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.

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.

Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience.

Charged particle therapy is generally regarded as cutting-edge technology in oncology. Many proton therapy centres are active in the USA, Europe, and Asia, but only a few centres use heavy ions, even though these ions are much more effective than x-rays owing to the special radiobiological properties of densely ionising radiation. The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. So far, more than 8000 patients have had this treatment at NIRS, and the centre thus has by far the greatest experience in carbon ion treatment worldwide. A panel of radiation oncologists, radiobiologists, and medical physicists from the USA and Europe recently completed peer review of the carbon ion therapy at NIRS. The review panel had access to the latest developments in treatment planning and beam delivery and to all updated clinical data produced at NIRS. A detailed comparison with the most advanced results obtained with x-rays or protons in Europe and the USA was then possible. In addition to those tumours for which carbon ions are known to produce excellent results, such as bone and soft-tissue sarcoma of the skull base, head and neck, and pelvis, promising data were obtained for other tumours, such as locally recurrent rectal cancer and pancreatic cancer. The most serious impediment to the worldwide spread of heavy ion therapy centres is the high initial capital cost. The 20 years of clinical experience at NIRS can help guide strategic decisions on the design and construction of new heavy ion therapy centres.

Clinical outcomes of carbon ion radiotherapy for locally advanced adenocarcinoma of the uterine cervix in phase 1/2 clinical trial (protocol 9704).

BACKGROUND: This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial. METHODS: The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions. RESULTS: Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively. CONCLUSIONS: Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy.

Dose-escalation study of carbon ion radiotherapy for locally advanced squamous cell carcinoma of the uterine cervix (9902).

OBJECTIVE: The authors performed phase I/II clinical trial to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced squamous cell carcinoma of the uterine cervix. METHODS: Between April 2000 and January 2006, 22 patients for Protocol 9902 were treated with C-ion RT. The number of patients with stage IIB, IIIB, and IVA diseases was 1, 18, and 3, respectively. All patients had bulky tumors measuring 4.0-12.0 cm (median 6.2 cm). The whole pelvic dose was fixed at 39.0 GyE for 13 fractions, and additional 15.0 GyE for 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, a dose-escalation study was planned for 2 fractions to GTV. Total dose to the cervical tumor was 64.0-72.0 GyE for 20 fractions. RESULTS: All patients completed the scheduled therapy and no patient developed Grade 2 or higher acute toxicity. There was no Grade 3 or higher late complications at each dose. The 5-year overall survival rate and local control rate were 50.0% and 68.2%, respectively. Seven out of the 16 patients who received 64.0-68.0 GyE developed local recurrences, but all patients who received 72.0 GyE maintained local control. CONCLUSIONS: There were no severe acute or late complications in this trial. C-ion RT has the potential to improve the treatment for locally advanced bulky cervical cancer by applying a total dose of 72.0 GyE, with the results lending incentive to further investigations to confirm the therapeutic efficacy.

Post-therapeutic needle biopsy in patients with hepatocellular carcinoma is a useful tool to evaluate response to proton irradiation.

AIM: Proton beam therapy is safe and more effective than conventional radiation therapy for the local control of nodular hepatocellular carcinoma (HCC). However, evaluating therapeutic response by imaging is not accurate during the early post-irradiation period. Therefore, we examined whether the histopathological study of biopsy specimens obtained at 3 weeks after irradiation can be used to more accurately assess therapeutic response. METHODS: Fifteen HCC lesions from 13 patients were treated with proton beam irradiation. Tissue biopsy samples were obtained using abdominal ultrasound-guided percutaneous fine-needle aspiration from the center of the tumor before, 3 weeks after and 1 year post-proton therapy. The specimens were examined after staining with hematoxylin-eosin (HE) and a MIB-1 antibody. RESULTS: MIB-1 labeling indices (LI) before treatment were 13.0 ± 8.5% (mean ± SD; range, 0.6-27.0), whereas those 3 weeks after proton therapy were significantly reduced to 3.2 ± 2.4% (range, 0.6-8.9) (P < 0.05). Although the tumor size was reduced, we did not observe a reduction in tumor blood flow by dynamic computed tomography or degenerative changes by HE. All lesions that displayed reduced MIB-1 LI at 3 weeks post-proton treatment were ultimately diagnosed as complete response at 1 year after treatment. In contrast, one case with increased MIB-1 LI at 3 weeks had significant tumor size progression at 1 year post-treatment. CONCLUSION: The percutaneous fine-needle aspiration biopsy of HCC is a safe and useful tool that can be used to evaluate the response to proton irradiation. In particular, MIB-1 LI may provide additional information to assess the therapeutic response of HCC during the early post-irradiated period.

