Inhibition of potential lethal damage repair and related gene expression after carbon-ion beam irradiation to human lung cancer grown in nude mice

Using cultured and nude mouse tumor cells (IA) derived from a human lung cancer, we previously demonstrated their radiosensitivity by focusing attention on the dynamics of tumor clonogens and the early and rapid survival recovery (potential lethal damage repair: PLD repair) occurring after X-ray irradiation. To the authors knowledge, this is the first study demonstrating gene expression in association with PLD repair after carbon-ion beam or X-ray irradiation to cancer cells. In this study we tried to detect the mechanism of DNA damage and repair of the clonogens after X-ray or carbon-ion beam irradiation. At first, colony assay method was performed after irradiation of 12 Gy of X-ray or 5 Gy of carbon-ion beam to compare the time dependent cell survival of the IA cells after each irradiation pass. Second, to search the genes causing PLD repair after irradiation of X-ray or carbon-ion beam, we evaluated gene expressions by using semi-quantitative RT-PCR with the selected 34 genes reportedly related to DNA repair. The intervals from the irradiation were 0, 6, 12 and 24hr for colony assay method, and 0, 3, 18hr for RT-PCR method. From the result of survival assay, PLD repair was not significantly observed in carbon-ion beam as compared to X-ray. The results of RT-PCR were as follows. The gene showing significantly higher expressions after X-ray irradiation than after carbon-ion beam irradiation was PCNA. The genes showing significantly lower expressions after X-ray irradiation rather than after carbon-ion beam irradiation were RAD50, BRCA1, MRE11A, XRCC3, CHEK1, MLH1, CCNB1, CCNB2 and LIG4. We think PCNA among them could be a most hopeful candidate gene for PLD repair

Carbon ion radiotherapy in hypofraction regimen for stage I non-small cell lung cancer

From 1994 to 1999, we conducted a phase I/II clinical trial for stage I non-small cell lung cancer (NSCLC) by using carbon ion beams and demonstrated an optimal dose. In the present study, the total dose was fixed at 72GyE in 9 fractions over 3 weeks and at 52.8GyE for stage IA and at 60GyE for stage 1B in 4 fractions over 1 week. On this schedule, we conducted a phase II clinical trial for 127 patients with stage I NSCLC from 1999 to 2003. The local control rate for 131primary lesions was 91.5%. The local control rate for T1 and T2 tumors was 96.3% and 84.7%, respectively. There was statistical difference for the different tumor size. The five- year cause-specific survival rate of the patients was 67.7% (IA: 84.8, IB: 43.7), and their overall survival was 45.3% (IA: 53.9, 1B: 34.2). No toxicities occurred in the skin and no adverse effects worse than grade III. Carbon beam radiotherapy, which is an excellent new modality in terms of high QOL and ADL, was proven to be a valid alternative to surgery for stage I cancer, especially for elderly and inoperable patients.10th Central European Lung Cancer Conferenc

Carbon Ion Radiotherapy in Hypofraction Regimen for Stage I Non-Small Cell Lung Cancer

From 1994 to 1999, we conducted a phase I/II clinical trial for stage I non-small cell lung cancer (NSCLC) by using carbon ion beams alone, demonstrating optimal doses of 90 GyE in 18 fractions over 6 weeks and 72 GyE in 9 fractions over 3 weeks for achieving more than 95% local control with minimal pulmonary damage. In the present study, the total dose was fixed at 72 GyE in 9 fractions over 3 weeks, and at 52.8 GyE for stage IA and 60 GyE for stage 1B in 4 fractions over 1 week. Following this schedule, we conducted a phase II clinical trial for stage I NSCLC from 1999 to 2003. Most targets were irradiated from four oblique directions. A respiratory-gated irradiation system was used for all sessions. Local control and survival were assessed by the Kaplan-Meier method. For statistical testing, the long-rank test was used.The local control rate for all patients was 91.5%, and those for T1 and T2 tumors were 96.3% and 84.7%, respectively. While there was significant difference (p=0.0156) in tumor control rate between T1 and T2, there was no significant difference (P=0.1516) between squamous and non-squamous. The five-year cause-specific survival rate was 67.0% (IA: 84.4, IB: 43.7), and overall survival was 45.3% (IA: 53.9, 1B: 34.2). No adverse effects greater than grade 3 occurred in the lung. Carbon beam radiotherapy, an excellent new modality in terms of high QOL and ADL, was proven to be a valid alternative to surgery for stage I cancer, especially for elderly and inoperable patients

