Hidemasa Kawamura

Long-term results of curative intraluminal high dose rate brachytherapy for endobronchial carcinoma

BackgroundThe treatment strategy of central lung tumors is not established. Intraluminal brachytherapy (ILBT) is widely used for palliative treatment of endobronchial tumors, however, it is also a promising option for curative treatment with limited data. This study evaluates the results after ILBT for endobronchial carcinoma.MethodSixteen-endobronchial carcinoma of 13 patients treated with ILBT in curative intent for 2000 to 2008 were retrospectively reviewed. ILBT using high dose rate 192 iridium thin wire system was performed with 5 Gy/fraction at mucosal surface. The patient age ranged from 57 to 82 years old with median 75 years old. The 16 lesions consisted of 13 central endobronchial cancers including 7 roentgenographically occult lung cancers and 3 of tracheal cancers. Of them, 10 lesions were treated with ILBT of median 20 Gy combined with external beam radiation therapy of median 45 Gy and 6 lesions were treated with ILBT alone of median 25 Gy.ResultsMedian follow-up time was 32.5 months. Two-year survival rate and local control rate were 92.3% and 86.2%, respectively. Local recurrences were observed in 2 lesions. Three patients died due to lung cancer (1 patient) and intercurrent disease (2 patients). Complications greater than grade 2 were not observed except for one grade 3 dyspnea.ConclusionsILBT combined with or without EBRT might be a curative treatment option in inoperable endobronchial carcinoma patients with tolerable complication.

Differential Bystander Signaling Between Radioresistant Chondrosarcoma Cells and Fibroblasts After X-Ray, Proton, Iron Ion and Carbon Ion Exposures

PURPOSE Chondrosarcoma is well known as a radioresistant tumor, but the mechanisms underlying that resistance are still unclear. The bystander effect is well documented in the field of radiation biology. We investigated the bystander response induced by X-rays, protons, carbon ions, and iron ions in chondrosarcoma cells using a transwell insert co-culture system that precludes physical contact between targeted and bystander cells. METHODS AND MATERIALS Human chondrosarcoma cells were irradiated with 0.1-, 0.5-, 1-, and 2-Gy X-rays, protons, carbon ions or iron ions using a transwell insert co-culture system. Formation of micronuclei and p53 binding protein 1 staining in bystander and irradiated cells were analyzed and bystander signaling between mixed cultures of chondrosarcoma cells, and normal human skin fibroblasts was investigated. RESULTS In this study, we show that the fraction of cells with DNA damages in irradiated chondrosarcoma cells showed dose-dependent increases with all beams. However, the fraction of cells with DNA damages in all bystander chondrosarcoma cells did not show any change from the levels in control cells. In the bystander signaling between mixed cultures of chondrosarcoma cells and fibroblasts, the amount of micronucleus formation in all bystander chondrosarcoma cells co-cultured with irradiated fibroblasts were the same as the levels for control cells. However, all bystander fibroblasts co-cultured with irradiated chondrosarcoma cells showed significant increases in the fraction of micronucleated cells compared to the rate of control cells. CONCLUSIONS We conclude that chondrosarcoma cells in the transwell insert co-culture system could release bystander stimulations but could not develop bystander responses.

Effects of Charged Particles on Human Tumor Cells

The use of charged particle therapy in cancer treatment is growing rapidly, in large part because the exquisite dose localization of charged particles allows for higher radiation doses to be given to tumor tissue while normal tissues are exposed to lower doses and decreased volumes of normal tissues are irradiated. In addition, charged particles heavier than protons have substantial potential clinical advantages because of their additional biological effects, including greater cell killing effectiveness, decreased radiation resistance of hypoxic cells in tumors, and reduced cell cycle dependence of radiation response. These biological advantages depend on many factors, such as endpoint, cell or tissue type, dose, dose rate or fractionation, charged particle type and energy, and oxygen concentration. This review summarizes the unique biological advantages of charged particle therapy and highlights recent research and areas of particular research needs, such as quantification of relative biological effectiveness (RBE) for various tumor types and radiation qualities, role of genetic background of tumor cells in determining response to charged particles, sensitivity of cancer stem-like cells to charged particles, role of charged particles in tumors with hypoxic fractions, and importance of fractionation, including use of hypofractionation, with charged particles.

