Rikiya Onimaru

Feasibility of insertion/implantation of 2.0-mm-diameter gold internal fiducial markers for precise setup and real-time tumor tracking in radiotherapy.

PURPOSE To examine the feasibility and reliability of insertion of internal fiducial markers into various organs for precise setup and real-time tumor tracking in radiotherapy (RT). MATERIALS AND METHODS Equipment and techniques for the insertion of 2.0-mm-diameter gold markers into or near the tumor were developed for spinal/paraspinal lesions, prostate tumors, and liver and lung tumors. Three markers were used to adjust the center of the mass of the target volume to the planned position in spinal/paraspinal lesions and prostate tumors (the three-marker method). The feasibility of the marker insertion and the stability of the position of markers were tested using stopping rules in the clinical protocol (i.e., the procedure was abandoned if 2 of 3 or 3 of 6 patients experienced marker dropping or migration). After the evaluation of the feasibility, the stability of the marker positions was monitored in those patients who entered the dose-escalation study. RESULTS Each of the following was shown to be feasible: bronchoscopic insertion for the peripheral lung; image-guided transcutaneous insertion for the liver; cystoscopic and image-guided percutaneous insertion for the prostate; and surgical implantation for spinal/paraspinal lesions. Transcutaneous insertion of markers for spinal/paraspinal lesions and bronchoscopic insertion for central lung lesions were abandoned. Overall, marker implantation was successful and was used for real-time tumor tracking in RT in 90 (90%) of 100 lesions. No serious complications related to the marker insertion were noted for any of the 100 lesions. Using three markers surgically implanted into the vertebral bone, the mean +/- standard deviation in distance among the three markers was within 0.2 +/- 0.6 mm (range -1.4 to 0.8) through the treatment period of 30 days. The distance between the three markers gradually decreased during RT in five of six prostate cancers, consistent with a mean rate of volume regression of 9.3% (range 0.015-13%) in 10 days. CONCLUSIONS Internal 2.0-mm-diameter gold markers can be safely inserted into various organs for real-time tumor tracking in RT using the prescribed equipment and techniques. The three-marker method has been shown to be a useful technique for precise setup for spinal/paraspinal lesions and prostate tumors.

Tolerance of organs at risk in small-volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers

PURPOSE To determine the organ at risk and the maximum tolerated dose (MTD) of radiation that could be delivered to lung cancer using small-volume, image-guided radiotherapy (IGRT) using hypofractionated, coplanar, and noncoplanar multiple fields. MATERIALS AND METHODS Patients with measurable lung cancer (except small-cell lung cancer) 6 cm or less in diameter for whom surgery was not indicated were eligible for this study. Internal target volume was determined using averaged CT under normal breathing, and for patients with large respiratory motion, using two additional CT scans with breath-holding at the expiratory and inspiratory phases in the same table position. Patients were localized at the isocenter after three-dimensional treatment planning. Their setup was corrected by comparing two linacographies that were orthogonal at the isocenter with corresponding digitally reconstructed images. Megavoltage X-rays using noncoplanar multiple static ports or arcs were used to cover the parenchymal tumor mass. Prophylactic nodal irradiation was not performed. The radiation dose was started at 60 Gy in 8 fractions over 2 weeks (60 Gy/8 Fr/2 weeks) for peripheral lesions 3.0 cm or less, and at 48 Gy/8 Fr/2 weeks at the isocenter for central lesions or tumors more than 3.0 cm at their greatest dimension. RESULTS Fifty-seven lesions in 45 patients were treated. Tumor size ranged from 0.6 to 6.0 cm, with a median of 2.6 cm. Using the starting dose, 1 patient with a central lesion died of a radiation-induced ulcer in the esophagus after receiving 48 Gy/8 Fr at isocenter. Although the contour of esophagus received 80% or less of the prescribed dose in the planning, recontouring of esophagus in retrospective review revealed that 1 cc of esophagus might have received 42.5 Gy, with the maximum dose of 50.5 Gy. One patient with a peripheral lesion experienced Grade 2 pain at the internal chest wall or visceral pleura after receiving 54 Gy/8 Fr. No adverse respiratory reaction was noted in the symptoms or respiratory function tests. The 3-year local control rate was 80.4% +/- 7.1% (a standard error) with a median follow-up period of 17 months for survivors. Because of the Grade 5 toxicity, we have halted this Phase I/II study and are planning to rearrange the protocol setting accordingly. The 3-year local control rate was 69.6 +/- 10.6% for patients who received 48 Gy and 100% for patients who received 60 Gy (p = 0.0442). CONCLUSIONS Small-volume IGRT using 60 Gy in eight fractions is highly effective for the local control of lung tumors, but MTD has not been determined in this study. The organs at risk are extrapleural organs such as the esophagus and internal chest wall/visceral pleura rather than the pulmonary parenchyma in the present protocol setting. Consideration of the uncertainty in the contouring of normal structures is critically important, as is uncertainty in setup of patients and internal organ in the high-dose hypofractionated IGRT.

