Hirotoshi Kato

Efficacy and Safety of Carbon Ion Radiotherapy in Bone and Soft Tissue Sarcomas

PURPOSE To evaluate the tolerance for and effectiveness of carbon ion radiotherapy in patients with unresectable bone and soft tissue sarcomas. PATIENTS AND METHODS We conducted a phase I/II dose escalation study of carbon ion radiotherapy. Fifty-seven patients with 64 sites of bone and soft tissue sarcomas not suited for resection received carbon ion radiotherapy. Tumors involved the spine or paraspinous soft tissues in 19 patients, pelvis in 32 patients, and extremities in six patients. The total dose ranged from 52.8 to 73.6 gray equivalent (GyE) and was administered in 16 fixed fractions over 4 weeks (3.3 to 4.6 GyE/fraction). The median tumor size was 559 cm(3) (range, 20 to 2,290 cm(3)). The minimum follow-up was 18 months. RESULTS Seven of 17 patients treated with the highest total dose of 73.6 GyE experienced Radiation Therapy Oncology Group grade 3 acute skin reactions. Dose escalation was then halted at this level. No other severe acute reactions (grade > 3) were observed in this series. The overall local control rates were 88% and 73% at 1 year and 3 years of follow-up, respectively. The median survival time was 31 months (range, 2 to 60 months), and the 1- and 3-year overall survival rates were 82% and 46%, respectively. CONCLUSION Carbon ion radiotherapy seems to be a safe and effective modality in the management of bone and soft tissue sarcomas not eligible for surgical resection, providing good local control and offering a survival advantage without unacceptable morbidity.

Carbon ion radiotherapy for stage I non-small cell lung cancer.

BACKGROUND AND PURPOSE Heavy ion radiotherapy is a promising modality because of its excellent dose localization and high biological effect on tumors. Using carbon beams, a dose escalation study was conducted for the treatment of stage I non-small cell lung cancer (NSCLC) to determine the optimal dose. MATERIALS AND METHODS The first stage phase I/II trial using 18 fractions over 6 weeks for 47 patients and the second one using nine fractions over 3 weeks for 34 patients were conducted by the dose escalation method from 59.4 to 95.4 Gray equivalents (GyE) in incremental steps of 10% and from 68.4 to 79.2 GyE in 5% increments, respectively. The local control and survival rates were obtained using the Kaplan-Meier method. RESULTS Radiation pneumonitis at grade III occurred in three of 81 patients, but they fully recovered. This was not a dose-limiting factor. The local control rates in the first and second trials were 64% and 84%, respectively. The total recurrence rate in both trials was 23.2%. The infield local recurrence in the first trial was significantly dependent on carbon dose. The doses greater than 86.4 GyE at 18 fractions and 72 GyE at nine fractions achieved a local control of 90% and 95%, respectively. The 5 year overall and cause-specific survivals in 81 patients were 42% and 60%, respectively. CONCLUSIONS With our dose escalation study, the optimum safety and efficacy dose of carbon beams was determined. Carbon beam therapy attained almost the same results as surgery for stage I NSCLC although this was a I/II study.

Overview of clinical experiences on carbon ion radiotherapy at NIRS

BACKGROUND AND PURPOSE Carbon ion beams provide physical and biological advantages over photons. This study summarizes the experiences of carbon ion radiotherapy at the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences. MATERIALS AND METHODS Between June 1994 and August 2003, a total of 1601 patients with various types of malignant tumors were enrolled in phase I/II dose-escalation studies and clinical phase II studies. All but malignant glioma patients received carbon ion radiotherapy alone with a fraction number and overall treatment time being fixed for each tumor site, given to one field per day and 3 or 4 days per week. In dose-escalation studies, the total dose was escalated by 5 or 10% increments to ensure a safe patient treatment and to determine appropriate dose levels. RESULTS In the initial dose-escalation studies, severe late complications of the recto-sigmoid colon and esophagus were observed in those patients who received high dose levels for prostate, uterine cervix and esophageal cancer. Such adverse effects, however, did shortly disappear as a result of determining safe dose levels and because of improvements in the irradiation method. Carbon ion radiotherapy has shown improvement of outcome for tumor entities: (a) locally advanced head and neck tumors, in particular those with non-squamous cell histology including adenocarcinoma, adenoid cystic carcinoma, and malignant melanoma; (b) early stage NSCLC and locally advanced NSCLC; (c) locally advanced bone and soft tissue sarcomas not suited for surgical resection; (d) locally advanced hepatocellular carcinomas; (e) locally advanced prostate carcinomas, in particular for high-risk patients; (f) chordoma and chondrosarcoma of the skull base and cervical spine, and (g) post-operative pelvic recurrence of rectal cancer. Treatment of malignant gliomas, pancreatic, uterine cervix, and esophageal cancer is being investigated within dose-escalation studies. There is a rationale for the use of short-course RT regimen due to the superior dose localization and the unique biological properties of high-LET beams. This has been proven in treatment of NSCLC and hepatoma, where the fraction number has been successfully reduced to 4-12 fractions delivered within 1-3 weeks. Even for other types of tumors including prostate cancer, bone/soft tissue sarcoma and head/neck tumors, it was equally possible to apply the therapy in much shorter treatment times as compared to conventional RT regimen. CONCLUSION Carbon ion radiotherapy, due to its physical and biologic advantages over photons, has provided improved outcome in terms of minimized toxicity and high local control rates for locally advanced tumors and pathologically non-squamous cell type of tumors. Using carbon ion radiotherapy, hypofractionated radiotherapy with application of larger doses per fraction and a reduction of overall treatment times as compared to conventional radiotherapy was enabled.

