- [Show abstract] [Hide abstract] ABSTRACT: 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.
- [Show abstract] [Hide abstract] ABSTRACT: Platinum-based chemoradiotherapy (CRT) is a standard front-line treatment for locally advanced non-small cell lung cancer (NSCLC). However, no clinical trials have compared the efficacy and toxicity of platinum combination and docetaxel as subsequent re-challenge chemotherapies after cancer recurrence following CRT. This study aimed to evaluate the efficacy and toxicity of platinum combination chemotherapy versus docetaxel monotherapy in NSCLC patients previously treated with platinum-based CRT. From September 2002 to December 2009, at three participating institutions, 24 patients with locally advanced NSCLC, who had previously received platinum-based CRT, were treated with platinum combination re-challenge therapy, whereas 61 received docetaxel monotherapy. We reviewed their medical charts to evaluate patient characteristics and data regarding treatment response, survival, and toxicity. The response rates were 16.7% and 6.6% in the platinum combination chemotherapy and docetaxel monotherapy groups, respectively (p = 0.09), whereas disease control rates were 58.3% and 57.4%, respectively (p = 0.82). Progression-free survival was similar between the two groups (median, 4.2 vs. 2.3 months; hazard ratio [HR] = 0.81; 95% confidence interval [CI] = 0.51–1.29; p = 0.38), as was overall survival (median, 16.5 vs. 13.0 months; HR = 0.82; 95% CI = 0.47–1.41; p = 0.47). The incidence and severity of toxicity was also similar between the two groups. Hematological toxicity, particularly leukopenia and neutropenia, was more frequent in the docetaxel group. Our results indicated that platinum combination re-challenge was equivalent to docetaxel for relapsed patients previously treated with platinum-based CRT.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose: To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors. Methods: Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient. Results: The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2-3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively. Conclusions: The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2-3 ARM.
- [Show abstract] [Hide abstract] ABSTRACT: Background: The purpose of this study was to assess the incidence, risk factors, and dose-volume relationship of radiation-induced rib fracture (RIRF) after carbon ion radiotherapy for lung cancer. Material and methods: Fifty-seven ribs of 18 patients with peripheral stage I non-small cell lung cancer treated with carbon ion radiotherapy were analyzed on rib fracture. The patients were treated at a total dose of 52.8 Gy [relative biologic effectiveness (RBE)] or 60.0 Gy (RBE) in 4 fractions and were followed at least six months. Patient characteristics and dosimetric parameters were analyzed for associations with RIRF. Results: Eighteen patients and 57 ribs were included in this study. The median length of follow-up was 36.5 months. RIRF was observed in seven (39%) of the 18 patients, and in 11 (19%) of 57 ribs. Only one patient developed symptomatic fracture. The distance from the ribs to the tumor site was significantly shorter in fractured ribs than in non-fractured ribs (1.4 ± 0.3 cm vs. 2.5 ± 0.3 cm). Receiver operating characteristic curve analysis showed that [Formula: see text] as a cut-off value for discriminating RIRF had the largest area under the curve (AUC =0.78). Comparison of the two-year cumulative incidence of RIRF among two groups as determined by cut-off values, yielded the following result: 53% vs. 4% [[Formula: see text], ≥ 38.2 Gy (RBE) or less]. Results from the two groups were significantly different (p < 0.05). Conclusion: The crude incidence of RIRF after carbon ion radiotherapy was 39% but incidence of symptomatic fracture was low. The [Formula: see text] as cut-off values may be helpful for discriminating the risk of RIRF.
