Jun-etsu Mizoe

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.

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.

Results of carbon ion radiotherapy for head and neck cancer

PURPOSE To evaluate the efficacy of carbon ion radiotherapy for head-and-neck cancer in a phase II clinical trial. MATERIALS AND METHODS Between April 1997 and February 2006, 236 patients with locally advanced, histologically proven, and new or recurrent cancer of the head and neck were treated with carbon ions. The treatment dose was 64.0 GyE/16 fractions/4 weeks (or 57.6 GyE/16 fractions/4 weeks when the wide-range skin was included in the target volume). RESULTS There were grade 3 acute skin reactions in 6% and grade 3 acute mucosal reactions in 10% with no acute reactions worse than grade 3, and grade 2 late skin reactions in 3% and grade 2 late mucosal reactions in 2% with no late reactions worse than grade 2. The 5-year local control rate, by histological type, was 75% for the 85 patients with malignant melanoma, 73% for the 69 with adenoid cystic carcinoma, 73% for the 27 with adenocarcinoma, 61% for the 13 with papillary adenocarcinoma, 61% for the 12 with squamous cell carcinoma and 24% for the 14 with sarcomas. The 5-year over-all survival rate was 68% for adenoid cystic carcinoma, 56% for adenocarcinoma and 35% for malignant melanoma. CONCLUSIONS Carbon ion radiotherapy for head and neck cancer showed the therapeutic effectiveness for malignant melanoma and adenoid cystic carcinoma without severe morbidity of the normal tissues.

High linear energy transfer carbon radiation effectively kills cultured glioma cells with either mutant or wild-type p53

PURPOSE A mutation in the p53 gene is believed to play an important role in the radioresistance of many cancer cell lines. We studied cytotoxic effects of high linear energy transfer (LET) carbon beams on glioma cell lines with either mutant or wild-type p53. METHODS AND MATERIALS Cell lines U-87 and U-138 expressing wild-type p53 and U-251 and U-373 expressing mutant p53 were used. These cells were irradiated with 290 MeV/u carbon beams generated by the Heavy Ion Medical Accelerator in the National Institute of Radiologic Science or X-rays. A standard colony-forming assay and flow cytometric detection of apoptosis were performed. Cell cycle progression and the expression of p53, p21, and bax proteins were examined. RESULTS High LET carbon radiation was more cytotoxic than low LET X-ray treatment against glioma cells. The effects of the carbon beams were not dependent on the p53 gene status but were reduced by G(1) arrest, which was independent of p21 expression. The expression of bax remained unchanged in all four cell lines. CONCLUSION These results indicate that high LET charged particle radiation can induce cell death in glioma cells more effectively than X-rays and that cell death other than p53-dependent apoptosis may participate in the cytotoxicity of heavy charged particles. Thus, it might prove to be an effective alternative radiotherapy for patients with gliomas harboring mutated p53 gene.

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.

Carbon Ion Radiation Therapy for Primary Renal Cell Carcinoma: Initial Clinical Experience

PURPOSE Renal cell carcinoma (RCC) is known as a radioresistant tumor, and there are few reports on radiotherapy for primary RCC. We evaluated the efficacy of carbon ion radiotherapy (CIRT) for patients with RCC. METHODS AND MATERIALS Data for patients with RCC who received CIRT were analyzed. A median total dose of 72 GyE (gray equivalents) in 16 fractions was administered without any additional treatment. Clinical stage was determined based on TNM classification by the International Union Against Cancer (UICC). Local recurrence was defined as definite tumor regrowth after treatment. RESULTS Data for 10 patients were included in the analyses, including 7 patients with Stage I and 3 patients with Stage IV (T4NxM0 or TxN2M0) disease. The median maximum diameter of the tumor was 43 mm (24-120 mm). The median follow-up for surviving patients was 57.5 months (9-111 months). The 5-year local control rate, progression-free survival rate, cause-specific survival rate, and overall survival rates were 100%, 100%, 100%, and 74%, respectively. Interestingly, treated tumors showed very slow shrinkage, and the tumor in 1 case has been shrinking for 9 years. One patient with muscular invasion (T4 tumor) developed Grade 4 skin toxicity, but no other toxicity greater than Grade 2 was observed. CONCLUSIONS This is one of the few reports on curative radiotherapy for primary RCC. The response of the tumor to treatment was uncommon. However despite inclusion of T4 and massive tumors, favorable local controllability has been shown. The results indicate the possibility of radical CIRT, as well as surgery, for RCC.

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.