Kazuo Miyasaka

Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy.

PURPOSE In this work, three-dimensional (3D) motion of lung tumors during radiotherapy in real time was investigated. Understanding the behavior of tumor motion in lung tissue to model tumor movement is necessary for accurate (gated or breath-hold) radiotherapy or CT scanning. METHODS Twenty patients were included in this study. Before treatment, a 2-mm gold marker was implanted in or near the tumor. A real-time tumor tracking system using two fluoroscopy image processor units was installed in the treatment room. The 3D position of the implanted gold marker was determined by using real-time pattern recognition and a calibrated projection geometry. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within a certain volume. The system provided the coordinates of the gold marker during beam-on and beam-off time in all directions simultaneously, at a sample rate of 30 images per second. The recorded tumor motion was analyzed in terms of the amplitude and curvature of the tumor motion in three directions, the differences in breathing level during treatment, hysteresis (the difference between the inhalation and exhalation trajectory of the tumor), and the amplitude of tumor motion induced by cardiac motion. RESULTS The average amplitude of the tumor motion was greatest (12 +/- 2 mm [SD]) in the cranial-caudal direction for tumors situated in the lower lobes and not attached to rigid structures such as the chest wall or vertebrae. For the lateral and anterior-posterior directions, tumor motion was small both for upper- and lower-lobe tumors (2 +/- 1 mm). The time-averaged tumor position was closer to the exhale position, because the tumor spent more time in the exhalation than in the inhalation phase. The tumor motion was modeled as a sinusoidal movement with varying asymmetry. The tumor position in the exhale phase was more stable than the tumor position in the inhale phase during individual treatment fields. However, in many patients, shifts in the exhale tumor position were observed intra- and interfractionally. These shifts are the result of patient relaxation, gravity (posterior direction), setup errors, and/or patient movement.The 3D trajectory of the tumor showed hysteresis for 10 of the 21 tumors, which ranged from 1 to 5 mm. The extent of hysteresis and the amplitude of the tumor motion remained fairly constant during the entire treatment. Changes in shape of the trajectory of the tumor were observed between subsequent treatment days for only one patient. Fourier analysis revealed that for 7 of the 21 tumors, a measurable motion in the range 1-4 mm was caused by the cardiac beat. These tumors were located near the heart or attached to the aortic arch. The motion due to the heartbeat was greatest in the lateral direction. Tumor motion due to hysteresis and heartbeat can lower treatment efficiency in real-time tumor tracking-gated treatments or lead to a geographic miss in conventional or active breathing controlled treatments. CONCLUSION The real-time tumor tracking system measured the tumor position in all three directions simultaneously, at a sampling rate that enabled detection of tumor motion due to heartbeat as well as hysteresis. Tumor motion and hysteresis could be modeled with an asymmetric function with varying asymmetry. Tumor motion due to breathing was greatest in the cranial-caudal direction for lower-lobe unfixed tumors.

Physical aspects of a real-time tumor-tracking system for gated radiotherapy

PURPOSE To reduce uncertainty due to setup error and organ motion during radiotherapy of tumors in or near the lung, by means of real-time tumor tracking and gating of a linear accelerator. METHODS AND MATERIALS The real-time tumor-tracking system consists of four sets of diagnostic X-ray television systems (two of which offer an unobstructed view of the patient at any time), an image processor unit, a gating control unit, and an image display unit. The system recognizes the position of a 2.0-mm gold marker in the human body 30 times per second using two X-ray television systems. The marker is inserted in or near the tumor using image guided implantation. The linear accelerator is gated to irradiate the tumor only when the marker is within a given tolerance from its planned coordinates relative to the isocenter. The accuracy of the system and the additional dose due to the diagnostic X-ray were examined in a phantom, and the geometric performance of the system was evaluated in 4 patients. RESULTS The phantom experiment demonstrated that the geometric accuracy of the tumor-tracking system is better than 1.5 mm for moving targets up to a speed of 40 mm/s. The dose due to the diagnostic X-ray monitoring ranged from 0.01% to 1% of the target dose for a 2.0-Gy irradiation of a chest phantom. In 4 patients with lung cancer, the range of the coordinates of the tumor marker during irradiation was 2.5-5.3 mm, which would have been 9.6-38.4 mm without tracking. CONCLUSION We successfully implemented and applied a tumor-tracking and gating system. The system significantly improves the accuracy of irradiation of targets in motion at the expense of an acceptable amount of diagnostic X-ray exposure.

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.

Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and nasopharyngeal carcinomas

PURPOSE Accurate diagnosis of tumor extent is important in three-dimensional conformal radiotherapy. This study reports the use of image fusion between (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) and magnetic resonance imaging/computed tomography (MRI/CT) for better targets delineation in radiotherapy planning of head-and-neck cancers. METHODS AND MATERIALS The subjects consisted of 12 patients with oropharyngeal carcinoma and 9 patients with nasopharyngeal carcinoma (NPC) who were treated with radical radiotherapy between July 1999 and February 2001. Image fusion between 18FDG-PET and MRI/CT was performed using an automatic multimodality image registration algorithm, which used the brain as an internal reference for registration. Gross tumor volume (GTV) was determined based on clinical examination and 18FDG uptake on the fusion images. Clinical target volume (CTV) was determined following the usual pattern of lymph node spread for each disease entity along with the clinical presentation of each patient. RESULTS Except for 3 cases with superficial tumors, all the other primary tumors were detected by 18FDG-PET. The GTV volumes for primary tumors were not changed by image fusion in 19 cases (89%), increased by 49% in one NPC, and decreased by 45% in another NPC. Normal tissue sparing was more easily performed based on clearer GTV and CTV determination on the fusion images. In particular, parotid sparing became possible in 15 patients (71%) whose upper neck areas near the parotid glands were tumor-free by 18FDG-PET. Within a mean follow-up period of 18 months, no recurrence occurred in the areas defined as CTV, which was treated prophylactically, except for 1 patient who experienced nodal recurrence in the CTV and simultaneous primary site recurrence. CONCLUSION This preliminary study showed that image fusion between 18FDG-PET and MRI/CT was useful in GTV and CTV determination in conformal RT, thus sparing normal tissues.