- [Show abstract] [Hide abstract] ABSTRACT: Background: The purpose of this study was to compare carbon ion radiotherapy (C-ion RT) and stereotactic radiotherapy (SBRT) with photon beams for the treatment of hepatocellular carcinoma (HCC), specifically with regard to the dose volume parameters for target coverage and normal tissue sparing. Methods: Data of 10 patients who were treated using C-ion RT with a total dose of 60 Gy(RBE) in four fractions were used. The virtual plan of SBRT was simulated on the treatment planning computed tomography images of C-ion RT. Dose volume parameters such as minimum dose covering 90 % of the planning target volume (PTV D90), homogeneity index (HI), conformity index (CI), mean liver dose (MLD), volume of the liver receiving 5 to 60 Gy (V5-60), and max point dose (Dmax) of gastrointestinal (GI) tract were calculated from both treatment plans. Results: The PTV D90 was 59.6 ± 0.2 Gy(RBE) in C-ion RT, as compared to 56.6 ± 0.3 Gy in SBRT (p < 0.05). HI and CI were 1.19 ± 0.03 and 0.79 ± 0.06, respectively in C-ion RT, as compared to 1.21 ± 0.01 and 0.37 ± 0.02, respectively in SBRT. Only CI showed a significant difference between two modalities. Mean liver dose was 8.1 ± 1.4 Gy(RBE) in C-ion RT, as compared to 16.1 ± 2.5 Gy in SBRT (p < 0.05). V5 to V50 of liver were higher in SBRT than C-ion RT and significant differences were observed for V5, V10 and V20. Dmax of the GI tract was higher in SBRT than C-ion RT, but did not show a significantly difference. Conclusions: C-ion RT provides an advantage in both target conformity and normal liver sparing compared with SBRT.
- [Show abstract] [Hide abstract] ABSTRACT: Precise target detection is essential for radiosurgery, neurosurgery and hypofractionated radiotherapy because treatment results and complication rates are related to accuracy of the target definition. In skull base tumors and tumors around the optic pathways, exact anatomical evaluation of cranial nerves are important to avoid adverse effects on these structures close to lesions. Three-dimensional analyses of structures obtained with MR heavy T2-images and image fusion with CT thin-sliced sections are desirable to evaluate fine structures during radiosurgery and microsurgery. In vascular lesions, angiography is most important for evaluations of whole structures from feeder to drainer, shunt, blood flow and risk factors of bleeding. However, exact sites and surrounding structures in the brain are not shown on angiography. True image fusions of angiography, MR images and CT on axial planes are ideal for precise target definition. In malignant tumors, especially recurrent head and neck tumors, biologically active areas of recurrent tumors are main targets of radiosurgery. PET scan is useful for quantitative evaluation of recurrences. However, the examination is not always available at the time of radiosurgery. Image fusion of MR diffusion images with CT is always available during radiosurgery and useful for the detection of recurrent lesions. All images are fused and registered on thin sliced CT sections and exactly demarcated targets are planned for treatment. Follow-up images are also able to register on this CT. Exact target changes, including volume, are possible in this fusion system. The purpose of this review is to describe the usefulness of image fusion for 1) skull base, 2) vascular, 3) recurrent target detection, and 4) follow-up analyses in radiosurgery, neurosurgery and hypofractionated radiotherapy.
Article: [Particle beam radiotherapy][Show abstract] [Hide abstract] ABSTRACT: Recently, particle beam radiotherapy with protons or carbon ions has been used in cancer treatment. Energy deposition with particle beams increases as depth increases. Furthermore, carbon ion beams have stronger biological effects than X-rays or proton beams, because carbon beams generate denser ionization along the pathway of the particles. In Japan, clinical study with carbon ions for cancer therapy was initiated in 1994 at the National Institute of Radiological Science(NIRS). Four treatment facilities are now in operation, including Gunma University Heavy Ion Medical Center. The experience with carbon ion radiotherapy at NIRS has demonstrated advantages for the following types of cancer. In terms of histological type, adenocarcinomas, sarcomas, and melanomas that are relatively radioresistant to conventional X-ray radiotherapy may be sensitive to carbon ion radiotherapy. Primary sites that may be sensitive include the head and neck region, lung, liver, prostate, bone and soft tissue, and pelvis(for recurrence of rectal cancer). Combined with surgery, cytotoxic drugs, molecular targeted drugs, and immunotherapy, carbon ion radiotherapy promises to be an important modality in the future.