Carbon ion radiotherapy in hypofraction regimen for stage I non-small cell lung cancer

From 1994 to 1999, we conducted a phase I/II clinical trial for stage I non-small cell lung cancer (NSCLC) by using carbon ion beams and demonstrated an optimal dose. In the present study, the total dose was fixed at 72GyE in 9 fractions over 3 weeks and at 52.8GyE for stage IA and at 60GyE for stage 1B in 4 fractions over 1 week. On this schedule, we conducted a phase II clinical trial for 127 patients with stage I NSCLC from 1999 to 2003. The local control rate for 131primary lesions was 91.5%. The local control rate for T1 and T2 tumors was 96.3% and 84.7%, respectively. There was statistical difference for the different tumor size. The five- year cause-specific survival rate of the patients was 67.7% (IA: 84.8, IB: 43.7), and their overall survival was 45.3% (IA: 53.9, 1B: 34.2). No toxicities occurred in the skin and no adverse effects worse than grade III. Carbon beam radiotherapy, which is an excellent new modality in terms of high QOL and ADL, was proven to be a valid alternative to surgery for stage I cancer, especially for elderly and inoperable patients.10th Central European Lung Cancer Conferenc

A combination-weighted Feldkamp-based reconstruction algorithm for cone-beam CT

The combination-weighted Feldkamp algorithm (CW-FDK) was developed and tested in a phantom in order to reduce cone beam artifacts and enhance cranio-caudal reconstruction coverage in an attempt to improve image quality when utilizing cone beam CT (CBCT).Using a 256-slice cone-beam CT (256CBCT), image quality (CT-number uniformity and geometrical accuracy) was quantitatively evaluated in phantom and clinical studies and the results were compared to those with the original Feldkamp algorithm. Clinical study was done in lung cancer patients under breath-holding and free breathing.Image quality for the original Feldkamp algorithm is degraded at the edge of the scan region due to the missing volume, commensurate with the cranio-caudal distance between the reconstruction and central planes. The CW-FDK extended the reconstruction coverage to equal the scan coverage and improved reconstruction accuracy, unaffected by cranio-caudal distance.The extended reconstruction coverage with good image quality provided by the CW-FDK will be clinically investigated for improving diagnostic and radiotherapy applications. In addition, this algorithm can also be adapted for use in relatively wide cone-angle CBCT such as with a flat-panel detector CBCT

Four-Dimensional Measurement of Lung Tumor Displacement Using 256-Multi-Slice CT-Scanner

The concept of internal target volume is of marked importance for radiotherapy to lung tumors as respiration-induced motion is important. Individualized assessment of motion is required as tumour site may not predict the extent or pattern of tumour motion. We performed volumetric cine scanning using the 256-multi-slice CT (256MSCT) to study tumor motion during free breathing in 14 inpatients who were treated with carbon-ion radiotherapy. Motion assessment in 16 respiratory phases of the cine CT revealed most tumors to show hysteresis-like behavior. Isocenter displacement between peak exhalation and inhalation for the average of the right and left lungs were 7 mm, 7 mm and 15 mm for the upper, middle and lower lobes, respectively. Cine CT with the 256MSCT improved the evaluation of tumor displacement and overcomes some of the limitations associated with current CT methods. Volumetric cine CT data provides useful data on motion for planning in all radiation approaches for lung tumors

Design of a Compensating Bolus by Use of Exhalation CT Data for Covering Residual Motion in Respiratory-Gated Charged-Particle Lung Therapy: Four-Dimensional Carbon Beam Dose Calculation

We developed an algorithm which we used to design a compensating bolus by using respiratory-gated CT data for respiratory-gated carbon beam lung therapy and evaluated it by calculating dose distributions as a function of time. Four-dimensional CT (4DCT) images were obtained for seven lung cancer patients under free breathing conditions. The internal target volume (ITV) was calculated by maximum intensity projection processing which use of three types of gross tumor volumes (GTVs): at peak exhalation and with a 5 mm shift of the GTV to both superior and inferior sides. Then a compensating bolus was designed which use of the ITV and applied to 4DCT data at the gating window (around exhalation phase). The carbon beam distribution was calculated by a pencil-beam algorithm as a function of time. The compensating bolus provides a sufficient prescribed dose to the target in the gating window and minimizes any excessive dose to the normal tissues. The metric of dosimetric assessment metrics of D95 in all patients is greater than 96% of the prescribed dose in the gating window. Our results will be beneficial for improving the accuracy of charged-particle radiotherapy for hospitals where 4DCT cannot be used