THREE-DIMENSIONAL INTRAFRACTIONAL MOVEMENT OF PROSTATE MEASURED DURING REAL-TIME TUMOR-TRACKING RADIOTHERAPY IN SUPINE AND PRONE TREATMENT POSITIONS

PURPOSE To quantify three-dimensional (3D) movement of the prostate gland with the patient in the supine and prone positions and to analyze the movement frequency for each treatment position. METHODS AND MATERIALS The real-time tumor-tracking radiotherapy (RTRT) system was developed to identify the 3D position of a 2-mm gold marker implanted in the prostate 30 times/s using two sets of fluoroscopic images. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within the region of the planned coordinates relative to the isocenter. Ten patients with prostate cancer treated with RTRT were the subjects of this study. The coordinates of the gold marker were recorded every 0.033 s during RTRT in the supine treatment position for 2 min. The patient was then moved to the prone position, and the marker was tracked for 2 min to acquire data regarding movement in this position. Measurements were taken 5 times for each patient (once a week); a total of 50 sets for the 10 patients was analyzed. The raw data from the RTRT system were filtered to reduce system noise, and the amplitude of movement was then calculated. The discrete Fourier transform of the unfiltered data was performed for the frequency analysis of prostate movement. RESULTS No apparent difference in movement was found among individuals. The amplitude of 3D movement was 0.1-2.7 mm in the supine and 0.4-24 mm in the prone positions. The amplitude in the supine position was statistically smaller in all directions than that in the prone position (p < 0.0001). The amplitude in the craniocaudal and AP directions was larger than in the left-right direction in the prone position (p < 0.0001). No characteristic movement frequency was detected in the supine position. The respiratory frequency was detected for all patients regarding movement in the craniocaudal and AP directions in the prone position. The results of the frequency analysis suggest that prostate movement is affected by the respiratory cycle and is influenced by bowel movement in the prone position. CONCLUSION The results of this study have confirmed that internal organ motion is less frequent in the supine position than in the prone position in the treatment of prostate cancer. RTRT would be useful in reducing uncertainty due to the effects of the respiratory cycle, especially in the prone position.

Registration accuracy and possible migration of internal fiducial gold marker implanted in prostate and liver treated with real-time tumor-tracking radiation therapy (RTRT)

