relative biological effectiveness) and 16% for 60 grays ( relative biological effectiveness). The mean Musculoskeletal Tumor Society score and Toronto Extremity Salvage Score were 53% and 64%, respectively, and the mean EuroQol 5 dimensions questionnaire index was 0.587. Patients aged >50 years and those with periacetabular tumors were found to have significantly lower Toronto Extremity Salvage Scores. CONCLUSIONS: Femoral head necrosis, pelvic fracture, and nerve damage are common complications with the use of CIRT for pelvic bone sarcoma. To prevent femoral head necrosis, the radiation dose to the femoral head should be kept below the estimated tolerance curve presented in the current study. The functional outcome is nearly equivalent to that of surgery. CIRT may be a promising alternative to surgery for patients with unresectable pelvic bone sarcoma.

Risk of subsequent primary cancers after carbon ion radiotherapy, photon radiotherapy, or surgery for localised prostate cancer: a propensity score-weighted, retrospective, cohort study.

BACKGROUND: The risk of subsequent primary cancers in patients with prostate cancer after treatment with photon radiotherapy is small in absolute numbers, but it is higher than that after surgical treatment. Carbon ion radiotherapy has a theoretically lower risk of inducing secondary malignancies than photon radiotherapy, but this risk has not been investigated in practice because of the low number of facilities offering such therapy worldwide and the limited data on long-term follow-up because the therapy has only been available since 1994. We aimed to analyse the risk of subsequent primary cancers after treatment with carbon ion radiotherapy in patients with localised prostate cancer and to compare it with that after photon radiotherapy or surgery in this setting. METHODS: In this retrospective cohort study, we reviewed records of patients who received carbon ion radiotherapy for prostate cancer between June 27, 1995, and July 10, 2012, at the National Institute of Radiological Sciences (NIRS) in Japan. We also retrieved the records of patients diagnosed and treated for prostate cancer between Jan 1, 1994, and Dec 31, 2012, from the Osaka Cancer Registry. Eligible patients had histologically confirmed localised prostate cancer and a minimum follow-up of at least 3 months; no age restrictions were applied. We excluded patients with metastasis, node-positive disease, or locally invasive (T4 stage) prostate cancer, those with previous or synchronous malignancies, and those who received previous radiotherapy or chemotherapy. We did a multivariable analysis to estimate predictors of subsequent cancers after carbon ion radiotherapy treatment. We also used propensity score inverse probability weighting to retrospectively compare the incidence of subsequent cancers in patients with localised prostate cancer treated with carbon beams, photon radiotherapy, or surgery. FINDINGS: Of 1580 patients who received carbon radiotherapy for prostate cancer at the NIRS, 1455 (92%) patients met the eligibility criteria. Of 38 594 patients with prostate cancer identified in the Osaka registry, 1983 (5%) patients treated with photon radiotherapy and 5948 (15%) treated with surgery were included. Median follow-up durations were 7·9 years (IQR 5·9-10·0) for patients who received carbon ion radiotherapy (after limiting the database to 10-year maximum follow-up), 5·7 years (4·5-6·4) for patients who received photon radiotherapy, and 6·0 years (5·0-8·6) for those who received surgery. 234 subsequent primary cancers were diagnosed in the carbon ion radiotherapy cohort; some patients developed several tumours. On multivariable analysis, age (p=0·0021 for 71-75 years vs ≤60 years; p=0·012 for >75 years vs ≤60 years) and smoking (p=0·0005) were associated with a higher risk of subsequent primary cancers in patients treated with carbon ion radiotherapy. In the propensity score-weighted analyses, carbon ion radiotherapy was associated with a lower risk of subsequent primary cancers than photon radiotherapy (hazard ratio [HR] 0·81 [95% CI 0·66-0·99]; p=0·038) or surgery (HR 0·80 [0·68-0·95]; p=0·0088), whereas photon radiotherapy was associated with a higher risk of subsequent primary cancers than surgery (HR 1·18 [1·02-1·36]; p=0·029). INTERPRETATION: Our analysis suggests that patients with localised prostate cancer treated with carbon ion radiotherapy appear to have a lower risk of subsequent primary cancers than those treated with photon radiotherapy. Although prospective evaluation with longer follow-up is warranted to support these results, our data supports a wider adoption of carbon ion radiotherapy for patients with expected long-term overall survival or those with poor outcomes after receiving conventional treatments. FUNDING: Research Project for Heavy Ions at the National Institute of Radiological Sciences (Japan).

