Takashi Mizowaki

Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame

PURPOSE This study was performed to evaluate the clinical outcomes of three-dimensional (3D) conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame. MATERIALS AND METHODS Forty patients who were treated between July 1998 and November 2000 and were followed for >10 months were included in this study. Of the 40 patients, 31 had primary lung cancer and 9 had metastatic lung cancer. The primary lung cancer was staged as T1N0M0, T2N0M0, and T3N0M0 in 19, 8, and 4 patients, respectively. The primary sites of metastatic lung cancer were the colon in 4, tongue in 2, and osteosarcoma, lung cancer, and hepatocellular carcinoma in 1 each. 3D treatment planning was performed to maintain the target dose homogeneity within 15% and to decrease the irradiated lung volume from >20 Gy to <25%. All patients were irradiated using a stereotactic body frame and received 4 times 10-12 Gy single high-dose radiation at the isocenter during a period of 5-13 days (median 12). RESULTS The initial 3 patients received 40, and the remaining 37 patients received 48 Gy after dose escalation. Of the 33 tumors followed >6 months, 6 tumors (18%) disappeared completely after treatment. Twenty-five tumors (76%) decreased in size by 30% or more after treatment. Therefore, 31 tumors (94%) showed a local response. During the follow-up of 4-37 months (median 19), no pulmonary complications greater than National Cancer Institute-Common Toxicity Criteria Grade 2 were noted. Of the 16 patients with histologically confirmed T1N0M0 primary lung cancer who received 48 Gy, all tumors were locally controlled during the follow-up of 6-36 months (median = 19). In 9 tumors with lung metastases that were irradiated with 48 Gy in total, 2 tumors did not show a local response. Finally, 3 tumors (33%) with lung metastases relapsed locally at 6-12 months (median 7) after treatment during the follow-up of 3-29 months (median 18). CONCLUSION 3D conformal hypofractionated single high-dose radiotherapy of 48 Gy in 4 fractions using a stereotactic body frame was useful for the treatment of lung tumors.

The effectiveness of an immobilization device in conformal radiotherapy for lung tumor: reduction of respiratory tumor movement and evaluation of the daily setup accuracy.

PURPOSE To evaluate the daily setup accuracy and the reduction of respiratory tumor movement using a body frame in conformal therapy for solitary lung tumor. METHODS AND MATERIALS Eighteen patients with a solitary lung tumor underwent conformal therapy using a body frame. The body shell of the frame was shaped to the patients body contour. The respiratory tumor movement was estimated using fluoroscopy, and if it was greater than 5 mm, pressure was applied to the patients abdomen with the goal of minimizing tumor movement. CT images were then obtained, and a treatment planning was made. A total dose of 40 or 48 Gy was delivered in 4 fractions. Portal films were obtained at each treatment, and the field displacements between them and the simulation films were measured for daily setup errors. The patients were repositioned if the setup error was greater than 3 mm. Correlations were analyzed between patient characteristics and the tumor movement, or the tumor movement reduction and the daily setup errors. RESULTS Respiratory tumor movement ranged from 0 to 20 mm (mean 7.7 mm). The abdominal press reduced the tumor movement significantly from a range of 8 to 20 mm to a range of 2 to 11 mm (p = 0.0002). Daily setup errors were within 5 mm in 90%, 100%, and 93% of all verifications in left-right, anterior-posterior, and cranio-caudal directions, respectively. Patient repositioning was performed in 25% of all treatments. No significant correlation was detected between patient characteristics and tumor movement, tumor movement reduction, and the daily setup errors. CONCLUSIONS The abdominal press was successful in reducing the respiratory tumor movement. Daily setup accuracy using the body frame was acceptable. Verification should be performed at each treatment in hypofractionated conformal therapy.

Survey of Stereotactic Body Radiation Therapy in Japan by the Japan 3-D Conformal External Beam Radiotherapy Group