Effect of histologic type on recurrence pattern in radiation therapy for medically inoperable patients with stage I non-small-cell lung cancer.

Japanese randomized trials showed that there was a significant impact on survival from stage I adenocarcinoma (AD) of the lung by adjuvant chemotherapy with uracil-tegaful after complete resection but there was no effect for patients with squamous cell carcinoma (SQ). The purpose of this study was to examine the correlation of tumor histology and clinical outcome of radiation therapy (RT) for stage I non-small-cell lung cancer (NSCLC) and to consider the necessity of adjuvant chemotherapy after RT for these patients. The subjects were 83 patients, 54 with SQ and 29 with AD; they had received definitive RT with the total dose ranging from 60 to 80 Gy with conventional fractionation at a daily dose of 2 Gy. The differences between SQ and AD with respect to survival and recurrence pattern were investigated. The 5-year overall survival and cause-specific survival rates were 26.5% and 49.1%, respectively. No difference in survival was observed between SQ and AD patients, and the recurrence rates were almost identical (44% for SQ and 45% for AD). However, the 5-year primary control rate of SQ was significantly poorer than that of AD (SQ: 61.5%; AD: 87.6%; p = 0.03). Conversely, the 5-year metastasis-free survival rate of SQ was significantly better than that of AD (SQ: 88.2%; AD: 53.0%; p = 0.005). The different failure pattern, according to tumor histology, indicates that taking into consideration the difference in their clinical behaviors would also be important for planning RT and surgery for early lung cancer.

Phase I study of oral S-1 plus Cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer.

PURPOSE To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m(-2)/day(-1)]/cisplatin [mg/m(-2)/day(-1)]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to a total dose of 60 Gy. RESULTS Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed >or=Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. CONCLUSIONS The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC.

Risk factors for rectal bleeding associated with I-125 brachytherapy for prostate cancer.

The purpose of this study was to determine the risk factors for rectal bleeding after prostate brachytherapy. Between April 2005 and September 2009, 89 patients with T1c-2cN0M0 prostate cancer were treated with permanent I-125 seed implantation alone. The prostate prescription dose was 145 Gy, and the grade of rectal bleeding was scored according to the Common Terminology Criteria for Adverse Events version 4.0. Post-treatment planning was performed with fusion images of computerized tomography and magnetic resonance imaging 4–5 weeks after brachytherapy. Patient characteristics and dosimetric parameters were evaluated to determine risk factors for bleeding. The calculated parameters included the rectal volume in cubic centimeters that received >50–200% of the prescribed dose (RV50–200) and the minimal doses received by 1–30% of the rectal volume (RD1–30). The median follow-up time was 42 months (ranging 18–73 months). Grade 1 rectal bleeding occurred in 24 (27.0%) patients, but no Grade 2 or severe bleeding was observed. Usage of anticoagulants had a significant correlation with the occurrence of bleeding (P = 0.007). The RV100–150 and RD1–10 were significantly higher in patients with rectal bleeding than in those without bleeding. The RV100 was identified as a possible threshold value; the 3-year rectal bleeding rate in patients with an RV100 > 1.0 cm3 was 36%, whereas that with an RV100 ≤ 1.0 cm3 was 14% (P < 0.05). Although no Grade 2 morbidity developed in this study, the RV100 should be kept below 1.0 cm3, especially in additional dose-escalated brachytherapy.

Evaluation of therapeutic gain for fractionated carbon-ion radiotherapy using the tumor growth delay and crypt survival assays

BACKGROUND AND PURPOSE The aim of the study was to evaluate the therapeutic gain of carbon ion (C-ion) radiotherapy using a mouse model. MATERIALS AND METHODS Transplanted fibrosarcoma (NFSa) growing in C3H/He mice and murine small intestine were irradiated with 290 MeV/nucleon C-ion beams (C-ions) in 1-12 fractions separated by 4h. The cell killing efficiencies of C-ions were measured using jejunum crypt survival and tumor growth delay (TGD) assays. RESULTS The equieffect dose for crypt survival and TGD increased with increasing number of fractions after X-rays and 20 keV/μm C-ions, whereas TGD after 77 keV/μm C-ions rather decreased. Crypts showed stronger LET-dependent increase in α terms than the tumor while β terms less depended on LET irrespective of tissues. Therapeutic gain factor, i.e., a ratio of tumor RBE over crypt RBE, of 77 keV/μm C-ions was more than unity at any doses while that of 20 keV/μm C-ions increased with an increase in dose per fraction. CONCLUSIONS These specific data imply that use of large dose per fraction would be suitable for C-ion radiotherapy irrespective of LET from the point of view of therapeutic gain, though small dose per fraction by high-LET radiation decreases total dose for tumor.