Clinical outcomes of carbon-ion radiotherapy for locally advanced non-small-cell lung cancer.

The efficacy and safety of carbon-ion radiotherapy (CIRT) for locally advanced non-small-cell lung cancer (LA-NSCLC) remain unclear. We reported the clinical outcomes of CIRT for LA-NSCLC. Data for 141 eligible patients who received CIRT between 1995 and 2015 were retrospectively analyzed. Local control (LC), locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. The median age was 75.0 years. Overall, 21 (14.9%), 57 (40.4%), 43 (30.5%) and 20 (14.2%) patients had T1, T2, T3 and T4 disease, respectively. Moreover, 51 (36.2%), 45 (31.9%), 40 (28.4%) and 5 (3.5%) patients had N0, N1, N2 and N3 disease, respectively. Furthermore, 34 (24.1%), 42 (29.8%), 45 (31.9%) and 20 (14.2%) patients had stages IIA, IIB, IIIA and ΙΙΙB disease, respectively. Overall, 62 (44.0%), 60 (42.6%), 8 (5.7%) and 11 (7.8%) patients had adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and others, respectively. The median dose was 72.0 Gy (relative biological effectiveness). No patient received concurrent chemotherapy. Median follow-up periods were 29.3 (1.6-207.7) and 40.0 (10.7-207.7) months for all patients and survivors, respectively. Two-year LC, PFS and OS rates were 80.3%, 40.2% and 58.7%, respectively. Overall, 1 (0.7%), 5 (3.5%) and 1 (0.7%) patient developed Grades 4 (mediastinal hemorrhage), 3 (radiation pneumonitis) and 3 (bronchial fistula) toxicities, respectively. Multivariate analysis showed adenocarcinoma and N2/3 classification as significant poor prognosticators of PFS. CIRT is an effective treatment with acceptable toxicity for LA-NSCLC, especially for elderly patients or patients with severe comorbidities who cannot be treated with surgery or chemoradiotherapy.

Single fraction carbon ion radiotherapy for colorectal cancer liver metastasis: A dose escalation study.

Prognosis is usually grim for those with liver metastasis from colorectal cancer (CRC) who cannot receive resection. Radiation therapy can be an option for those unsuitable for resection, with carbon ion radiotherapy (CIRT) being more effective and less toxic than X-ray due to its physio-biological characteristics. The objective of this study is to identify the optimal dose of single fraction CIRT for colorectal cancer liver metastasis. Thirty-one patients with liver metastasis from CRC were enrolled in the present study. Twenty-nine patients received a single-fraction CIRT, escalating the dose from 36 Gy (RBE) in 5% to 10% increments until unacceptable incidence of dose-limiting toxicity was observed. Dose-limiting toxicity was defined as grade ≥3 acute toxicity attributed to radiotherapy. The prescribed doses were as follows: 36 Gy (RBE) (3 cases), 40 Gy (2 cases), 44 Gy (4 cases), 46 Gy (6 cases), 48 Gy (3 cases), 53 Gy (8 cases) and 58 Gy (3 cases). Dose-limiting toxicity was not observed, but late grade 3 liver toxicity due to biliary obstruction was observed in 2 patients at 53 Gy (RBE). Both cases had lesions close to the hepatic portal region, and, therefore, the dose was escalated to 58 Gy (RBE), limited to peripheral lesions. The 3-year actuarial overall survival rate of all 29 patients was 78%, and the median survival time was 65 months. Local control improved significantly at ≥53 Gy (RBE), with a 3-year actuarial local control rate of 82%, compared to 28% in lower doses. Treatment for CRC liver metastasis with single-fraction CIRT appeared to be safe up to 58 Gy (RBE) as long as the central hepatic portal region was avoided.

