Organ motion in image-guided radiotherapy: lessons from real-time tumor-tracking radiotherapy

External radiotherapy using imaging technology for patient setup is often called image-guided radiotherapy (IGRT). The most important problem to solve in IGRT is organ motion. Four-dimensional radiotherapy (4DRT), in which the accuracy of localization is improved – not only in space but also in time – in comparison to 3DRT, is required in IGRT. Real-time tumor-tracking radiotherapy (RTRT) has been shown to be feasible for performing 4DRT with the aid of a fiducial marker near the tumor. Lung, liver, prostate, spinal/paraspinal, gynecological, head and neck, esophagus, and pancreas tumors are now ready for dose escalation studies using RTRT.     

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.     

Detection of lung tumor movement in real-time tumor-tracking radiotherapy

PURPOSE: External radiotherapy for lung tumors requires reducing the uncertainty due to setup error and organ motion. We investigated the three-dimensional movement of lung tumors through an inserted internal marker using a real-time tumor-tracking system and evaluated the efficacy of this system at reducing the internal margin. METHODS AND MATERIALS: Four patients with lung cancer were analyzed. A 2.0-mm gold marker was inserted into the tumor. The real-time tumor-tracking system calculates and stores three-dimensional coordinates of the marker 30 times/s. The system can trigger the linear accelerator to irradiate the tumor only when the marker is located within the predetermined "permitted dislocation." The value was set at +/-1 to +/-3 mm according to the patient's characteristics. We analyzed 10,413-14,893 data sets for each of the 4 patients. The range of marker movement during normal breathing (beam-off period) was compared with that during gated irradiation (beam-on period) by Student's t test. RESULTS: The range of marker movement during the beam-off period was 5.5-10.0 mm in the lateral direction (x), 6.8-15.9 mm in the craniocaudal direction (y) and 8.1-14.6 mm in the ventrodorsal direction (z). The range during the beam-on period was reduced to within 5.3 mm in all directions in all 4 patients. A significant difference was found between the mean of the range during the beam-off period and the mean of the range during the beam-on period in the x (p = 0.007), y (p = 0.025), and z (p = 0.002) coordinates, respectively. CONCLUSION: The real-time tumor-tracking radiotherapy system was useful to analyze the movement of an internal marker. Treatment with megavoltage X-rays was properly given when the tumor marker moved into the "permitted dislocation" zone from the planned position.     

Conformal radiotherapy for brain tumors.

The technical improvements of three-dimensional conformal radiotherapy can decrease the toxicity of brain treatment to acceptable levels. The adoption of the technique by more centers would allow for the potential advantages of three-dimensional radiotherapy to be employed in a greater number of patients. Further studies evaluating the use of three-dimensional conformal radiotherapy in patients with nervous system neoplasms should focus on determining the effects on quality of life for the patient and survival compared with more standard treatment techniques.     

Histopathologic consideration of fiducial gold markers inserted for real-time tumor-tracking radiotherapy against lung cancer

PURPOSE: Internal fiducial gold markers, safely inserted with bronchoscopy, have been used in real-time tumor-tracking radiotherapy for lung cancer. We investigated the histopathologic findings at several points after the insertion of the gold markers. METHODS AND MATERIALS: Sixteen gold markers were inserted for preoperative marking in 7 patients who subsequently underwent partial resection of tumors by video-assisted thoracoscopic surgery within 7 days. RESULTS: Fibrotic changes and hyperplasia of type 2 pneumocytes around the markers were seen 5 or 7 days after insertion, and fibrin exudation without fibrosis was detected 1 or 2 days after insertion. CONCLUSIONS: Because fibroblastic changes start approximately 5 days after gold marker insertion, real-time tumor-tracking radiotherapy should be started >5 days after gold marker insertion.     

Intercepting radiotherapy using a real-time tumor-tracking radiotherapy system for highly selected patients with hepatocellular carcinoma unresectable with other modalities

PURPOSE: To assess the clinical outcome of intercepting radiotherapy, in which radiotherapy is delivered only when a tumor in motion enters a target area, using a real-time tumor-tracking radiotherapy (RTRT) system for patients with hepatocellular carcinoma who were untreatable with other modalities because the tumors were adjacent to crucial organs or located too deep beneath the skin surface. METHODS AND MATERIALS: Eighteen tumors, with a mean diameter of 36 mm, were studied in 15 patients. All tumors were treated on a hypofractionated schedule with a tight margin for setup and organ motion using a 2.0-mm fiducial marker in the liver and the RTRT system. The most commonly used dose of radiotherapy was 48 Gy in 8 fractions. Sixteen lesions were treated with a BED(10) of 60 Gy or more (median, 76.8 Gy). RESULTS: With a mean follow-up period of 20 months (range, 3-57 months), the overall survival rate was 39% at 2 years after RTRT. The 2-year local control rate was 83% for initial RTRT but was 92% after allowance for reirradiation using RTRT, with a Grade 3 transient gastric ulcer in 1 patient and Grade 3 transient increases of aspartate amino transaminase in 2 patients. CONCLUSIONS: Intercepting radiotherapy using RTRT provided effective focal high doses to liver tumors. Because the fiducial markers for RTRT need not be implanted into the tumor itself, RTRT can be applied to hepatocellular carcinoma in patients who are not candidates for other surgical or nonsurgical treatments.     

