Masayori Ishikawa

Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy

PURPOSE We evaluated the relationship between the mean lung dose (MLD) and the incidence of radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT), and compared this with conventional fractionated radiation therapy (CFRT). MATERIALS AND METHODS For both SBRT (n=128) and CFRT (n=142) patients, RP grade > or = 2 was scored. Toxicity models predicting the probability of RP as a function of the MLD were fitted using maximum log likelihood analysis. The MLD was NTD (Normalized Total Dose) corrected using an alpha/beta ratio of 3 Gy. RESULTS SBRT patients were treated with 6-12 Gy per fraction with a median MLD of 6.4 Gy (range: 1.5-26.5 Gy). CFRT patients were treated with 2 Gy or 2.25 Gy per fraction, the median MLD was 13.2 Gy (range: 3.0-23.0 Gy). The crude incidence rates of RP were 10.9% and 17.6% for the SBRT and CFRT patients, respectively. A significant dose-response relationship for RP was found after SBRT, which was not significantly different from the dose-response relationship for CFRT (p=0.18). CONCLUSION We derived a significant dose-response relationship between the risk of RP and the MLD for SBRT from the clinical data. This relation was not significantly different from the dose-response relation for CFRT, although statistical analysis was hampered by the low number of patients in the high dose range.

Real-time tumor-tracking radiotherapy for adrenal tumors

PURPOSE To investigate the three-dimensional movement of internal fiducial markers near the adrenal tumors using a real-time tumor-tracking radiotherapy (RTRT) system and to examine the feasibility of high-dose hypofractionated radiotherapy for the adrenal tumors. MATERIALS AND METHODS The subjects considered in this study were 10 markers of the 9 patients treated with RTRT. A total of 72 days in the prone position and 61 treatment days in the supine position for nine of the 10 markers were analyzed. All but one patient were prescribed 48 Gy in eight fractions at the isocenter. RESULTS The average absolute amplitude of the marker movement in the prone position was 6.1+/-4.4 mm (range 2.3-14.4), 11.1+/-7.1 mm (3.5-25.2), and 7.0+/-3.5 mm (3.9-12.5) in the left-right (LR), craniocaudal (CC), and anterior-posterior (AP) directions, respectively. The average absolute amplitude in the supine position was 3.4+/-2.9 mm (0.6-9.1), 9.9+/-9.8 mm (1.1-27.1), and 5.4+/-5.2 mm (1.7-26.6) in the LR, CC, and AP directions, respectively. Of the eight markers, which were examined in both the prone and supine positions, there was no significant difference in the average absolute amplitude between the two positions. No symptomatic adverse effects were observed within the median follow-up period of 16 months (range 5-21 months). The actuarial freedom-from-local-progression rate was 100% at 12 months. CONCLUSIONS Three-dimensional motion of a fiducial marker near the adrenal tumors was detected. Hypofractionated RTRT for adrenal tumors was feasible for patients with metastatic tumors.

A noninvasive dose estimation system for clinical BNCT based on PG-SPECT--conceptual study and fundamental experiments using HPGe and CdTe semiconductor detectors.

A noninvasive method for measuring the absorbed dose distribution during the administration of clinical boron neutron capture therapy (BNCT) using an online three-dimensional (3D) imaging system is presented. This system is designed to provide more accurate information for treatment planning and dosimetry. The single-photon emission computed tomography (SPECT) technique is combined with prompt gamma-ray analysis (PGA) to provide an ideal dose estimation system for BNCT. This system is termed PG-SPECT. The fundamental feasibility of the PG-SPECT system for BNCT is confirmed under the following conditions: (1) a voxel size of 1 x 1 x 1 cm3, comparable to the spatial resolution of our standard dosimetric technique using gold wire activation, where data are available for every 5-10 mm of wire length; (2) a reaction rate of 10B(n,alpha)7Li within the measurement volume is greater than 1.1 x l0(6) interactions/cm3/s, corresponding to a thermal neutron flux of 5 x 10(8) n/cm2/s and a 10B concentration of greater than 10 ppm for the deepest part of the tumor volume under typical BNCT clinical conditions; (3) statistical uncertainty of the count rate for 10B(n,alpha)7Li prompt gamma rays is 10% or less. The desirable characteristics of a detector for the PG-SPECT system were determined by basic experiments using both HPGe and CdTe semiconductor detectors. The CdTe semiconductor detector has the greatest potential for this system because of its compactness and simplicity of maintenance.