Clinical advantages of carbon-ion radiotherapy

Carbon-ion radiotherapy (C-ion RT) possesses physical and biological advantages. It was started at NIRS in 1994 using the Heavy Ion Medical Accelerator in Chiba (HIMAC); since then more than 50 protocol studies have been conducted on almost 4000 patients with a variety of tumors. Clinical experiences have demonstrated that C-ion RT is effective in such regions as the head and neck, skull base, lung, liver, prostate, bone and soft tissues, and pelvic recurrence of rectal cancer, as well as for histological types including adenocarcinoma, adenoid cystic carcinoma, malignant melanoma and various types of sarcomas, against which photon therapy could be less effective. Furthermore, when compared with photon and proton RT, a significant reduction of overall treatment time and fractions has been accomplished without enhancing toxicities. Currently, the number of irradiation sessions per patient averages 13 fractions spread over approximately three weeks. This means that in a carbon therapy facility a larger number of patients than is possible with other modalities can be treated over the same period of time.

Comparison of efficacy and toxicity of short-course carbon ion radiotherapy for hepatocellular carcinoma depending on their proximity to the porta hepatis

BACKGROUND AND PURPOSE To compare the efficacy and toxicity of short-course carbon ion radiotherapy (C-ion RT) for patients with hepatocellular carcinoma (HCC) in terms of tumor location: adjacent to the porta hepatis or not. MATERIALS AND METHODS The study consisted of 64 patients undergoing C-ion RT of 52.8 GyE in four fractions between April 2000 and March 2003. Of these patients, 18 had HCC located within 2 cm of the main portal vein (porta hepatis group) and 46 patients had HCC far from the porta hepatis (non-porta hepatis group). We compared local control, survival, and adverse events between the two groups. RESULTS The 5-year overall survival and local control rates were 22.2% and 87.8% in the porta hepatis group and 34.8% and 95.7% in the non-porta hepatis group, respectively. There were no significant differences (P=0.252, P=0.306, respectively). Further, there were no significant differences in toxicities. Biliary stricture associated with C-ion RT did not occur. CONCLUSIONS Excellent local control was obtained independent of tumor location. The short-course C-ion RT of 52.8 GyE in four fractions appears to be an effective and safe treatment modality in the porta hepatis group just as in the non-porta hepatis group.

Estimating uncertainties of the geometrical range of particle radiotherapy during respiration

PURPOSE To propose a method for estimating uncertainties of the range calculation in particle radiotherapy associated with patient respiration. MATERIALS AND METHODS A set of sequential CT images at every 0.2 s was reconstructed from continuous X-ray projection data accumulated by dynamic helical scanning. At the same time that CT data was acquired, the respiratory signal of the patient and the X-ray on/off signal on CT scanner were recorded. Each CT image was timed according to the phase of respiration waveform. Conversion of the CT number to the water equivalent path length (WEL) was performed with our treatment planning system that included a conversion table. As an illustration, the CT images of a patient with liver cancer at the right upper lobe were analyzed. The geometric size of the liver and WELs from body surface to isocenter were measured in each CT image. RESULTS Variations of WEL from body surface to isocenter at the anterior-posterior and posterior-anterior direction were 6.2 mm and 18.9 mm, respectively. Liver size changed by 35.2 mm. However, these variations were shown to be considerably reduced by gated irradiation. CONCLUSIONS A method using sequential CT images with respiration waveform was proposed. It appeared to be useful in evaluating the uncertainties of the range calculation associated with patient breathing.

