Azusa Hasegawa

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.

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.

Carbon Ion Radiotherapy for Skull Base Chordoma

OBJECTIVE To present the results of the clinical study of carbon ion radiotherapy (CIRT) for skull base and paracervical spine tumors at the National Institute of Radiological Sciences in Chiba, Japan. METHODS The study is comprised of three protocols: a pilot study, a phase I/II dose escalation study, and a phase II study. All the patients were treated by 16 fractions for 4 weeks with total doses of 48.0, 52.8, 57.6, and 60.8 Gy equivalents (GyE). RESULTS As a result of the dose escalation study of CIRT for skull base tumors, a dose fractionation of 60.8 GyE/16 fractions for 4 weeks was decided as the recommended dose because of acceptable normal tissue reactions and good local tumor control. CONCLUSIONS Preliminary results of the phase II clinical study of CIRT for skull base chordoma showed local control at 5 years at 100%, and normal tissues showed a mild reaction without any severe morbidity of important organs.

Carbon Ion Radiation Therapy Improves the Prognosis of Unresectable Adult Bone and Soft-Tissue Sarcoma of the Head and Neck

PURPOSE To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) with 70.4 GyE for unresectable bone and soft-tissue sarcoma of the adult head and neck. METHODS AND MATERIALS Twenty-seven patients (mean age, 46.2 years) were enrolled in this prospective study on C-ion RT with 70.4 GyE/16 fractions (fr) between April 2001 and February 2008. The primary end points were acute and late reactions of normal tissues, local control rate, and overall survival rate. The secondary end point was efficacy of the treatment in comparison to historical results with 57.6 or 64.0 GyE/16 fr. RESULTS The 3-year local control rate and overall survival rate for all patients were 91.8% (95% confidence interval [CI] = 81.0-100%) and 74.1% (95% CI = 57.5-90.6%), respectively. Acute reaction of Grade 3 or more was observed in only 1 patient. With regard to late reactions, visual loss was observed in 1 patient and a Grade 3 reaction of the maxillary bone was observed in 4 patients. A comparison with historical results revealed that the local control rate with 70.4 GyE was significantly higher than that with 57.6 or 64.0 GyE (3-year, 91.8% vs. 23.6%, p < 0.0001). Furthermore, the overall survival with 70.4 GyE tended to be higher than that with 57.6 or 64.0 GyE (3-year, 74.1% vs. 42.9%, p = 0.09). CONCLUSION C-ion RT with 70.4 GyE/16 fr for bone and soft-tissue sarcoma of the adult head and neck appears to be effective with acceptable toxicities in comparison to conventional RT and C-ion RT with lower doses.

Discrimination between low-grade oligodendrogliomas and diffuse astrocytoma with the aid of 11C-methionine positron emission tomography.

OBJECT The diagnostic usefulness of (11)C-methionine PET scans in gliomas is still controversial. The authors investigated the clinical significance of (11)C-methionine PET findings in preoperative diagnosis of histological type and grade. METHODS The tissue uptake of (11)C-methionine was assessed using PET in 70 patients with histologically confirmed intracerebral gliomas. The ratio of maximum standard uptake values in tumor areas to the mean standard uptake values in the contralateral normal brain tissue (tumor/normal tissue [T/N] ratio) was calculated and correlated with tumor type, histological grade, contrast enhancement on MR imaging, Ki 67 labeling index, and 1p/19q status. RESULTS The T/N ratio was significantly increased as tumor grade advanced in astrocytic tumors (WHO Grade II vs Grade III, p = 0.0011; Grade III vs Grade IV, p = 0.0007). Among Grade II gliomas, the mean T/N ratio was significantly higher in oligodendroglial tumors than in diffuse astrocytomas (DAs) (p < 0.0001). All T/N ratios for oligodendroglial tumors were ≥ 1.46, and those for DA were consistently < 1.46, with the exception of 2 cases of gemistocytic astrocytoma. The Ki 67 labeling index significantly correlated with T/N ratio in astrocytic tumors, but not in oligodendrogliomas. Oligodendroglial tumors without 1p/19q deletion had a significantly higher T/N ratio than those with the codeletion. In combination with Gd-enhanced MR imaging, 67% of nonenhanced tumors with a T/N ratio of ≥ 1.46 were proved to be Grade II oligodendrogliomas. CONCLUSIONS These results clearly show that (11)C-methionine PET T/N ratios in Grade II oligodendrogliomas were higher than those in DAs independently of their proliferative activity. This information contributes to preoperative differential diagnoses of histological type, especially in suspected low-grade gliomas.

A robust algorithm of intensity modulated proton therapy for critical tissue sparing and target coverage.

Intensity modulated proton therapy (IMPT) offers the possibility of generating excellent target coverage while sparing the neighbouring organs at risk. However, treatment plans optimized for IMPT may be very sensitive to range and setup uncertainties. We developed a method to deal with these uncertainties in the dose optimization. This method aims at two objectives: one for maintaining the dose coverage within the target, and the other for preventing undesired exposure to organs at risk. The former objective was achieved by the algorithm described in our previous paper to suppress the in-field dose gradient within the target. In this study, the latter objective was achieved by a novel algorithm in which we suppressed pencil beams with high risk to deliver undesired doses to organs at risk under conditions where range and setup uncertainties occur. We defined the risk index that quantifies the likelihood of each pencil beam delivering high doses to organs at risk, and introduced it into the objective function of dose optimizations. In order to test the algorithms performance, this method was applied to an RTOG benchmark phantom geometry and to a cervical chordoma case. These simulations demonstrated that our method provides IMPT plans that are more robust against range and setup errors compared to conventional IMPT plans. Compared to the conventional IMPT plan, the optimization time for the robust plan increased by a factor of only 3, from 4 to 11 min.

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.

Feasibility of carbon ion radiotherapy for locally advanced sinonasal adenocarcinoma.

BACKGROUND AND PURPOSE To evaluate the safety and efficacy of carbon ion radiotherapy (CIRT) for locally advanced sinonasal adenocarcinoma. MATERIAL AND METHODS Twenty-two patients with sinonasal adenocarcinoma were treated with CIRT. CIRT was the primary treatment for 16 patients. Four patients received CIRT for local recurrence after surgery and two for residual tumour after surgery or chemotherapy. At the start of CIRT, 1 patient had T-classification (T) 2 disease, 2 had T3 disease, 5 had T4a disease, and 14 had T4b disease. Fourteen patients were treated with 57.6 Gy equivalent (GyE)/16 fractions, and 8, with 64.0 GyE/16 fractions. RESULTS The median follow-up period was 43 months for all patients. The 3-year local control and loco-regional control rates for all patients were 76.9% (95% confidence interval [CI]=56.7-97.1%) and 61.3% (95% CI=38.5-84.1%), respectively. The 3-year overall survival and disease-specific survival rates were 59.1% (95% CI=38.6-79.6%) and 65.6% (95% CI=44.9-86.3%), respectively. Acute reactions of grade 3 of the skin and mucosa were observed in 2 and 4 patients, respectively. Late reactions included lateral visual loss (5 patients), mucosal ulceration (1 patient), and brain necrosis with clinical symptoms (1 patient). In the 5 patients who developed visual loss, the optic nerve was close to the tumour. CONCLUSIONS CIRT was effective and generally safe for locally advanced sinonasal adenocarcinoma.

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.