Dosimetric comparison of carbon ion and X-ray radiotherapy for Stage IIIA non–small cell lung cancer

The present study compared the dose–volume histograms of patients with Stage IIIA non–small cell lung cancer (NSCLC) treated with carbon ion radiotherapy with those of patients treated with X-ray radiotherapy. Patients with Stage IIIA NSCLC (n = 10 patients for each approach) were enrolled. Both radiotherapy plans were calculated with the same targets and organs at risk on the same CT. The treatment plan for the prophylactic lymph node and primary tumor (PTV1) delivered 40 Gy for X-ray radiotherapy and 40 Gy (relative biological effectiveness; RBE) for carbon ion radiotherapy. The total doses for the primary tumor and clinically positive lymph nodes (PTV2) were 60 Gy for X-ray radiotherapy and 60 Gy (RBE) for carbon ion radiotherapy. The homogeneity indexes for PTV1 and PTV2 were superior for carbon ion radiotherapy in comparison with X-ray radiotherapy (PTV1, 0.57 vs 0.65, P = 0.009; PTV2, 0.07 vs 0.16, P = 0.005). The normal lung mean dose, V5, V10 and V20 for carbon ion radiotherapy were 7.7 Gy (RBE), 21.4%, 19.7% and 17.0%, respectively, whereas the corresponding doses for X-ray radiotherapy were 11.9 Gy, 34.9%, 26.6% and 20.8%, respectively. Maximum spinal cord dose, esophageal maximum dose and V50, and bone V10, V30 and V50 were lower with carbon ion radiotherapy than with X-ray radiotherapy. The present study indicates that carbon ion radiotherapy provides a more homogeneous target dose and a lower dose to organs at risk than X-ray radiotherapy for Stage IIIA non–small cell lung cancer.

Changes in Rectal Dose Due to Alterations in Beam Angles for Setup Uncertainty and Range Uncertainty in Carbon-Ion Radiotherapy for Prostate Cancer

Background and Purpose Carbon-ion radiotherapy of prostate cancer is challenging in patients with metal implants in one or both hips. Problems can be circumvented by using fields at oblique angles. To evaluate the influence of setup and range uncertainties accompanying oblique field angles, we calculated rectal dose changes with oblique orthogonal field angles, using a device with fixed fields at 0° and 90° and a rotating patient couch. Material and Methods Dose distributions were calculated at the standard angles of 0° and 90°, and then at 30° and 60°. Setup uncertainty was simulated with changes from −2 mm to +2 mm for fields in the anterior-posterior, left-right, and cranial-caudal directions, and dose changes from range uncertainty were calculated with a 1 mm water-equivalent path length added to the target isocenter in each angle. The dose distributions regarding the passive irradiation method were calculated using the K2 dose algorithm. Results The rectal volumes with 0°, 30°, 60°, and 90° field angles at 95% of the prescription dose were 3.4±0.9 cm3, 2.8±1.1 cm3, 2.2±0.8 cm3, and 3.8±1.1 cm3, respectively. As compared with 90° fields, 30° and 60° fields had significant advantages regarding setup uncertainty and significant disadvantages regarding range uncertainty, but were not significantly different from the 90° field setup and range uncertainties. Conclusions The setup and range uncertainties calculated at 30° and 60° field angles were not associated with a significant change in rectal dose relative to those at 90°.

Prospective observational study of carbon‐ion radiotherapy for non‐squamous cell carcinoma of the head and neck

To evaluate the efficacy and safety of carbon‐ion radiotherapy for non‐squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end‐point was the 3‐year local control rate, and the secondary end‐points included the 3‐year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow‐up time for all patients was 39 months. Thirty‐two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3‐year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2–3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon‐ion radiotherapy achieved excellent local control and overall survival rates for non‐squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.