BACKGROUND AND PURPOSE We have developed a linear accelerator synchronized with a fluoroscopic real-time tumor-tracking system to reduce errors due to setup and organ motion. In the real-time tumor-tracking radiation therapy (RTRT) system, the accuracy of tumor tracking depends on the registration of the markers coordinates. The registration accuracy and possible migration of the internal fiducial gold marker implanted into prostate and liver was investigated. MATERIALS AND METHODS Internal fiducial gold markers were implanted in 14 patients with prostate cancer and four patients with liver tumors. Computed tomography (CT) was carried out as a part of treatment planning in the 18 patients. A total of 72 follow-up CT scans were taken. We calculated the relative relationship between the coordinates of the center of mass (CM) of the organs and those of the marker. The discrepancy in the CM coordinates during a follow-up CT compared to those recorded during the planning CT was used to study possible marker migration. RESULTS The standard deviation (SD) of interobserver variations in the CM coordinates was within 2.0 and 0.4 mm for the organ and the marker, respectively, in seven observers. Assuming that organs do not shrink, grow, or rotate, the maximum SD of migration error in each direction was estimated to be less than 2.5 and 2.0 mm for liver and prostate, respectively. There was no correlation between the marker position and the time after implantation. CONCLUSION The degree of possible migration of the internal fiducial marker was within the limits of accuracy of the CT measurement. Most of the marker movement can be attributed to the measurement uncertainty, which also influences registration in actual treatment planning. Thus, even with the gold marker and RTRT system, a planning target volume margin should be used to account for registration uncertainty.

Hypofractionated stereotactic radiotherapy alone without whole—brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull

PURPOSE To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) using noninvasive fixation of the skull on solitary or oligo brain metastatic patients as an alternative to stereotactic radiosurgery (SRS) using invasive fixation. PATIENTS AND METHODS The subjects were 87 patients who had 4 or fewer brain metastases (50 solitary, 37 oligometastases). Treatment was conducted on 159 metastases by using a linac-based stereotactic system. The median isocentric dose was 35 Gy in 4 fractions. Whole-brain irradiation was not applied as an initial treatment. For the salvage treatment of metachronous brain metastases, repeat HSRT or whole-brain irradiation was applied. RESULTS The actuarial 1-year local tumor control rate was 81%. Treatment-related complications were observed in 4 patients in the early period (<3 months) and in 2 patients in the late period. The median survival period was 8.7 months. Metachronous brain metastases occurred in 30 patients, and none of the 18 patients who were eligible for salvage HSRT refused to receive it again. CONCLUSIONS Hypofractionated stereotactic radiotherapy achieved tumor control and survival equivalent to those of SRS reported in the literature. The results suggested that HSRT could be an alternative for solitary or oligo brain metastatic patients with less toxicity and less invasiveness compared to SRS.

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.

Tumor location, cirrhosis, and surgical history contribute to tumor movement in the liver, as measured during stereotactic irradiation using a real-time tumor-tracking radiotherapy system.

PURPOSE To investigate the three-dimensional (3D) intrafractional motion of liver tumors during real-time tumor-tracking radiotherapy (RTRT). MATERIALS AND METHODS The data of 20 patients with liver tumors were analyzed. Before treatment, a 2-mm gold marker was implanted near the tumor. The RTRT system used fluoroscopy image processor units to determine the 3D position of the implanted marker. A linear accelerator was triggered to irradiate the tumor only when the marker was located within a permitted region. The automatically recorded tumor-motion data were analyzed to determine the amplitude of the tumor motion, curve shape of the tumor motion, treatment efficiency, frequency of movement, and hysteresis. Each of the following clinical factors was evaluated to determine its contribution to the amplitude of movement: tumor position, existence of cirrhosis, surgical history, tumor volume, and distance between the isocenter and the marker. RESULTS The average amplitude of tumor motion in the 20 patients was 4 +/- 4 mm (range 1-12), 9 +/- 5 mm (range 2-19), and 5 +/- 3 mm (range 2-12) in the left-right, craniocaudal, and anterior-posterior (AP) direction, respectively. The tumor motion of the right lobe was significantly larger than that of the left lobe in the left-right and AP directions (p = 0.01). The tumor motion of the patients with liver cirrhosis was significantly larger than that of the patients without liver cirrhosis in the left-right and AP directions (p < 0.004). The tumor motion of the patients who had received partial hepatectomy was significantly smaller than that of the patients who had no history of any operation on the liver in the left-right and AP directions (p < 0.03). Thus, three of the five clinical factors examined (i.e., tumor position in the liver, cirrhosis, and history of surgery on the liver) significantly affected the tumor motion of the liver in the transaxial direction during stereotactic irradiation. Frequency analysis revealed that for 9 (45%) of the 20 tumors, the cardiac beat caused measurable motion. The 3D trajectory of the tumor showed hysteresis for 4 (20%) of the 20 tumors. The average treatment efficiency of RTRT was 40%. CONCLUSIONS Tumor location, cirrhosis, and history of surgery on the liver all had an impact on the intrafractional tumor motion of the liver in the transaxial direction. This finding should be helpful in determining the smallest possible margin in individual cases of radiotherapy for liver malignancy.

