Riwa Kishimoto

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.

Four-dimensional measurement of intrafractional respiratory motion of pancreatic tumors using a 256 multi-slice CT scanner

PURPOSE To quantify pancreas and pancreatic tumor movement due to respiratory motion using volumetric cine CT images. MATERIALS AND METHODS Six patients with pancreatic tumors were scanned in cine mode with a 256 multi-slice CT scanner under free breathing conditions. Gross tumor volume (GTV) and pancreas were manually contoured on the CT data set by a radiation oncologist. Intrafractional respiratory movement of the GTV and pancreas was calculated, and the results were compared between the respiratory ungated and gated phases, which is a 30% duty cycle around exhalation. RESULTS Respiratory-induced organ motion was observed mainly in the anterior abdominal side than the posterior side. Average GTV displacement (ungated/gated phases) was 0.7 mm/0.2mm in both the left and right directions, and 2.5mm/0.9 mm in the anterior, 0.1 mm/0mm in the posterior, and 8.9 mm/2.6mm in the inferior directions. Average pancreas center of mass displacement relative to that at peak exhalation was mainly in the inferior direction, at 9.6mm in the ungated phase and 2.3mm in the gated phase. CONCLUSIONS By allowing accurate determination of the margin, quantitative analysis of tumor and pancreas displacement provides useful information in treatment planning in all radiation approaches for pancreatic tumors.

ADC value and diffusion tensor imaging of prostate cancer: Changes in carbon-ion radiotherapy

To assess the apparent diffusion coefficient (ADC) value and diffusion tensor image (DTI) including fractional anisotropy (FA) of the noncancerous prostate and prostate cancer before and after carbon‐ion radiotherapy (CIRT).

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.

Detection of bone metastases using diffusion weighted magnetic resonance imaging: comparison with 11C-methionine PET and bone scintigraphy

PURPOSE We evaluated the ability of diffusion-weighted imaging (DWI) to detect bone metastasis by comparing the results obtained using this modality with those obtained using (11)C-methionine (MET) positron emission tomography (PET) and bone scintigraphy. MATERIALS AND METHODS This retrospective study involved 29 patients with bone metastasis. DWI was obtained using a single-shot echo planar imaging (EPI) sequence with fat suppression using a short inversion time inversion recovery sequence. The detection capabilities of DWI for bone metastases were compared with those of whole body MET PET (in 19 patients) and 99mTc-methylene diphosphonate bone scintigraphy (in 15 patients). RESULTS Among the 19 patients who were diagnosed using DWI and PET, the PET identified 39 bone metastases, while the DWI identified 60 metastases out of 69 metastases revealed with conventional magnetic resonance imaging (MRI). Among the 15 patients who were diagnosed using DWI and bone scintigraphy, the bone scintigraphy identified 18 bone metastases, while the DWI identified 72 metastases out of 78 metastases revealed with conventional MRI. The overall bone metastasis detection rates were 56.5% for PET, 23.1% for bone scintigraphy and 92.3% for DWI. CONCLUSION DWI is a very sensitive method for detecting bone metastasis and is superior to MET PET and bone scintigraphy in terms of its detection capabilities.

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.

Malignant mucosal melanoma treated with carbon ion radiotherapy with concurrent chemotherapy: Prognostic value of pretreatment apparent diffusion coefficient (ADC)

BACKGROUND AND PURPOSE To evaluate the potential of apparent diffusion coefficient (ADC) value before carbon ion radiotherapy (C-ion RT) for malignant mucosal melanoma (MMM) to predict prognosis. MATERIALS AND METHODS We recruited 37 patients with MMM in the head and neck treated by C-ion RT with concomitant chemotherapy. Univariate and multivariate analyses of minimum ADC, mean ADC, tumor volume, age, PS, and gender were performed to identify prognostic factors. RESULTS The 3-year local control rate, distant metastasis-free survival rate and overall survival rate of all patients were 81.1%, 37.6% and 65.3%, respectively, with a median follow-up period of 19.0 months. In univariate analyses, lower minimum ADC (≤0.6380 × 10(-3) mm(2)/s) and lower mean ADC (≤1.1523 × 10(-3) mm(2)/s) were unfavorable prognostic factors for distant metastasis (p=0.029 and p=0.014, respectively), and lower minimum ADC was an unfavorable prognostic factor for overall survival (p=0.019). However, there was no significant prognostic factor of local control including ADC value. In multivariate analyses, only minimum ADC was selected as a prognostic factor of distant metastasis-free survival and overall survival (p=0.015 and p=0.006, respectively). CONCLUSION Minimum ADC can be a prognostic factor of MMM in the head and neck after C-ion RT.

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.

Compensatory enlargement of the liver after treatment of hepatocellular carcinoma with carbon ion radiotherapy - relation to prognosis and liver function.

BACKGROUND AND PURPOSE To examine whether liver volume changes affect prognosis and hepatic function in patients treated with carbon ion radiotherapy (CIRT) for hepatocellular carcinoma (HCC). MATERIAL AND METHODS Between April 1995 and March 2003, among the cases treated with CIRT, 43 patients with HCC limited to the right hepatic lobe were considered eligible for the study. The left lateral segment was defined as the non-irradiated region. Liver volume was measured using contrast CT at 0, 3, 6, and 12 months after CIRT. We examined serum albumin, prothrombin activity, and total bilirubin level as hepatic functional reserve. RESULTS After CIRT, the non-irradiated region showed significant enlargement, and enlarged volume of this region 3 months after CIRT 50 cm(3) was a prognostic factor. The 5-year overall survival rates were 48.9% in the larger enlargement group (enlarged volume of non-irradiated region 3 months after CIRT > or =50 cm(3)) and 29.4% in the smaller enlargement group (as above, <50 cm(3)). The larger enlargement group showed better hepatic functional reserve than the smaller enlargement group 12 months after CIRT. CONCLUSIONS This study suggests that compensatory enlargement in the non-irradiated liver after CIRT contributes to the improvement of prognosis.

Risk factors for brain injury after carbon ion radiotherapy for skull base tumors

BACKGROUND AND PURPOSE This study aimed to determine the risk factors for radiation-induced brain injury (RIBI) after carbon ion radiotherapy (CIRT) for treating skull base tumors. MATERIALS AND METHODS Between April 1997 and January 2009, CIRT at a total dose of 48.0-60.8Gy equivalent (GyE) was administered in 16 fractions to 47 patients with skull base tumors. Of these patients, 39 who were followed up with magnetic resonance imaging (MRI) for more than 24months were analyzed. RIBI was assessed according to the MRI findings based on the Late Effects of Normal Tissue-Subjective, Objective, Management, Analytic criteria; clinical symptoms were assessed according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer tables. The correlations of clinical and dosimetric parameters with incidence of ⩾grade 2 RIBI were retrospectively analyzed. RESULTS The median follow-up period was 67months. The 5-year actuarial likelihoods of ⩾grade 2 RIBI and ⩾grade 2 clinical symptoms were 24.5% and 7.0%, respectively. Multivariate analysis demonstrated that the brain volume receiving more than 50GyE (V50) was a significant risk factor for the development of ⩾grade 2 RIBI (p=0.004). CONCLUSION V50 was a significant risk factor for ⩾grade 2 RIBI after CIRT using a 16-fraction regimen.