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.

External dosimetry audit for quality assurance of carbon-ion radiation therapy clinical trials.

PURPOSE: The QA team of the Japan carbon-ion radiation oncology study group (J-CROS) was organized in 2015 to enhance confidence in the accuracy of clinical dosimetry and ensure that the facility QA procedures are adequate. The team conducted onsite dosimetry audits in all the carbon-ion radiation therapy centers in Japan. MATERIALS AND METHODS: A special phantom was fabricated for the onsite dosimetry audit. Target volumes such as the GTV, CTV, and PTV were contoured to the obtained CT images, and two plans with different isocenter depths were created. The dose at the isocenter was measured by an ionization chamber, in the onsite audit and compared with the calculated dose. RESULTS: For all the centers, the average of the percentage ratio between the measured and calculated doses (measured/calculated) was 0.5% (-2.7% to +2.6%) and the standard deviation, 1.7%. In all the centers, the beams were within the set tolerance level of 3%. CONCLUSIONS: The audit demonstrated that the dose at a single point in the water phantom was within tolerance, but it is a big step to say that all doses are correct. In addition, this external dosimetry audit encouraged centers to improve the quality of their dosimetry systems.

Feasibility of carbon-ion radiotherapy for re-irradiation of locoregionally recurrent, metastatic, or secondary lung tumors.

Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re-irradiation with carbon-ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors.

A retrospective multicenter study of carbon-ion radiotherapy for major salivary gland carcinomas: Subanalysis of J-CROS 1402 HN.

A retrospective multicenter study was carried out to assess the clinical outcomes of carbon-ion radiotherapy for head and neck malignancies (Japan Carbon-Ion Radiation Oncology Study Group [J-CROS] study: 1402 HN). We evaluated the safety and efficacy of carbon-ion radiotherapy in patients with major salivary gland carcinoma. Sixty-nine patients treated with carbon-ion radiotherapy at four Japanese institutions were analyzed. Thirty-three patients (48%) had adenoid cystic carcinomas, 10 (14%) had mucoepidermoid carcinomas, and 26 (38%) had other disease types. Three patients (4%) had T1 disease, 8 (12%) had T2, 25 (36%) had T3, and 33 (48%) had T4. The median radiation dose was 64 Gy (relative biological effectiveness) in 16 fractions. The median gross tumor volume was 27 mL. The median follow-up period was 32.7 months. The 3-year local control rate and overall survival rate were 81% and 94%, respectively. Regarding acute toxicities, seven patients had grade 3 mucositis and seven had grade 3 dermatitis. Regarding late toxicities, one patient had grade 3 dysphagia and one had a grade 3 brain abscess. No grade 4 or worse late reactions were observed. In conclusion, definitive carbon-ion radiotherapy was effective with acceptable toxicity for major salivary gland carcinomas.

Updated long-term outcomes after carbon-ion radiotherapy for primary renal cell carcinoma.

Long-term oncological outcomes for primary renal cell carcinoma (RCC) treated with carbon-ion radiotherapy (CIRT) are poorly understood. Patients with primary RCC were treated with 12 or 16-fraction CIRT at The Hospital of the National Institute of Radiological Sciences outside of clinical trials. Outcome data were pooled and retrospectively analyzed for toxicity, local control, and disease-free, cancer-specific, and overall survival. From 1997 to 2014, 19 RCC patients (11 with T1aN0M0, 4 with T1bN0M0, and 4 with inoperable advanced stage [T4N0M0, T3aN1M0, and T1aN0M1]) were treated with CIRT and followed up for a median of 6.6 (range, 0.7-16.5) years; 9 of these patients were inoperable because of comorbidities or advanced-stage disease. Diagnoses were confirmed by imaging in 11 patients and by biopsy in the remaining 8. In 4 of 5 patients with definitive renal comorbidities, including diabetic nephropathy, sclerotic kidney or solitary kidney pre-CIRT progressed to grade 4 chronic kidney disease (CKD). In contrast, the remaining 14 patients without definitive renal comorbidities did not progress to grade 3 or higher CKD. Furthermore, although 1 case of grade 4 dermatitis was observed, there were no other grade 3 or higher non-renal adverse events. Local control rate, and disease-free, cancer-specific, and overall survival rates at 5 years of all 19 patients were 94.1%, 68.9%, 100%, and 89.2%, respectively. This updated retrospective analysis based on long-term follow-up data suggests that CIRT is a safe treatment for primary RCC patients without definitive renal comorbidities pre-CIRT, and yield favorable treatment outcomes, even in inoperable cases.