- [Show abstract] [Hide abstract] ABSTRACT: BackgroundA single-institutional prospective study of optimal hypofractionated conformal radiotherapy for large brain metastases with high risk factors was performed based on the risk prediction of radiation-related complications.Methods Eighty-eight patients with large brain metastases ¿10 cm3 in critical areas treated from January 2010 to February 2014 using the CyberKnife were evaluated. The optimal dose and number of fractions were determined based on the surrounding brain volume circumscribed with a single dose equivalent (SDE) of 14 Gy (V14) to be less than 7 cm3 for individual lesions. Univariate and multivariate analyses were conducted.ResultsAs a result of optimal treatment, 92 tumors ranging from 10 to 74.6 cm3 (median, 16.2 cm3) in volume were treated with a median prescribed isodose of 57% and a median fraction number of five. In order to compare the results according to the tumor volume, the tumors were divided into the following three groups: 1) 10¿19.9 cm3, 2) 20¿29.9 cm3 and 3) ¿30 cm3. The lesions were treated with a median prescribed isodose of 57%, 56% and 55%, respectively, and the median fraction number was five in all three groups. However, all tumors ¿20 cm3 were treated with¿¿¿five fractions. The median SDE of the maximum dose in the three groups was 47.2 Gy, 48.5 Gy and 46.5 Gy, respectively. Local tumor control was obtained in 90.2% of the patients, and the median survival was nine months, with a median follow-up period of seven months (range, 3-41 months). There were no significant differences in the survival rates among the three groups. Six tumors exhibited marginal recurrence 7-36 months after treatment. Ten patients developed symptomatic brain edema or recurrence of pre-existing edema, seven of whom required osmo-steroid therapy. No patients developed radiation necrosis requiring surgical resection.Conclusion Our findings demonstrate that the administration of optimal hypofractionated conformal radiotherapy based on the dose-volume prediction of complications (risk line for hypofractionation), as well as Kjellberg¿s necrosis risk line used in single-session radiosurgery, is effective and safe for large brain metastases or other lesions in critical areas.
- [Show abstract] [Hide abstract] ABSTRACT: Between 2011 and 2013, concurrent chemoradiotherapy with IMRT was performed for 11 advanced oropharyngeal cancer patients and median follow-up was 11 months. The local-regional failure was not observed. Acute incidence of grade 2 xerostomia was 7 patients (64%). After 6 and 12 months, grade 2 xerostomia was 11% and 0%, respectively. Further follow-up was required to evaluate local control and the late adverse events after IMRT.
- [Show abstract] [Hide abstract] ABSTRACT: The actual risk of complications after hypofractionated conformal radiotherapy can be best predicted using a model that accounted for the SDE of the maximum dose and V14.
- [Show abstract] [Hide abstract] ABSTRACT: We investigated the rectal dose-sparing effect and tumor control of a point A dose-reduced plan in patients with Stage I-II cervical cancer (≤4 cm) arising from a small-sized uterus. Between October 2008 and August 2011, 19 patients with Stage I-II cervical cancer (≤4 cm) were treated with external beam radiotherapy (EBRT) for the pelvis and CT-guided brachytherapy. Seven patients were treated with brachytherapy with standard loading of source-dwell positions and a fraction dose of 6 Gy at point A (conventional brachy-plan). The other 12 patients with a small uterus close to the rectum or small intestine were treated with brachytherapy with a point A dose-reduction to match D2cc of the rectum and <6 Gy as the dose constraint ('point A dose-reduced plan') instead of the 6-Gy plan at point A ('tentative 6-Gy plan'). The total doses from EBRT and brachytherapy were added up and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2). The median doses to the high-risk clinical target volume (HR-CTV) D90 in the conventional brachy-plan, tentative 6-Gy plan and point A dose-reduced plan were 62 GyEQD2, 80 GyEQD2 and 64 GyEQD2, respectively. The median doses of rectal D2cc in the corresponding three plans were 42 GyEQD2, 62 GyEQD2 and 51 GyEQD2, respectively. With a median follow-up period of 35 months, three patients developed Grade-1 late rectal complications and no patients developed local recurrence. Our preliminary results suggested that CT-guided brachytherapy using an individualized point A dose-reduced plan might be useful for reducing late rectal complications while maintaining primary tumor control.