Radiation Pneumonitis After Hypofractionated Radiotherapy: Evaluation of the LQ(L) Model and Different Dose Parameters

PURPOSE To evaluate the linear quadratic (LQ) model for hypofractionated radiotherapy within the context of predicting radiation pneumonitis (RP) and to investigate the effect if a linear (L) model in the high region (LQL model) is used. METHODS AND MATERIALS The radiation doses used for 128 patients treated with hypofractionated radiotherapy were converted to the equivalent doses given in fractions of 2 Gy for a range of alpha/beta ratios (1 Gy to infinity) according to the LQ(L) model. For the LQL model, different cut-off values between the LQ model and the linear component were used. The Lyman model parameters were fitted to the events of RP grade 2 or higher to derive the normal tissue complication probability (NTCP). The lung dose was calculated as the mean lung dose and the percentage of lung volume (V) receiving doses higher than a threshold dose of xGy (V(x)). RESULTS The best NTCP fit was found if the mean lung dose, or V(x), was calculated with an alpha/beta ratio of 3 Gy. The NTCP fit of other alpha/beta ratios and the LQL model were worse but within the 95% confidence interval of the NTCP fit of the LQ model with an alpha/beta ratio of 3 Gy. The V(50) NTCP fit was better than the NTCP fit of lower threshold doses. CONCLUSIONS For high fraction doses, the LQ model with an alpha/beta ratio of 3 Gy was the best method for converting the physical lung dose to predict RP.

Three-Dimensional Intrafractional Motion of Breast During Tangential Breast Irradiation Monitored With High-Sampling Frequency Using a Real-Time Tumor-Tracking Radiotherapy System

PURPOSE To evaluate the three-dimensional intrafraction motion of the breast during tangential breast irradiation using a real-time tracking radiotherapy (RT) system with a high-sampling frequency. METHODS AND MATERIALS A total of 17 patients with breast cancer who had received breast conservation RT were included in this study. A 2.0-mm gold marker was placed on the skin near the nipple of the breast for RT. A fluoroscopic real-time tumor-tracking RT system was used to monitor the marker. The range of motion of each patient was calculated in three directions. RESULTS The mean +/- standard deviation of the range of respiratory motion was 1.0 +/- 0.6 mm (median, 0.9; 95% confidence interval [CI] of the marker position, 0.4-2.6), 1.3 +/- 0.5 mm (median, 1.1; 95% CI, 0.5-2.5), and 2.6 +/- 1.4 (median, 2.3; 95% CI, 1.0-6.9) for the right-left, craniocaudal, and anteroposterior direction, respectively. No correlation was found between the range of motion and the body mass index or respiratory function. The mean +/- standard deviation of the absolute value of the baseline shift in the right-left, craniocaudal, and anteroposterior direction was 0.2 +/- 0.2 mm (range, 0.0-0.8 mm), 0.3 +/- 0.2 mm (range, 0.0-0.7 mm), and 0.8 +/- 0.7 mm (range, 0.1-1.8 mm), respectively. CONCLUSION Both the range of motion and the baseline shift were within a few millimeters in each direction. As long as the conventional wedge-pair technique and the proper immobilization are used, the intrafraction three-dimensional change in the breast surface did not much influence the dose distribution.