Daily targeting of intrahepatic tumors for radiotherapy.

INTRODUCTION: A system has been developed for daily targeting of intrahepatic tumors using a combination of ventilatory immobilization, in-room diagnostic imaging, and on-line setup adjustment. By reducing geometric position uncertainty, as well as organ movement, this system permits reduction of margins and thus potentially higher treatment doses. This paper reports our initial experience treating 8 patients with focal liver tumors using this system. METHODS AND MATERIALS: The system includes diagnostic X-ray tubes mounted on the wall and ceiling of a treatment room, an active matrix flat panel imager, in-room control for image acquisition and setup adjustment, and a ventilatory immobilization system via active breathing control (ABC). Eight patients participated in the study, two using an early prototype ABC unit, and the remaining six with a commercial ABC system and improved setup measurement tools. Treatment margins were reduced, and dose consequently increased because of increased confidence in target position under this protocol. After daily setup via skin marks, orthogonal radiographs were acquired at suspended ventilation. The images were aligned to the CT model using the diaphragm for inferior-superior (IS) alignment, and the skeleton for left-right (LR) and anterior-posterior (AP) alignment. Adjustments were made for positioning errors greater than a threshold (3 or 5 mm). After treatment, retrospective analysis determined the final setup accuracy, as well as the error in initial setup measurement performed before setup adjustment. RESULTS: Two hundred sixty-two treatment fractions were delivered on eight patients, with 171 treatments requiring repositioning. Typical treatment times were 25-30 min. Patients were able to tolerate ABC throughout the course of treatment. Breath holds up to 35 s long were used for treatment. The use of on-line imaging and setup adjustment reduced setup errors (sigma) from 4.0 mm (LR), 6.7 mm (IS), and 3.8 mm (AP) to 2.1 mm (LR), 3.5 mm (IS), and 2.3 mm (AP). Prescribed doses were increased using this system by an average of 5 Gy. CONCLUSIONS: Daily targeting of intrahepatic targets has been demonstrated to be feasible. The potential for reduction in treatment margin and consequential safe dose escalation has been demonstrated, while maintaining reasonable treatment delivery times.     

Palliative radiotherapy for symptomatic adrenal metastases

To evaluate the role of palliative radiotherapy for adrenal metastases, a retrospective review was performed on 16 patients treated between 1972 and 1988 for palliation of symptomatic adrenal metastases. The median patient age was 56 years. In 15 cases lung cancer was the primary site (7 adenocarcinomas, 3 squamous cell carcinomas, 3 large cell carcinomas, and 2 small cell carcinomas) and in 1 case there was an unknown primary (squamous cell carcinoma). Ten of 16 patients were treated with 3000 cGy to opposed anterior and posterior fields (300-cGy fractions [four patients] and 250-cGy fractions [six patients]). The remaining six patients were treated with a variety of techniques, with total doses ranging from 2925 cGy to 4500 cGy. The patients were analyzed for response at their first follow-up visit (2 to 4 weeks after treatment). The overall response rate was 75% (12 of 16 patients). Six patients (38%) had complete pain relief without medication that lasted until death. Two patients had marked pain relief, but still required analgesics. Four patients had marked or moderate pain relief that did not continue through follow-up. Four patients had minimal to no response. All patients were observed until death, with a median survival time after irradiation of 3 months (range, 0.5 to 11 months). Although the prognosis for patients with adrenal metastases is poor, radiotherapy to symptomatic adrenal metastases can be administered with a high probability of achieving effective palliation.     