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose To determine the efficacy and safety of oral 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 (50 mg/m2) was administered orally twice daily for 14 days, with cisplatin (40 mg/m2) on days 1 and 8 of each cycle every 3 weeks, for 2–4 cycles. Thoracic radiation therapy was administered in 2 Gy fractions five times weekly for a total dose of 60 Gy. The primary endpoint was the response rate, and secondary endpoints included progression-free survival, overall survival and safety. Results Forty-one patients were enrolled in this study. The objective response rate was 87.8% (98% CI: 77.8–97.8%). The median progression-free survival was 467 days (15.4 months), and the median survival time was 904 days (29.7 months). The overall survival rates at 1- and 2-years were 85.7% and 52.9%, respectively. Hematological toxicities included grade 3/4 neutropenia (17%) and grade 3/4 leukopenia (27%). No grade 3 febrile neutropenia was detected, and grade 3/4 non-hematological toxicities were also mild. A grade 3 gastrointestinal hemorrhage was observed in one patient. Conclusions The combination of oral S-1 plus cisplatin with concurrent radiotherapy is a promising treatment with a high efficacy and lower toxicity in patients with locally advanced NSCLC.
- [Show abstract] [Hide abstract] ABSTRACT: The efficacy and toxicity of five-fraction CyberKnife radiotherapy were evaluated in patients with large brain metastases in critical areas. A total of 85 metastases in 78 patients, including tumors >30 cm3 (4 cm in diameter) were treated with five-fraction CyberKnife radiotherapy with a median marginal dose of 31 Gy at a median prescribed isodose of 58%. Changes in the neurological manifestations, local tumor control, and adverse effects were investigated after treatment. The surrounding brain volumes circumscribed with 28.8 Gy (single dose equivalent to 14 Gy: V14) were measured to evaluate the risk of radiation necrosis. Neurological manifestations, such as motor weakness, visual disturbances and aphasia improved in 28 of 55 patients (50.9%). Local tumor control was obtained in 79 of 85 metastases (92.9%) during a median follow-up of eight months. Symptomatic edema occurred in 10 patients, and two of them (2.6%) required surgical resection because of radiation necrosis. The V14 of these patients was 3.0–19.7 cm3. There were 16 lesions with a V14 of ≥7.0 cm3, and two of these lesions developed extensive brain edema due to radiation necrosis. None of the patients with a V14 of <7.0 cm3 exhibited edema requiring surgical intervention. We therefore conclude that a high rate of local tumor control and low rates of complications can be obtained after five-fraction CyberKnife radiotherapy for large metastases in critical areas. The V14 of the surrounding brain is therefore a useful indicator for the risk of radiation necrosis in patients with large metastases.
- [Show abstract] [Hide abstract] ABSTRACT: To prospectively investigate the changes in bone mineral density (BMD) after pelvic radiation therapy in patients with uterine cervical cancer. Of 52 cervical cancer patients who received pelvic RT in our university hospital between 2009 and 2011, 46 patients without recurrence and who were followed up for more than 12 months were included in the study. The BMD of the irradiated region and nonirradiated regions, serum estradiol, tartrate-resistant acid phosphatase-5b, and N-terminal cross-linking telopeptide of collagen 1 were measured before, at 3 months after, and at 12 months after RT. The patient cohort was divided into 2 groups according to estradiol level before RT, and the groups were defined as postmenopausal (<40 pg/mL) and premenopausal (≥40 pg/mL). The mean BMDs within the irradiation field (lumbar vertebra 5) in the postmenopausal and the premenopausal groups were 0.825 and 0.910 g/cm(2) before RT and 0.746 and 0.841 g/cm(2) 12 months after RT, respectively. Significant decreases were observed in both groups (P<.05 and P<.01, respectively). In addition, in the premenopausal group the mean BMDs of the nonirradiated regions at thoracic vertebrae 9-12 and lumbar vertebrae 2-4 were 0.753 and 0.958 g/cm(2) before RT and were significantly decreased to 0.706 and 0.921 g/cm(2) 12 months after RT (P<.01 and P<.05, respectively). Estradiol significantly decreased 3 months after RT, whereas tartrate-resistant acid phosphatase-5b and N-terminal cross-linking telopeptide of collagen 1 continued to increase over time in the premenopausal group. A decrease in BMD in the irradiated region after RT was observed within 1 year, regardless of menopausal status. Furthermore, in premenopausal patients, pelvic RT caused a decrease in systemic BMD.