Short-course carbon-ion radiotherapy for hepatocellular carcinoma: A multi-institutional retrospective study.

BACKGROUND & AIMS: Carbon-ion radiation therapy has shown encouraging results in hepatocellular carcinoma patients in single-centre studies. We evaluated the effectiveness and safety of short-course carbon-ion radiation therapy for hepatocellular carcinoma in a multicentre study conducted by the Japan Carbon Ion Radiation Oncology Study Group. METHODS: Consecutive hepatocellular carcinoma patients who were treated with carbon-ion radiation therapy in four or fewer fractions at four Japanese institutions between April 2005 and November 2014 were analysed retrospectively. The primary outcome was overall survival; secondary outcomes were local control rate, treatment-related toxicity and radiation-induced liver disease. RESULTS: A total of 174 patients were included in this study. Prescribed carbon-ion radiation therapy doses were (relative biological effectiveness): 48.0 Gy in two fractions (n = 46), and 52.8 Gy (n = 108) and 60.0 Gy (n = 20) in four fractions. The median follow-up period was 20.3 (range, 2.9-103.5) months. The overall survival and local control rates at 1, 2 and 3 years were 95.4%, 82.5% and 73.3%; and 94.6%, 87.7% and 81.0% respectively. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status 1-2, Child-Pugh class B, maximum tumour diameter ≥3 cm, multiple tumours and serum alpha foetoprotein level >50 ng/mL were significant prognostic factors of overall survival. No treatment-related death occurred during the follow-up period. Grades 3 or 4 treatment-related toxicities were observed in 10 patients (5.7%); radiation-induced liver disease was observed in three patients (1.7%). CONCLUSIONS: Short-course carbon-ion radiation therapy is a safe, effective and potentially curative therapy for hepatocellular carcinoma.

Changes in arrhythmogenic properties and five-year prognosis after carbon-ion radiotherapy in patients with mediastinum cancer.

INTRODUCTION: Carbon-ion irradiation of rabbit hearts has improved left ventricular conduction abnormalities through upregulation of gap junctions. However, to date, there has been no investigation on the effect of carbon-ion irradiation on electrophysiological properties in human. We investigated this effect in patients with mediastinum extra-cardiac cancer treated with carbon-ion radiotherapy that included irradiating the heart. METHODS AND RESULTS: In April-December 2009, eight patients were prospectively enrolled (including two male, aged 72.5 ± 13.0 years). They were treated with 44-72 Gray equivalent (GyE), with their hearts exposed to 1.3-19.1 GyE. High-resolution ambulatory electrocardiography was performed before and after radiotherapy to investigate arrhythmic events, late potentials (LPs), and heart rate variability. Five patients had pre-existing premature ventricular contraction (PVC)/atrial contraction (PAC) or paroxysmal atrial fibrillation (PAF)/AF; after irradiation, this improved in four patients with PVC/PAF/AF and did not deteriorate in one patient with PAC. Ventricular LP findings did not deteriorate and improved in one patient. In eight cases with available atrial LP findings, there was no deterioration, and two patients showed improvements. The low frequency/high frequency ratio of heart rate variability improved or did not deteriorate in the six patients who received radiation exposure to the bilateral stellate ganglions. During the five-year follow-up for the prognosis, six of the eight patients died because of cancer; there was no history of hospitalization for cardiac events. CONCLUSION: Although this preliminary study has several limitations, carbon-ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction.