PURPOSE To recognize the current status of stereotactic body radiotherapy (SBRT) in Japan, using a nationwide survey conducted by the Japan 3-D Conformal External Beam Radiotherapy Group. METHODS AND MATERIALS The questionnaire was sent by mail to 117 institutions. Ninety-four institutions (80%) responded by the end of November 2005. Fifty-three institutions indicated that they have already started SBRT, and 38 institutions had been reimbursed by insurance. RESULTS A total of 1111 patients with histologically confirmed lung cancer were treated. Among these patients, 637 had T1N0M0 and 272 had T2N0M0 lung cancer. Metastatic lung cancer was found in 702 and histologically unconfirmed lung tumor in 291 patients. Primary liver cancer was found in 207 and metastatic liver cancer in 76 patients. The most frequent schedule used for primary lung cancer was 48 Gy in 4 fractions at 22 institutions (52%), followed by 50 Gy in 5 fractions at 11 institutions (26%) and 60 Gy in 8 fractions at 4 institutions (10%). The tendency was the same for metastatic lung cancer. The average number of personnel involved in SBRT was 1.8 radiation oncologists, including 1.1 certified radiation oncologists, 2.8 technologists, 0.7 nurses, and 0.6 certified quality assurance personnel and 0.3 physicists. The most frequent amount of time for treatment planning was 61-120 min, for quality assurance was 50-60 min, and for treatment was 30 min. There were 14 (0.6% of all cases) reported Grade 5 complications: 11 cases of radiation pneumonitis, 2 cases of hemoptysis, and 1 case of radiation esophagitis. CONCLUSION The current status of SBRT in Japan was surveyed.

Dose--volume metrics associated with radiation pneumonitis after stereotactic body radiation therapy for lung cancer.

PURPOSE To identify dose-volume factors associated with radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT) for lung cancer. METHODS AND MATERIALS This study analyzed 74 patients who underwent SBRT for primary lung cancer. The prescribed dose for SBRT was uniformly 48 Gy in four fractions at the isocenter. RP was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.3. Symptomatic RP was defined as grade 2 or worse. Optimal cut-offs dividing the patient population into two subgroups based on the incidence of symptomatic RP were sought using the following dose-volume metrics: PTV volume (ml), mean lung dose (Gy), and V5, V10, V15, V20, V25, V30, V35, and V40 (%) of both lungs excluding the PTV. RESULTS With a median follow-up duration of 31.4 months, symptomatic RP was observed in 15 patients (20.3%), including 1 patient with grade 3. Optimal cut-offs for pulmonary dose-volume metrics were V25 and V20. These two factors were highly correlated with each other, and V25 was more significant. Symptomatic RP was observed in 14.8% of the patients with V25 <4.2%, and the rate was 46.2% in the remainder (p = 0.019). PTV volume was another significant factor. The symptomatic RP rate was significantly lower in the group with PTV <37.7 ml compared with the larger PTV group (11.1% vs. 34.5%, p = 0.020). The patients were divided into three subgroups (patients with PTV <37.7 ml; patients with, PTV ≥37.7 ml and V25 <4.2%; and patients with PTV ≥37.7 ml and V25 ≥4.2%); the incidence of RP grade 2 or worse was 11.1%, 23.5%, and 50.0%, respectively (p = 0.013). CONCLUSIONS Lung V25 and PTV volume were significant factors associated with RP after SBRT.

Prognostic Factors in Stereotactic Body Radiotherapy for Non–Small-Cell Lung Cancer

PURPOSE To investigate the factors that influence clinical outcomes after stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS A total of 101 consecutive patients who underwent SBRT with 48 Gy in 4 fractions for histologically confirmed Stage I NSCLC were enrolled in this study. Factors including age, maximal tumor diameter, sex, performance status, operability, histology, and overall treatment time were evaluated with regard to local progression (LP), disease progression (DP), and overall survival (OS) using the Cox proportional hazards model. Prognostic models were built with recursive partitioning analysis. RESULTS Three-year OS was 58.6% with a median follow-up of 31.4 months. Cumulative incidence rates of LP and DP were 13.2% and 40.8% at 3 years, respectively. Multivariate analysis demonstrated that tumor diameter was a significant factor in all endpoints of LP, DP, and OS. Other significant factors were age in DP and sex in OS. Recursive partitioning analysis indicated a condition for good prognosis (Class I) as follows: female or T1a (tumor diameter ≤20 mm). When the remaining male patients with T1b-2a (>20 mm) were defined as Class II, 3-year LP, DP, and OS were 6.8%, 23.6%, and 69.9% in recursive partitioning analysis Class I, respectively, whereas these values were 19.9%, 58.3%, and 47.1% in Class II. The differences between the classes were statistically significant. CONCLUSIONS Tumor diameter and sex were the most significant factors in SBRT for NSCLC. T1a or female patients had good prognosis.