- [Show abstract] [Hide abstract] ABSTRACT: The efficacy and toxicity of three-fraction CyberKnife radiotherapy were evaluated in patients with brain metastases in critical areas. One hundred and fifty-nine metastases in 145 patients including tumors >10 cm3 were treated with three-fraction CyberKnife radiotherapy with a median marginal dose of 27 Gy at a median prescribed isodose of 60%. Changes in the neurological manifestations, local tumor control and adverse effects were investigated after treatment. The surrounding brain volumes circumscribed with 23.1 Gy (single dose equivalence of 14 Gy: V14) were measured to evaluate the risk of adverse effects. Neurological manifestations, such as motor weakness, visual disturbances and aphasia improved in 26 of 97 patients (26.8%). Local tumor control was obtained in 137 of 143 metastases (95.8%) during a median follow-up of 7 months. Nine patients had symptomatic edema and three of them (2.1%) required surgical resection because of radiation necrosis. The V14 of these patients was 4.6–31.5 cm3. There were 35 lesions with a V14 of 7 cm3 or more and three of them developed extensive brain edema due to radiation necrosis. None of the patients with a V14 of <7 cm3 exhibited edema requiring an operation. We therefore conclude that a high rate of local tumor control and low rates of complications are obtained after three-fraction CyberKnife radiotherapy for metastases in critical areas. The V14 of the surrounding brain therefore seems to be a useful indicator for the risk evaluation of radiation necrosis in patients with larger metastases.
- [Show abstract] [Hide abstract] ABSTRACT: Recently, it has become clear that acute hypoxia affecting radioresistance exists widely in tumor tissues. Concurrently, hypoxia-inducible factor-1α (HIF-1α) is recognized as an essential transcriptional factor, enabling cells to survive through hypoxia. However, it is unclear as to whether HIF-1α plays a direct role in the radioresistance caused by acute hypoxia. Therefore, in this study, we investigated the in vitro response of the human lung adenocarcinoma cell line, A549, to ionizing radiation in an experimental model that imitates acute hypoxia in the presence and absence of HIF-1α expression, using the HIF-1α inhibitor 5-[1-(phenylmethyl)-1H-indazol-3-yl]-2-furanmethanol (YC-1). Cells were treated with or without 10 μM YC-1 for 2 h. Cells were exposed to either 95% N(2) and 5% CO(2) (hypoxic condition of <0.1 mmHg) or atmospheric air (normoxic condition) for 1 h, and irradiated with 2, 5 and 10 Gy. Western blot analysis revealed that, without YC-1, cells exposed to hypoxic conditions expressed increased levels of HIF-1α compared with those exposed to normoxic conditions. Under hypoxic conditions, HIF-1α expression was suppressed by YC-1 to the same extent as that observed in cells exposed to normoxic conditions without YC-1. Clonogenic survival assay revealed that under hypoxic conditions there was no significant difference between the surviving fraction of cells treated with YC-1 and without YC-1 at any dose point examined. The oxygen enhancement ratio at 10% surviving fraction was calculated as 2.7 and 2.6 in the presence and the absence of YC-1, respectively. These results indicate that HIF-1α itself is not an immediate cause of acute hypoxia-induced radioresistance in A549 cells.
Gunma UniversityMaebashi, Gunma, Japan