How much margin reduction is possible through gating or breath hold

We determined the relationship between intra-fractional breathing motion and safety margins, using daily real-time tumour tracking data of 40 patients (43 tumour locations), treated with radiosurgery at Hokkaido University. We limited our study to the dose-blurring effect of intra-fractional breathing motion, and did not consider differences in positioning accuracy or systematic errors. The additional shift in the prescribed isodose level (e.g. 95 %) was determined by convolving a one-dimensional dose profile, having a dose gradient representing an 8 MV beam through either lung or water, with the probability density function (PDF) of breathing. This additional shift is a measure for the additional margin that should be applied in order to maintain the same probability of tumour control as without intra-fractional breathing. We show that the required safety margin is a nonlinear function of the peak-to-peak breathing motion. Only a small reduction in the shift of isodose curves was observed for breathing motion up to 10 mm. For larger motion, 20 or 30 mm, control of patient breathing during irradiation, using either gating or breath hold, can allow a substantial reduction in safety margins of about 7 or 12 mm depending on the dose gradient prior to blurring. Clinically relevant random setup uncertainties, which also have a blurring effect on the dose distribution, have only a small effect on the margin needed for intra-fractional breathing motion. Because of the one-dimensional nature of our analysis, the resulting margins are mainly applicable in the superior-inferior direction. Most measured breathing PDFs were not consistent with the PDF of a simple parametric curve such as cos4, either because of irregular breathing or base-line shifts. Instead, our analysis shows that breathing motion can be modelled as Gaussian with a standard deviation of about 0.4 times the peak-to-peak breathing motion.

Superselective high-dose cisplatin infusion with concomitant radiotherapy in patients with advanced cancer of the nasal cavity and paranasal sinuses: a single institution experience.

The current study aimed to evaluate the efficacy of superselective high‐dose cisplatin infusion with concomitant radiotherapy (RADPLAT) for previously untreated patients with advanced cancer of the nasal cavity and paranasal sinuses.

Magnetic resonance imaging system for three-dimensional conformal radiotherapy and its impact on gross tumor volume delineation of central nervous system tumors.

PURPOSE We developed an MRI system for three-dimensional planning in radiotherapy. Its contribution on gross tumor volume (GTV) delineation of central nervous system (CNS) diseases was evaluated. METHODS AND MATERIALS The MRI system, with corrected distortion, was registered on computed tomography (CT) by means of fiducial/anatomic landmarks. In 41 consecutive patients with various CNS diseases, GTVs determined by MRI/CT registration (MR/CT-GTV) and CT alone (CT-GTV) were compared. Hard copies of diagnostic MRI were shown to doctors when CT-GTV was determined to simulate a conventional planning situation. Multi-observer volumetric analysis was conducted, assessing interobserver deviations among four radiation oncologists and intermethodological deviations between MR/CT-GTV and CT-GTV. RESULTS Overall, the mean of geometric distortion was significantly reduced from 1.08 mm to 0.3 mm by distortion correction (p < 0.0001). The contribution of the correction was apparent at >12.0 cm radius from the center of the magnetic field. Interobserver deviation was significantly reduced by MR/CT registration (p = 0.005). The improvement was significant for acoustic neurinoma (p = 0.038), astrocytomas (p = 0.043), and lesions at the cerebellum/brainstem (p = 0.008). The regression coefficient between MR/CT-GTV and CT-GTV was <0.9 for cerebellum/brainstem lesions, suggesting that MRI/CT-GTV was smaller than CT-GTV. CONCLUSIONS This system is feasible for three-dimensional planning and was shown to reduce interobserver deviations in GTV delineation for CNS diseases.