The geometric accuracy of frameless stereotactic radiosurgery using a 6D robotic couch system

The aim of this paper is to assess the overall geometric accuracy of the Novalis system using the Robotic Tilt Module in terms of the uncertainty in frameless stereotactic radiotherapy. We analyzed the following three metrics: (1) the correction accuracy of the robotic couch, (2) the uncertainty of the isocenter position with gantry and couch rotation, and (3) the shift in position between the isocenter and central point detected with the ExacTrac x-ray system. Based on the concept of uncertainty, the overall accuracy was calculated from these values. The accuracy in positional correction with the robotic couch was 0.07 +/- 0.22 mm, the positional shift of the isocenter associated with gantry rotation was 0.35 mm, the positional shift of the isocenter associated with couch rotation was 0.38 mm and the difference in position between the isocenter and the ExacTrac x-ray system was 0.30 mm. The accuracy of intracranial stereotactic radiosurgery with the Novalis system in our clinic was 0.31 +/- 0.77 mm. The overall geometric accuracy based on the concept of uncertainty was 0.31 +/- 0.77 mm, which is within the tolerance given in the American Association of Physicists in Medicine report no. 54.

Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment

The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate-dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.

Initial validations for pursuing irradiation using a gimbals tracking system

Our newly designed image-guided radiotherapy (IGRT) system enables the dynamic tracking irradiation with a gimbaled X-ray head and a dual on-board kilovolt imaging subsystem for real-time target localization. Examinations using a computer-controlled three-dimensionally movable phantom demonstrated that our gimbals tracking system significantly reduced motion blurring effects in the dose distribution compared to the non-tracking state.

Evaluation of mass-like consolidation after stereotactic body radiation therapy for lung tumors

BackgroundThe purpose of this study was to evaluate the characteristics of mass-like consolidation of the lung on computed tomography (CT) after stereotactic body radiation therapy (SBRT) retrospectively.MethodsForty lung tumors in 37 patients who underwent SBRT were evaluated. Mass-like consolidation was defined as a dense consolidation that newly appeared over or around the original tumor, which included radiation-induced lung injury (RILI) and local recurrence. Time of appearance, initial CT findings (ectatic bronchi and conformity to dose distribution) and serial changes in the size of the mass-like consolidation were evaluated.ResultsMass-like consolidation appeared in 27 (68%) of 40 tumors at a median of 5 months after SBRT. Follow-up examination revealed that 24 (89%) of the 27 mass-like consolidations were RILI and 3 (11%) were local recurrence. There were no significant differences in the initial CT findings between RILI and local recurrence. The size of the mass-like consolidation varied in the 12 months after SBRT. After 12 months or more, however, the size did not increase in any of the RILI cases, but it did increase in all recurrence cases.ConclusionMass-like consolidations were observed in 68% of cases at a median of 5 months after SBRT. Although most of the mass-like consolidations were RILI, local recurrence was observed in a few cases. Early detection of local recurrence after SBRT was difficult.

Impact of Pretreatment Interstitial Lung Disease on Radiation Pneumonitis and Survival after Stereotactic Body Radiation Therapy for Lung Cancer

Introduction: To investigate the impact of pre-existing radiological interstitial lung disease (ILD) findings on the incidence of radiation pneumonitis (RP) and clinical outcomes after stereotactic body radiation therapy (SBRT) for stage I non–small-cell lung cancer. Methods: We included 157 consecutive patients who underwent SBRT alone for stage I non–small-cell lung cancer and whose pretreatment lung computed tomography images were available for retrospective review. The pretreatment computed tomography images were evaluated retrospectively for the presence of ILD. The incidence of RP, overall survival (OS) rate, and the incidence of disease progression and local progression were evaluated between patients with ILD (ILD[+]) and without ILD (ILD[−]). Results: Pre-existing ILD was identified in 20 patients. The median follow-up period was 39.5 months. The incidences of RP worse than grade 2 (≥ Gr2 RP) and worse than grade 3 (≥ Gr3 RP) were significantly higher in ILD(+) than ILD(−) (1 year ≥ Gr2 RP rate, 55.0% versus 13.3%; p < 0.001 and 1year ≥ Gr3 RP rate 10.0% versus 1.5%; p = 0.020). Multivariate analysis also indicated that ILD(+) was a risk factor for ≥ Gr2 and ≥ Gr3 RP, and the volume of the irradiated lung. The OS rate tended to be worse in ILD(+) than ILD(−) (3-year OS, 53.8% versus 70.8%; p = 0.28). No difference was observed in the disease progression or local progression rates. Conclusions: Pre-existing ILD was a significant risk factor for symptomatic and severe RP. Prescreening for ILD findings is important for determining the radiation pneumonitis risk when planning SBRT.