Usefulness of J-CAPRA score for high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy.

BACKGROUND: A novel risk assessment method, Japan Cancer of the Prostate Risk Assessment, has been developed based on database of patients receiving primary androgen deprivation therapy. To investigate the usefulness of Japan Cancer of the Prostate Risk Assessment for non-metastatic, high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy. METHODS: Patients with non-metastatic, high-risk prostate cancer (T3, initial prostate specific antigen level ≥20 ng/ml, and/or Gleason score ≥8) were included. The patients were treated with carbon ion radiotherapy (the total dose from 57.6 Gy (relative biological effectiveness)/16 fractions to 66.0 Gy(relative biological effectiveness)/20 fractions), and neoadjuvant as well as adjuvant androgen deprivation therapy for at least 24 months. RESULTS: Four hundred and twenty-six patients were included with the median follow-up of 68.1 months. Of 426, 210 (49.3%), 270 (63.4%) and 251 (58.9%) had Gleason 8-10, prostate specific antigen ≥20 ng/ml and T3, respectively. The 10-year progression-free and cause-specific survival rates in Japan Cancer of the Prostate Risk Assessment 1-2 group (76.5 and 98.9%) were significantly better than those in Japan Cancer of the Prostate Risk Assessment 3-6 group (52.6 and 93.1%), (P < 0.001 and P = 0.044, respectively). The median progression-free survivals in the Japan Cancer of the Prostate Risk Assessment 1-2 and 3-6 groups were 158.9 months and 125.9 months (95% confidence interval: 108.6-143.2 months), respectively. CONCLUSIONS: For non-metastatic, high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy, Japan Cancer of the Prostate Risk Assessment score was useful for predicting the progression-free and cause-specific survivals.

Position statement on ethics, equipoise and research on charged particle radiation therapy.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

Health-related quality of life after carbon-ion radiotherapy for prostate cancer: a 3-year prospective study.

OBJECTIVES: To assess 3-year health-related quality of life of patients treated with carbon ion radiotherapy for prostate cancer. METHODS: A total of 213 patients received carbon-ion radiotherapy at a total dose of 66 Gy equivalent in 20 fractions over 5 weeks, and neoadjuvant and adjuvant androgen deprivation therapy were administered for high-risk patients for at least 12 months. A health-related quality of life assessment was carried out at four time-points (immediately before the initiation of carbon-ion radiotherapy, immediately after, 12 and 36 months after completion of carbon-ion radiotherapy) using Functional Assessment of Cancer Therapy General and for Prostate Cancer Patients. RESULTS: The evaluable response rates among all responses were more than 94%. Overall, a significant decrease in the scores of the health-related quality of life 12 months after carbon-ion radiotherapy returned to their baseline levels at 36 months. Additionally, no significant decrease was observed in the scores at any of the assessment time-points compared with their baseline scores in the group of carbon-ion radiotherapy without androgen deprivation therapy; however, the presence of morbidity and biochemical failure significantly worsened the scores, and the decreases in the scores did not improve even at 36 months after carbon-ion radiotherapy. CONCLUSIONS: An assessment based on a subjective scoring system shows a significant decrease in health-related quality of life at 12 months after carbon-ion radiation therapy, which tends to return to baseline levels at 36 months. The presence of morbidity and biochemical failure significantly worsen health-related quality of life scores. Further controlled studies focusing on health-related quality of life assessment in patients with prostate cancer are warranted.

[Heavy ion radiotherapy for recurrence of an esophageal primary malignant melanoma].

A 55-year-old man, with a prior diagnosis of primary malignant melanoma of the esophagus, had undergone esophagectomy 6 years prior. During the postoperative follow-up, a flat tumor with black pigmentation, about 2 cm in diameter, was detected during upper gastrointestinal endoscopy. A pathological examination of the biopsy specimen showed a recurrent malignant melanoma. He underwent heavy ion radiotherapy for the tumor, and it disappeared after 6 months. Subsequently, a mediastinal lymph node metastasis was detected a year after radiotherapy. He received heavy ion radiotherapy for that tumor, and it was reduced in size a year after radiotherapy. At present, the patient is alive, 13 years after the initial radiotherapy. Although malignant melanoma is generally considered to be a radioresistant cancer, heavy ion radiotherapy led to a favorable outcome. This is the first reported case of heavy ion radiotherapy for treating the recurrence of a primary malignant melanoma of the esophagus.

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.

Impact of carbon ion radiotherapy for primary spinal sarcoma.