Stereotactic Radiotherapy for Intracranial Nonacoustic Schwannomas Including Facial Nerve Schwannoma

PURPOSE Although the effectiveness of stereotactic radiosurgery for nonacoustic schwannomas is currently being assessed, there have been few studies on the efficacy of stereotactic radiotherapy (SRT) for these tumors. We investigated the long-term outcome of SRT for nonacoustic intracranial nerve schwannomas. METHODS AND MATERIALS Seventeen patients were treated between July 1994 and December 2006. Of these patients, 7 had schwannomas located in the jugular foramen, 5 in the trigeminal nerve, 4 in the facial nerve, and 1 in the oculomotor nerve. Radiotherapy was used as an initial treatment without surgery in 10 patients (59%) and after initial subtotal resection in the remaining patients. The tumor volume ranged from 0.3 to 31.3 mL (mean, 8.2 mL). The treatment dose was 40 to 54 Gy in 20 to 26 fractions. The median follow-up period was 59.5 months (range, 7.4-122.6 months). Local control was defined as stable or decreased tumor size on follow-up magnetic resonance imaging. RESULTS Tumor size was decreased in 3 patients, stable in 13, and increased in 1 after SRT. Regarding neurologic symptoms, 8 patients (47%) had improvement and 9 patients were unchanged. One patient had an increase in tumor size and received microsurgical resection at 32 months after irradiation. No patient had worsening of pre-existing neurologic symptoms or development of new cranial nerve deficits at the last follow-up. CONCLUSIONS SRT is an effective alternative to surgical resection for patients with nonacoustic intracranial nerve schwannomas with respect to not only long-term local tumor control but also neuro-functional preservation.

Real-time 4-D radiotherapy for lung cancer.

Respiratory motion considerably influences dose distribution, and thus clinical outcomes in radiotherapy for lung cancer. Breath holding, breath coaching, respiratory gating with external surrogates, and mathematical predicting models all have inevitable uncertainty due to the unpredictable variations of internal tumor motion. The amplitude of the same tumor can vary with standard deviations >5 mm occurring in 23% of T1–2N0M0 non‐small cell lung cancers. Residual motion varied 1–6 mm (95th percentile) for the 40% duty cycle of respiratory gating with external surrogates. The 4‐D computed tomography is vulnerable to problems relating to the external surrogates. Real‐time 4‐D radiotherapy (4DRT), where the temporal changes in anatomy during the delivery of radiotherapy are explicitly considered in real time, is emerging as a new method to reduce these known sources of uncertainty. Fluoroscopic, real‐time tumor‐tracking technology using internal fiducial markers near the tumor has ±2 mm accuracy, and has achieved promising clinical results when used with X‐ray therapy. Instantaneous irradiation based on real‐time verification of internal fiducial markers is considered the minimal requisite for real‐time 4DRT of lung cancers at present. Real‐time tracking radiotherapy using gamma rays from positron emitters in tumors is in the preclinical research stage, but has been successful in experiments in small animals. Real‐time tumor tracking via spot‐scanning proton beam therapy has the capability to cure large lung cancers in motion, and is expected to be the next‐generation real‐time 4DRT. (Cancer Sci 2012; 103: 1–6)

What is the appropriate size criterion for proton radiotherapy for hepatocellular carcinoma? A dosimetric comparison of spot-scanning proton therapy versus intensity-modulated radiation therapy

BackgroundWe performed a dosimetric comparison of spot-scanning proton therapy (SSPT) and intensity-modulated radiation therapy (IMRT) for hepatocellular carcinoma (HCC) to investigate the impact of tumor size on the risk of radiation induced liver disease (RILD).MethodsA number of alternative plans were generated for 10 patients with HCC. The gross tumor volumes (GTV) varied from 20.1 to 2194.5 cm3. Assuming all GTVs were spherical, the nominal diameter was calculated and ranged from 3.4 to 16.1 cm. The prescription dose was 60 Gy for IMRT or 60 cobalt Gy-equivalents for SSPT with 95% planning target volume (PTV) coverage. Using IMRT and SSPT techniques, extensive comparative planning was conducted. All plans were evaluated by the risk of RILD estimated using the Lyman-normal-tissue complication probability model.ResultsFor IMRT the risk of RILD increased drastically between 6.3–7.8 cm nominal diameter of GTV. When the nominal diameter of GTV was more than 6.3 cm, the average risk of RILD was 94.5% for IMRT and 6.2% for SSPT.ConclusionsRegarding the risk of RILD, HCC can be more safely treated with SSPT, especially if its nominal diameter is more than 6.3 cm.