Locoregional therapy with α-emitting trastuzumab against peritoneal metastasis of human epidermal growth factor receptor 2-positive gastric cancer in mice.

Peritoneal metastasis of gastric cancer (PMGC) is incurable and thus has an extremely poor prognosis. We have found, however, that locoregionally administered trastuzumab armed with astatine-211 (211 At-trastuzumab) is effective against human epidermal growth factor receptor 2 (HER2)-positive PMGC in a xenograft mouse model. We first observed that 211 At-trastuzumab can specifically bind and effectively kill NCI-N87 (N87) cells, which are HER2-positive human metastatic GC cells, both in vitro and in s.c. tumors. We established a PMGC mouse model using N87 xenografts stably expressing luciferase to test α-particle radioimmunotherapy with 211 At-trastuzumab against PMGC. Biodistribution analysis in this PMGC mouse model revealed that the i.p. administration of 211 At-trastuzumab (1 MBq) was a more efficient means of delivery of 211 At into metastatic tumors than i.v. injection; the maximum tumor uptake with i.p. administration was over 60% injected dose per gram of tissue (%ID/g) compared to approximately 18%ID/g with i.v. injection. Surprisingly, a single i.p. injection of 211 At-trastuzumab (1 MBq) was sufficient to completely eradicate intraperitoneally disseminated HER2-positive GC xenografts in two of six treated mice by inducing DNA double-strand breaks, and to drastically reduce the tumor burden in another three mice. No bodyweight loss, leukocytopenia, or significant biochemical changes in liver or kidney function were observed in the treatment group. Accordingly, locoregionally administered 211 At-trastuzumab significantly prolonged the survival time of HER2-positive PMGC mice compared with control treatments. Our results provide a proof-of-concept demonstration that locoregional therapy with 211 At-trastuzumab may offer a new treatment option for HER2-positive PMGC.

Multi-institutional retrospective study of mucoepidermoid carcinoma treated with carbon-ion radiotherapy.

This study aimed to evaluate the clinical outcomes of patients with mucoepidermoid carcinomas in the head and neck treated with carbon-ion radiotherapy. Data from 26 patients who underwent carbon-ion radiotherapy in four facilities were analyzed in this multi-institutional retrospective study: the Japan Carbon-ion Radiation Oncology Study Group. The median follow-up time was 34 months. One patient experienced local recurrence, and the 3-year local control rate was 95%. One patient developed lymph node recurrence and five developed distant metastases. The 3-year progression-free survival rate was 73%. Five patients died, two of mucoepidermoid carcinoma and three of intercurrent disease. The 3-year overall survival rate was 89%. Acute mucositis and dermatitis of grade 3 or higher were experienced by 19% and 8% of patients, respectively; these improved with conservative therapy. Late mucositis and osteonecrosis of jaw were observed in 12% and 23% of patients, respectively. The 3-year cumulative rate of any late adverse event of grade 3 or higher was 14%. None of the patients died of the acute or late adverse events. Carbon-ion radiotherapy was efficacious and safe for treating mucoepidermoid carcinoma in this multi-institutional retrospective study (registration no. UMIN000024473). We are currently undertaking a prospective multicenter study.

Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy.

The treatment outcomes of patients with high-risk localized prostate cancer (PC) after carbon-ion radiotherapy (CIRT) combined with long-term androgen deprivation therapy (LTADT) were analyzed, and compared with those of other treatment modalities, focusing on PC-specific mortality (PCSM). A total of 1247 patients were enrolled in three phase II clinical trials of fixed-dose CIRT between 2000 and 2013. Excluding patients with T4 disease, 608 patients with high-risk or very-high-risk PC, according to the National Comprehensive Cancer Network classification system, who received CIRT with LTADT were evaluated. The median follow-up time was 88.4 months, and the 5-/10-year PCSM rates were 1.5%/4.3%, respectively. T3b disease, Gleason score of 9-10 and percentage of positive biopsy cores >75% were associated with significantly higher PCSM on univariate and multivariate analyses. The 10-year PCSM rates of patients having all three (n = 16), two (n = 74) or one of these risk factors (n = 217) were 27.1, 11.6 and 5.7%, respectively. Of the 301 patients with none of these factors, only 1 PCSM occurred over the 10-year follow-up (10-year PCSM rate, 0.3%), and significant differences were observed among the four stratified groups (P <0.001). CIRT combined with LTADT yielded relatively favorable treatment outcomes in patients with high-risk PC and very favorable results in patients without any of the three abovementioned factors for PCSM. Because a significant difference in PCSM among the high-risk PC patient groups was observed, new categorization and treatment intensity adjustment may be required for high-risk PC patients treated with CIRT.

Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: Combined analyses of 2 prospective trials.

BACKGROUND: The objective of this study was to evaluate the safety and efficacy of carbon-ion radiotherapy (CIRT) in patients with hepatocellular carcinoma (HCC) with stepwise dose escalation and hypofractionation in 2 combined prospective trials. METHODS: Sequential phase 1/2 (protocol 9603) and phase 2 (protocol 0004) trials were conducted for patients with histologically proven HCC. The phase 1 component of protocol 9603 was a dose-escalation study; CIRT was delivered in 12, 8, or 4 fractions. After determination of the recommended dose, 2 phase 2 trials were performed in an expanded cohort, and the data were pooled to analyze toxicity, local control, and overall survival. RESULTS: In the phase 1 component of protocol 9603, 69.6, 58.0, and 52.8 Gy (relative biological effectiveness [RBE]) in 12, 8, and 4 fractions, respectively, constituted the maximum tolerated doses, and 52.8 Gy (RBE) in 4 fractions was established as the recommended dose regimen for the 2 phase 2 studies. In 124 patients with a total of 133 lesions, few severe adverse effects occurred, and local-control and overall survival rates at 1, 3, and 5 years were 94.7% and 90.3%, 91.4% and 50.0%, and 90.0% and 25.0%, respectively; this included 1-, 3-, and 5-year local-control rates of 97.8%, 95.5%, and 91.6%, respectively, in the phase 2 study. In a multivariate analysis, Child-Pugh class B and the presence of a tumor thrombus were significant factors for mortality. CONCLUSIONS: The safety and efficacy of CIRT in 12, 8, and 4 fractions were confirmed, with 52.8 Gy (RBE) in 4 fractions established as the recommended treatment course for eligible HCC patients. Cancer 2017;123:3955-65. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Carbon-ion radiotherapy for isolated para-aortic lymph node recurrence from colorectal cancer.

BACKGROUND: The safety and effectiveness of carbon-ion radiotherapy (CIRT) for isolated para-aortic lymph node (PALN) metastasis was evaluated retrospectively. METHODS: CIRT for isolated PALN metastasis from CRC was performed in 34 cases from June 2006 to August 2015 in our institute. A median dose of 52.8 Gy(RBE) (range, 48-52.8 Gy(RBE)) was delivered with a median daily dose of 4.4 Gy(RBE) (range, 4.0-4.4 Gy(RBE)). RESULTS: The median follow-up duration for all patients was 24.4 months (range, 7-82.8 months). There were 13 cases (38.2%) who achieved complete response after treatment. The local control rates at 2 and 3 years were 70.1% and 70.1%, respectively. The overall survival rates at 2 and 3 years were 83.3% and 63.0%, respectively. The 3-year survival rates for Stage I-III were 68.7%, while those for Stage IV was 0%. The overall survival of cases with rectal cancer or with high CA19-9 values pre-CIRT tended to be worse. The median survival period was 41.7 months. Twelve of the 34 patients survived for more than 3 years. There were no adverse effects of Grade 3 or higher. CONCLUSIONS: CIRT for isolated PALN recurrence after curative resection for CRC appears effective and safe, and it is considered a promising therapy.

Respiration-gated fast-rescanning carbon-ion radiotherapy.