BACKGROUND: Spinal sarcomas have been one of the most challenging diseases for orthopedic surgeons. The objective of this study was to retrospectively analyze carbon ion radiotherapy (CIRT) treatment results for spinal sarcoma. METHODS: Forty-seven patients with 48 medically unresectable spinal sarcomas, excluding sacral tumors, received treatment with CIRT between 1996 and 2011. All patients were enrolled in phase 1/2 and phase 2 clinical trials of CIRT for bone and soft tissue sarcoma. The applied dose ranged from 52.8 gray equivalents (GyE) to 70.4 GyE (median, 64.0 GyE) in 16 fixed fractions over 4 weeks. RESULTS: The median patient age was 54 years, and the cohort included 24 men and 23 women. Thirty-five patients were without prior treatment, and 12 patients had locally recurrent tumors after previous resection. The median follow-up was 25 months, and the median survival was 44 months (range, 5.2-148 months). The 5-year local control, overall survival, and progression free rates were 79%, 52%, and 48%, respectively. None of the 15 patients who had tumors measuring <100 cm(3) had a local recurrence. No fatal toxicities occurred during follow-up. One patient each had a grade 3 late skin reaction and a grade 4 late skin reaction. Vertebral body compression was observed in 7 patients. One patient had a grade 3 late spinal cord reaction. Twenty-two of the surviving 28 patients who had primary tumors remained ambulatory without supportive devices. CONCLUSIONS: CIRT appears to be both effective and safe for the treatment of patients with unresectable spinal sarcoma.

The clinical relative biological effectiveness and prostate-specific antigen kinetics of carbon-ion radiotherapy in low-risk prostate cancer.

BACKGROUND: To evaluate the clinical relative biological effectiveness (RBE) of carbon-ion radiotherapy (C-ion RT) for prostate cancer. METHODS: The records of 262 patients with low-risk prostate cancer (median age, 65 [47-80] years) treated with C-ion RT at QST Hospital, National Institutes for Quantum Science and Technology in Japan during 2000-2018 were reviewed retrospectively. Four different protocol outcomes and prostate-specific antigen (PSA) responses were evaluated. The median follow-up was 8.4 years. The Kaplan-Meier method was used to estimate the biochemical or clinical failure-free rate (BCFFR). Clinical RBE was calculated using the tumor control probability model. RESULTS: The 5-, 7-, and 10-year BCFFRs were 91.7%, 83.8%, and 73.2%, respectively. The 10-year BCFFRs of patients who received C-ion RT at 66 Gy (RBE) in 20 fractions, 63 Gy (RBE) in 20 fractions, and 57.6 Gy (RBE) in 16 fractions were 81.4%, 70.9%, and 68.9%, respectively. The PSA level and density during follow-up were better in the patients treated with the lower fraction size. A higher PSA nadir and shorter time to PSA nadir were risk factors for biochemical or clinical failure by multivariate Cox regression. The tumor control probability analysis showed that the estimated clinical RBE values to achieve an 80% BCFFR at 10 years for 20, 16, and 12 fractions were 2.19 (2.18-2.24), 2.16 (2.14-2.23), and 2.12 (2.09-2.21), respectively. CONCLUSIONS: Using clinical data from low-risk prostate cancer patients, we showed the clinical RBE of C-ion RT decreased with increasing dose per fraction.

Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk.

BACKGROUND: The authors summarized the outcomes of patients with unresectable osteosarcoma of the trunk who received carbon ion radiotherapy (CIRT). METHODS: The authors performed a retrospective analysis of 78 patients who had medically inoperable osteosarcoma of the trunk and received treatment with CIRT between 1996 and 2009. Tumor sites included the pelvis in 61 patients, the spine and paraspinal region in 15 patients, and other sites in 2 patients. The median applied CIRT dose was 70.4 Gray equivalent (GyE) in a total of 16 fixed fractions over 4 weeks. RESULTS: The minimum duration of follow-up for survivors was 14 months. Forty-eight patients remained alive. The 5-year overall survival rate was 33%, and the local control rate was 62%. Thirty-eight patients who had a clinical target volume <500 cm(3) had a 5-year overall survival rate of 46% and a 5-year local control rate of 88%. Except for 3 patients who experienced severe skin/soft tissue complications requiring skin grafts, no other severe toxicities were observed. Of 9 patients who were continuously disease free for >5 years, 8 were able to walk with or without the help of a cane, and 6 were free from pain killers. CONCLUSIONS: CIRT appeared to be a safe and effective modality for the management of unresectable osteosarcoma of the trunk, providing good local control and offering a survival advantage and good long-term functional results without unacceptable morbidity.

A phase I/II clinical trial of preoperative short-course carbon-ion radiotherapy for patients with squamous cell carcinoma of the esophagus.