Impact of Intrafractional Bowel Gas Movement on Carbon Ion Beam Dose Distribution in Pancreatic Radiotherapy

PURPOSE To assess carbon ion beam dose variation due to bowel gas movement in pancreatic radiotherapy. METHODS AND MATERIALS Ten pancreatic cancer inpatients were subject to diagnostic contrast-enhanced dynamic helical CT examination under breath-holding conditions, which included multiple-phase dynamic CT with arterial, venous, and delayed phases. The arterial-venous phase and arterial-delayed phase intervals were 35 and 145 s, respectively. A compensating bolus was designed to cover the target obtained at the arterial phase. Carbon ion dose distribution was calculated by applying the bolus to the CT data sets at the other two phases. RESULTS Dose conformation to the clinical target volume was degraded by beam overshoot/undershoot due to bowel gas movement. The D95 for clinical target volume was degraded from 98.2% (range, 98.0-99.1%) of the prescribed dose to 94.7% (range, 88.0-99.0%) at 145 s. Excessive dosing to normal tissues varied among tissues and was, for example, 12.2 GyE/13.1 GyE (0 s/145 s) for the cord and 38.8 GyE/39.8 GyE (0 s/145 s) for the duodenum. The magnitude of beam overshoot/undershoot was particularly exacerbated from the anterior and left directions. CONCLUSIONS Bowel gas movement causes dosimetric variation to the target during treatment for radiotherapy. The effect of bowel gas movement varies with beam angle, with greatest influence on the anterior-posterior and left-right beams.

Vascular Flow Patterns of Hepatic Tumors in Contrast-Enhanced 3-Dimensional Fusion Ultrasonography Using Plane Shift and Opacity Control Modes

This study was conducted to determine whether contrast‐enhanced 3‐dimensional (3D) fusion ultrasonography with combined use of the plane shift and opacity control modes can serve as a useful tool for identifying the vascular characteristics of hepatic tumors in 3D perspective.

COMPARISON OF RESPIRATORY-GATED AND RESPIRATORY-UNGATED PLANNING IN SCATTERED CARBON ION BEAM TREATMENT OF THE PANCREAS USING FOUR-DIMENSIONAL COMPUTED TOMOGRAPHY

PURPOSE We compared respiratory-gated and respiratory-ungated treatment strategies using four-dimensional (4D) scattered carbon ion beam distribution in pancreatic 4D computed tomography (CT) datasets. METHODS AND MATERIALS Seven inpatients with pancreatic tumors underwent 4DCT scanning under free-breathing conditions using a rapidly rotating cone-beam CT, which was integrated with a 256-slice detector, in cine mode. Two types of bolus for gated and ungated treatment were designed to cover the planning target volume (PTV) using 4DCT datasets in a 30% duty cycle around exhalation and a single respiratory cycle, respectively. Carbon ion beam distribution for each strategy was calculated as a function of respiratory phase by applying the compensating bolus to 4DCT at the respective phases. Smearing was not applied to the bolus, but consideration was given to drill diameter. The accumulated dose distributions were calculated by applying deformable registration and calculating the dose-volume histogram. RESULTS Doses to normal tissues in gated treatment were minimized mainly on the inferior aspect, which thereby minimized excessive doses to normal tissues. Over 95% of the dose, however, was delivered to the clinical target volume at all phases for both treatment strategies. Maximum doses to the duodenum and pancreas averaged across all patients were 43.1/43.1 GyE (ungated/gated) and 43.2/43.2 GyE (ungated/gated), respectively. CONCLUSIONS Although gated treatment minimized excessive dosing to normal tissue, the difference between treatment strategies was small. Respiratory gating may not always be required in pancreatic treatment as long as dose distribution is assessed. Any application of our results to clinical use should be undertaken only after discussion with oncologists, particularly with regard to radiotherapy combined with chemotherapy.

Mitochondrial Signal Lacking Manganese Superoxide Dismutase Failed to Prevent Cell Death by Reoxygenation Following Hypoxia in a Human Pancreatic Cancer Cell Line, KP4

One of the major characteristics of tumor is the presence of a hypoxic cell population, which is caused by abnormal distribution of blood vessels. Manganese superoxide dismutase (MnSOD) is a nuclear-encoded mitochondrial enzyme, which scavenges superoxide generated from the electron-transport chain in mitochondria. We examined whether MnSOD protects against hypoxia/reoxygenation (H/R)-induced oxidative stress using a human pancreas carcinoma-originated cell line, KP4. We also examined whether MnSOD is necessarily present in mitochondria to have a function. Normal human MnSOD and MnSOD without a mitochondrial targeting signal were transfected to KP4 cells, and reactive oxygen species, nitric oxide, lipid peroxidation, and apoptosis were examined as a function of time in air following 1 day of hypoxia as a H/R model. Our results showed H/R caused no increase in nitric oxide, but resulted in increases in reactive oxygen species, 4-hydroxy-2-nonenal protein adducts, and apoptosis. Authentic MnSOD protected against these processes and cell death, but MnSOD lacking a mitochondrial targeting signal could not. These results suggest that only when MnSOD is located in mitochondria is it efficient in protecting against cellular injuries by H/R, and they also indicate that mitochondria are primary sites of H/R-induced cellular oxidative injuries.