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.

Use of an implanted marker and real-time tracking of the marker for the positioning of prostate and bladder cancers

PURPOSE A real-time tracking radiotherapy was investigated to assess its usefulness in precise localization and verification of prostate and bladder cancers. METHODS AND MATERIALS The real-time tracking radiation therapy (RTRT) system consists of implantation of a 2.0-mm gold marker into a clinical target volume (CTV), three-dimensional radiation treatment planning (3DRTP) system, and the use of two sets of diagnostic x-ray television systems in the linear accelerator room, image processing units, and an image display unit. The position of the patient can be corrected by adjusting the actual marker position to the planned marker position, which has been transferred from the 3DRTP and superimposed on the fluoroscopic image on the display unit of the RTRT system. The position of the markers can be visualized during irradiation and after treatment delivery to verify the accuracy of the localization. Ten patients with prostate cancer and 5 patients with bladder cancer were examined using this system for the treatment setup on 91 occasions. RESULTS After manual setup using skin markers, the median of absolute value of discrepancies between the actual position of the marker and the planned position of the marker for prostate cancer was 3.4 (0.1-8.9) mm, 4.1 (0.2-18.1) mm, and 2.3 (0.0-10.6) mm for the lateral, anteroposterior, and craniocaudal directions, respectively. The 3D median distance between the actual and planned positions of the marker was 6.9 (1.1-18.2) mm for prostate cancer and 6.9 (1.7-18.6) mm for bladder cancer. After relocation using RTRT, the 3D distance between the actual and planned position of the marker was 0.9 +/- 0.9 mm. Median 3D distances between actual positions after treatment delivery and planned positions were 1.6 (0.0-6.3) mm and 2.0 (0.5-8.0) mm during daily radiotherapy for the marker in patients with prostate cancer and bladder cancer, respectively. CONCLUSION We believe the new positioning system can reduce uncertainty due to setup error and internal organ motion, although further improvement is needed for the system to account for the rotational and elastic changes of the affected tissues.

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.

Voluntary control of saccadic eye movement in patients with frontal cortical lesions and Parkinsonian patients in comparison with that in Schizophrenics

To investigate whether the abnormalities of antisaccades in schizophrenics could be explained by a dysfunction of the frontal cortex, we examined 10 patients with frontal cortical lesions and 22 patients with idiopathic Parkinsons disease with mild symptoms (Yahr I-II) using the same tasks, and compared the results with those obtained in schizophrenics. The frontal patients with lesions covering the frontal eye field and prefrontal cortex showed more errors, longer latencies, and lower peak velocities in the antisaccade task, despite giving normal results in the visually guided saccade task. This was similar to the results observed in schizophrenics. Parkinsonian patients did not consistently show a significant difference in the antisaccade task. These results indicate specific abnormalities of antisaccades in schizophrenics and patients with frontal cortical lesions but not consistently in Parkinsonian patients. This suggests that the abnormalities of antisaccades in schizophrenics might be explained by a frontal cortical dysfunction.

Induction Chemotherapy Followed by Low-Dose Involved-Field Radiotherapy for Intracranial Germ Cell Tumors

PURPOSE To investigate the efficacy of chemotherapy followed by low-dose involved-field radiotherapy for the treatment of intracranial germ cell tumors (GCTs). PATIENTS AND METHODS Thirty-three patients with GCTs, including 16 pure germinomas, 11 human chorionic gonadotropin-beta (HCG-beta)-secreting germinomas, three mixed GCTs composed of immature teratomas plus germinomas (IMT/G), and three highly malignant mixed GCTs, were treated. Etoposide and cisplatin (EP) were used for the treatment of solitary pure germinomas, and ifosfamide, cisplatin, and etoposide (ICE) were used for the treatment of other GCTs. The dose schedule was 24 Gy for germinomas and 40 to 54 Gy for other GCTs. An involved-field set-up was used except for highly malignant GCTs, in which craniospinal irradiation was used. The median follow-up was 58 months (range, 18 to 102 months). RESULTS Disease-related, overall, and relapse-free survival rates at 5 years were 100%, 93%, and 69% for all patients, 100%, 100%, and 86% for patients with pure germinomas, and 100%, 75%, and 44% for patients with HCG-beta-secreting germinomas, respectively. All six patients with nongerminomatous GCTs were alive at the last follow-up. All eight relapses (one pure germinoma, five HCG-beta-secreting germinomas, and two IMT/G), except one in a course of salvage treatment, were salvaged and free of disease at the last follow-up. No decline was observed in the full-scale, verbal, or performance intelligence quotient at 12 to 51 months after the treatment in 11 patients. CONCLUSION Our results support an excellent prognosis after EP and ICE regimens followed by radiotherapy. Dose and volume can be reduced to 24 Gy in 12 fractions and involve a field set-up after EP chemotherapy for the treatment of pure germinomas.