Lung Cancer Cells That Survive Ionizing Radiation Show Increased Integrin α2β1- and EGFR-Dependent Invasiveness

Ionizing radiation (IR)-enhanced tumor invasiveness is emerging as a contributor to the limited benefit of radiotherapy; however, its mechanism is still unclear. We previously showed that subcloned lung adenocarcinoma A549 cells (P cells), which survived 10 Gy IR (IR cells), acquired high invasiveness in vitro. Here, we tried to identify the mechanism by which IR cells increase their invasiveness by examining altered gene expression and signaling pathways in IR cells compared with those in P cells. To simulate the microenvironment in vivo, cells were embedded in a three-dimensional (3D) collagen type I gel, in which the IR cells were elongated, while the P cells were spherical. The integrin expression pattern was surveyed, and expression levels of the integrin α2 and β1 subunits were significantly elevated in IR cells. Knockdown of α2 expression or functional blockade of integrin α2β1 resulted in a round morphology of IR cells, and abrogated their invasion in the collagen matrix, suggesting the molecule’s essential role in cell spread and invasion in 3D collagen. Epidermal growth factor receptor (EGFR) also presented enhanced expression and activation in IR cells. Treatment with EGFR tyrosine kinase inhibitor, PD168393, decreased the ratio of elongated cells and cell invasiveness. Signaling molecules, including extracellular signal-regulated kinase-1/2 (Erk1/2) and Akt, exhibited higher activation in IR cells. Inhibition of Akt activation by treating with phosphoinositide 3-kinase (PI3K) inhibitor LY294002 decreased IR cell invasion, whereas inhibition of Erk1/2 activation by mitogen-activated protein kinase kinase (MEK) inhibitor U0126 did not. Our results show that integrin α2β1 and EGFR cooperatively promote higher invasiveness of IR-survived lung cancer cells, mediated in part by the PI3K/Akt signaling pathway, and might serve as alternative targets in combination with radiotherapy.

A real‐time dynamic‐MLC control algorithm for delivering IMRT to targets undergoing 2D rigid motion in the beam's eye view

An MLC control algorithm for delivering intensity modulated radiation therapy (IMRT) to targets that are undergoing two-dimensional (2D) rigid motion in the beams eye view (BEV) is presented. The goal of this method is to deliver 3D-derived fluence maps over a moving patient anatomy. Target motion measured prior to delivery is first used to design a set of planned dynamic-MLC (DMLC) sliding-window leaf trajectories. During actual delivery, the algorithm relies on real-time feedback to compensate for target motion that does not agree with the motion measured during planning. The methodology is based on an existing one-dimensional (ID) algorithm that uses on-the-fly intensity calculations to appropriately adjust the DMLC leaf trajectories in real-time during exposure delivery [McMahon et al., Med. Phys. 34, 3211-3223 (2007)]. To extend the 1D algorithms application to 2D target motion, a real-time leaf-pair shifting mechanism has been developed. Target motion that is orthogonal to leaf travel is tracked by appropriately shifting the positions of all MLC leaves. The performance of the tracking algorithm was tested for a single beam of a fractionated IMRT treatment, using a clinically derived intensity profile and a 2D target trajectory based on measured patient data. Comparisons were made between 2D tracking, 1D tracking, and no tracking. The impact of the tracking lag time and the frequency of real-time imaging were investigated. A study of the dependence of the algorithms performance on the level of agreement between the motion measured during planning and delivery was also included. Results demonstrated that tracking both components of the 2D motion (i.e., parallel and orthogonal to leaf travel) results in delivered fluence profiles that are superior to those that track the component of motion that is parallel to leaf travel alone. Tracking lag time effects may lead to relatively large intensity delivery errors compared to the other sources of error investigated. However, the algorithm presented is robust in the sense that it does not rely on a high level of agreement between the target motion measured during treatment planning and delivery.