BACKGROUND: Carbon-ion radiotherapy (CIR) has been under development. We report the results of a phase I/II clinical trial of preoperative CIR for esophageal squamous cell carcinoma (ESCC). METHODS: Thirty-one thoracic ESCC patients were enrolled. They were first treated with CIR. The radiation dose was escalated from the initial dose of 28.8 GyE up to 36.8. Four to 8 weeks after CIR followed by clinical evaluation of the therapy, surgery was performed. Thereafter, a pathological evaluation was made. RESULTS: Acute toxicity was not seen except in one case (3.2%), and there were no late toxicities. Throughout the study period, there were no cases of withdrawal due to the effects of preoperative CIR. Twelve out of 31 (38.7%) patients achieved a clinical complete response (CR) and 13 patients (41.9%) achieved a partial response. Twelve out of 31 patients (38.7%) achieved a pathological CR. The overall 1-, 3-, and 5-year survival rates in the stage I cases were 91%, 81%, and 61%, and was 100%, 85%, and 77% for the stage II, and 71%, 43%, and 29% for the stage III cases, respectively. CONCLUSIONS: CIR showed strong local tumor control and is highly effective as a neoadjuvant therapy without severe adverse events.

A review of update clinical results of carbon ion radiotherapy.

Among various types of ion species, carbon ions are considered to have the most balanced, optimal properties in terms of possessing physically and biologically effective dose localization in the body. This is due to the fact that when compared with photon beams, carbon ion beams offer improved dose distribution, leading to the concentration of the sufficient dose within a target volume while minimizing the dose in the surrounding normal tissues. In addition, carbon ions, being heavier than protons, provide a higher biological effectiveness, which increases with depth, reaching the maximum at the end of the beam's range. This is practically an ideal property from the standpoint of cancer radiotherapy. Clinical studies have been carried out in the world to confirm the efficacy of carbon ions against a variety of tumors as well as to develop effective techniques for delivering an efficient dose to the tumor. Through clinical experiences of carbon ion radiotherapy at the National Institute of Radiological Sciences and Gesellschaft für Schwerionenforschung, a significant reduction in the overall treatment time with acceptable toxicities has been obtained in almost all types of tumors. This means that carbon ion radiotherapy has meanwhile achieved for itself a solid place in general practice. This review describes clinical results of carbon ion radiotherapy together with physical, biological and technological aspects of carbon ions.

Carbon-ion radiation therapy for prostate cancer.

In 1994, carbon-ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy-Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phase I/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon-ion radiotherapy for both early- and advance-stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon-ion radiotherapy, a phase II study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5 weeks) obtained from the phase I/II studies, and was successfully completed in October 2003. The data from 175 patients in the phase II study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon-ion radiotherapy for prostate cancer was approved as "Highly Advanced Medical Technology" from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon-ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon-ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.

The Majority of United States Citizens With Cancer do not Have Access to Carbon Ion Radiotherapy.

As of December 31, 2020, there were 12 facilities located in Asia and Europe which were treating cancer patients with carbon ion radiotherapy (CIRT). Between June 1994 and December 2020, 37,548 patients were treated with CIRT worldwide. Fifteen of these patients were United States (U.S.) citizens. Using the Surveillance, Epidemiology, and End Results cancer statistics database, the Mayo Clinic in Rochester, MN has conservatively estimated that there are approximately 44,340 people diagnosed each year in the U.S. with malignancies that would benefit from treatment with CIRT. The absence of CIRT facilities in the U.S. not only limits access to CIRT for cancer care but also prevents inclusion of U.S. citizens in phase III clinical trials that will determine the comparative effectiveness and cost effectiveness of CIRT for a variety of malignancies for FDA approval and insurance coverage. Past and present phase III clinical trials have not been able to enroll U.S. citizens due to their unwillingness or inability to travel abroad for CIRT for an extended period. These barriers could be overcome with a limited number of CIRT facilities in the U.S.

Heavy charged particle radiobiology: using enhanced biological effectiveness and improved beam focusing to advance cancer therapy.

Ionizing radiation causes many types of DNA damage, including base damage and single- and double-strand breaks. Photons, including X-rays and γ-rays, are the most widely used type of ionizing radiation in radiobiology experiments, and in radiation cancer therapy. Charged particles, including protons and carbon ions, are seeing increased use as an alternative therapeutic modality. Although the facilities needed to produce high energy charged particle beams are more costly than photon facilities, particle therapy has shown improved cancer survival rates, reflecting more highly focused dose distributions and more severe DNA damage to tumor cells. Despite early successes of charged particle radiotherapy, there is room for further improvement, and much remains to be learned about normal and cancer cell responses to charged particle radiation.