Phase-controlled rescanning of the carbon-ion beam offers fast and precise dose application with decreased irradiation of normal tissue. However, organ movement with respiration remains a unique challenge. Technological development has enabled the simultaneous application of beam-energy-modulated markerless phase-controlled rescanning with respiration gating, allowing scanning treatment of respiration-mobile tumors with carbon. A total of 10 patients with tumors in the liver or lung were treated in a feasibility study at our facility using this combination. At a median of 10.5 months, follow-up examination including computed tomography/magnetic resonance imaging revealed no grade 2+ acute adverse effects with this new therapy. Two patients with complex disease experienced local recurrence, which may be improved with increased dose delivery. One patient died of unrelated causes. All other patients are alive with good control at the time of writing. Though long-term observation is pending, these are promising initial results for use of the carbon-beam phase-controlled rescanning method in respiration-mobile disease.

Significant impact of biochemical recurrence on overall mortality in patients with high-risk prostate cancer after carbon-ion radiotherapy combined with androgen deprivation therapy.

BACKGROUND: Whether biochemical recurrence (BR) is a significant predictive factor of mortality after definitive radiation therapy for prostate cancer remains unknown. The aim of the current study was to investigate the relation between BR and overall mortality (OAM) in high-risk prostate cancer patients who were treated with carbon-ion radiotherapy (CIRT) and had long-term follow-up in 2 prospective trials. METHODS: In the 2 phase 2 clinical trials, which involved 466 prostate cancer patients who received 63.0 to 66.0 Gy of CIRT (relative biological effect) in 20 fractions between 2000 and 2007, 324 patients who were deemed to be at high risk on the basis of the modified D'Amico classification criteria and received CIRT along with androgen-deprivation therapy (ADT) were examined. The OAM rate was adjusted for the ADT duration, and multivariate analyses using a Cox proportional hazards model were performed for OAM with BR as a time-dependent covariate. RESULTS: The median follow-up period was 107.4 months, and the 5- and 10-year OAM rates after adjustments for the ADT duration were 7.0% (95% confidence interval [CI], 4.0%-9.4%) and 23.9% (95% CI, 16.4%-26.2%), respectively. A multivariate analysis revealed that the presence of BR (hazard ratio, 2.82; 95% Cl, 1.57-5.08; P = .001) was one of the predictive factors for OAM. On the other hand, the duration of ADT had no impact on OAM. CONCLUSIONS: BR after CIRT combined with ADT is an independent predictive factor for OAM in high-risk prostate cancer patients. The results of this study could be applied to other high-dose radiation therapies. Cancer 2016;122:3225-31. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Brain contrasting ability of blood-brain-barrier-permeable nitroxyl contrast agents for magnetic resonance redox imaging.

PURPOSE: The detailed in vivo T1 -weighted contrasting abilities of nitroxyl contrast agents, which have been used as redox responsive contrast agents in several magnetic resonance-based imaging modalities, in mouse brain were investigated. METHODS: Distribution and pharmacokinetics of five types of five-membered-ring nitroxyl radical compound were compared using T1 -weighted MRI. RESULTS: The blood-brain barrier (BBB) -impermeable 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP) could not be distributed in the brain. The slightly lipophilic 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP) showed slight distribution only in the ventricle, but not in the medulla and cortex. The amphiphilic 3-methoxy-carbonyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl (MCP) had good initial uniform distribution in the brain and showed typical 2-phase signal decay profiles. A brain-seeking nitroxyl probe, acetoxymethyl-2,2,5,5-tetramethyl-pyrrolidine-N-oxyl-3-carboxylate (CxP-AM), showed an accumulating phase, and then its accumulation was maintained in the medulla and ventricle regions, but not in the cortex. The lipophilic 4-(N-methyl piperidine)-2,2,5,5-tetramethylpyrroline-N-oxyl (23c) was well distributed in the cortex and medulla, but slightly in the ventricle, and showed relatively rapid linear signal decay. CONCLUSION: Nitroxyl contrast agents equipped with a suitable lipophilic substitution group could be BBB-permeable functional contrast agents. MR redox imaging, which can estimate not only the redox characteristics but also the detailed distribution of the contrast agents, is a good candidate for a theranostic tool. Magn Reson Med 76:935-945, 2016. © 2015 Wiley Periodicals, Inc.