Takeshi Yanagi

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.

Carbon Ion Radiotherapy for Unresectable Sacral Chordomas

Purpose: The purpose is to evaluate the efficacy and toxicity of carbon ion radiotherapy for unresectable sacral chordomas. Experimental Design: We performed a retrospective analysis of 30 patients with unresectable sacral chordomas treated with carbon ion radiotherapy at the Heavy Ion Medical Accelerator in Chiba, Japan. Twenty-three patients presented with no prior treatment, and the remaining 7 patients had locally recurrent disease following previous surgical resection. The median clinical target volume was 546 cm3. The applied carbon ion dose ranged from 52.8 to 73.6 GyE (gray equivalent, median 70.4) in 16 fixed fractions over 4 weeks. Results: At median follow-up of 30 months (range, 9 to 87 months), 26 patients were still alive and 24 patients remained continuously disease-free. Overall and cause-specific survival rates at 5 years were 52 and 94%, respectively. The overall local control rate at 5years was 96%. Two patients experienced severe skin/soft tissue complications requiring skin grafts. No other treatment-related surgical interventions, including colostomy or urinary diversion, were carried out. All patients have remained ambulatory and able to stay at home after carbon ion radiotherapy. Conclusions: Carbon ion radiotherapy is effective and safe in the management of patients with unresectable sacral chordomas and offers a promising alternative to surgery.

Mucosal Malignant Melanoma of the Head and Neck Treated by Carbon Ion Radiotherapy

PURPOSE To evaluate the efficacy of carbon ion radiotherapy for mucosal malignant melanoma of the head and neck. METHODS AND MATERIALS Between 1994 and 2004, 72 patients with mucosal malignant melanoma of the head and neck were treated with carbon ion beams in three prospective studies. Total dose ranged from 52.8 GyE to 64 GyE given in 16 fixed fractions over 4 weeks. Clinical parameters including gender, age, Karnofsky index, tumor site, tumor volume, tumor status, total dose, fraction size, and treatment time were evaluated in relation to local control and overall survival. RESULTS The median follow-up period was 49.2 months (range, 16.8-108.5 months). Treatment toxicity was within acceptable limits, and no patients showed Grade 3 or higher toxicity in the late phase. The 5-year local control rate was 84.1%. In relation to local control, there were no significant differences in any parameters evaluated. The 5-year overall and cause-specific survival rates were 27.0% and 39.6%, respectively. For overall survival, however, tumor volume (>/=100 mL) was found to be the most significant prognostic parameter. Of the patients who developed distant metastasis, 85% were free from local recurrence. CONCLUSION Carbon ion radiotherapy is a safe and effective treatment for mucosal malignant melanoma of the head and neck in terms of high local control and acceptable toxicities. Overall survival rate was better than in those treated with conventional radiotherapy and was comparable to that with surgery.

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.

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.

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.

Dose-volume histogram and dose-surface histogram analysis for skin reactions to carbon ion radiotherapy for bone and soft tissue sarcoma.

BACKGROUND AND PURPOSE To evaluate the usefulness of the dose-volume histogram (DVH) and dose-surface histogram (DSH) as clinically relevant and available parameters that helped to identify bone and soft tissue sarcoma patients at risk of developing late skin reactions, including ulceration, when treated with carbon ion radiotherapy. MATERIALS AND METHODS Thirty-five patients with bone and soft tissue sarcoma treated with carbon ion beams were studied. The clinical skin reactions were evaluated. Some pretreatment variables were compared with the grade of late skin reactions. RESULTS Average DVH and DSH were established in accordance with the grading of the skin reactions. Prescribed dose, the difference in depths between the skin surface and the proximal extent of the tumor, and some DVH/DSH parameters were correlated with late skin reaction (> or = grade 3) according to univariate analysis. Furthermore, the area irradiated with over 60 GyE (S(60)>20 cm(2)) on DSH was the most important factor by multivariate analysis. CONCLUSIONS The area irradiated with over 60 GyE (S(60)>20 cm(2)) on DSH was found to be a parameter for use as a predictor of late skin reactions.

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.