Feasibility of synchronization of real-time tumor-tracking radiotherapy and intensity-modulated radiotherapy from viewpoint of excessive dose from fluoroscopy

PURPOSE: Synchronization of the techniques in real-time tumor-tracking radiotherapy (RTRT) and intensity-modulated RT (IMRT) is expected to be useful for the treatment of tumors in motion. Our goal was to estimate the feasibility of the synchronization from the viewpoint of excessive dose resulting from the use of fluoroscopy. METHODS AND MATERIALS: Using an ionization chamber for diagnostic X-rays, we measured the air kerma rate, surface dose with backscatter, and dose distribution in depth in a solid phantom from a fluoroscopic RTRT system. A nominal 50-120 kilovoltage peak (kVp) of X-ray energy and a nominal 1-4 ms of pulse width were used in the measurements. RESULTS: The mean +/- SD air kerma rate from one fluoroscope was 238.8 +/- 0.54 mGy/h for a nominal pulse width of 2.0 ms and nominal 100 kVp of X-ray energy at the isocenter of the linear accelerator. The air kerma rate increased steeply with the increase in the X-ray beam energy. The surface dose was 28-980 mGy/h. The absorbed dose at a 5.0-cm depth in the phantom was 37-58% of the peak dose. The estimated skin surface dose from one fluoroscope in RTRT was 29-1182 mGy/h and was strongly dependent on the kilovoltage peak and pulse width of the fluoroscope and slightly dependent on the distance between the skin and isocenter. CONCLUSION: The skin surface dose and absorbed depth dose resulting from fluoroscopy during RTRT can be significant if RTRT is synchronized with IMRT using a multileaf collimator. Precise estimation of the absorbed dose from fluoroscopy during RT and approaches to reduce the amount of exposure are mandatory.     

Real-time tumor-tracking radiation therapy for lung carcinoma by the aid of insertion of a gold marker using bronchofiberscopy

BACKGROUND: The authors developed fluoroscopic real-time tumor-tracking radiation therapy (RTRT) by insertion of a gold marker using bronchofiberscopy to reduce uncertainties in organ motion and set-up error in external radiotherapy for moving tumors. The purpose of the current study was to evaluate RTRT's feasibility in lung carcinoma treatment. METHODS: The three-dimensional position of a 1.0-2.0 mm gold marker in or near the tumor was detected by two sets of fluoroscopies every 0.03 seconds. The treatment beam was gated to irradiate the tumor only when the position of the marker coincided with its planned position using the RTRT system. Bronchofiberscopic equipment for insertion of the marker into the lung tumor was developed and used for 20 lung tumors in 18 patients. Patients were given high dose hypofractionated focal irradiation (35-48 Gy in 4-8 fractions in 4-10 days) with a planning target volume margin of 5 mm for the tumor. RESULTS: The markers were successfully inserted and maintained at the inserted position during and after the radiotherapy in 14 (88%) of 16 peripheral-type lung tumors and in none of four central-type lung tumors, indicating that this method of RTRT was not feasible for central-type lung tumors. Tracking of the marker was successfully performed in 1 of 2 tumors with a 1.0 mm marker and in all of 12 tumors with a 1.5-2.0 mm marker. On the whole, 13 (65%) of the 20 tumors were successfully treated with RTRT. Local tumor control was achieved and maintained for all 12 patients (13 tumors), who were treated with RTRT, with a median followup of 9 months (range, 5-15). Localized radiation pneumonitis was found radiographically at the lung volume that was irradiated with about 20 Gy, without symptoms in all but one patient. CONCLUSIONS: The insertion of a gold marker into or near peripheral-type lung tumors using bronchofiberscopy is a feasible and safe technique. Excellent initial response and low incidence of clinical complications suggest that the high dose hypofractionated focal irradiation using the RTRT system can be a good local treatment for peripheral-type lung tumors.     

Steep dose-response relationship for stage I non-small-cell lung cancer using hypofractionated high-dose irradiation by real-time tumor-tracking radiotherapy

PURPOSE: To investigate the clinical outcomes of patients with pathologically proven, peripherally located, Stage I non-small-cell lung cancer who had undergone stereotactic body radiotherapy using real-time tumor tracking radiotherapy during the developmental period. METHODS AND MATERIALS: A total of 41 patients (25 with Stage T1 and 16 with Stage T2) were admitted to the study between February 2000 and June 2005. A 5-mm planning target volume margin was added to the clinical target volume determined with computed tomography at the end of the expiratory phase. The gating window ranged from +/-2 to 3 mm. The dose fractionation schedule was 40 or 48 Gy in four fractions within 1 week. The dose was prescribed at the center of the planning target volume, giving more than an 80% dose at the planning target volume periphery. RESULTS: For 28 patients treated with 48 Gy in four fractions, the overall actuarial survival rate at 3 years was 82% for those with Stage IA and 32% for those with Stage IB. For patients treated with 40 Gy in four fractions within 1 week, the overall actuarial survival rate at 3 years was 50% for those with Stage IA and 0% for those with Stage IB. A significant difference was found in local control between those with Stage IB who received 40 Gy vs. 48 Gy (p = 0.0015) but not in those with Stage IA (p = 0.5811). No serious radiation morbidity was observed with either dose schedule. CONCLUSION: The results of our study have shown that 48 Gy in four fractions within 1 week is a safe and effective treatment for peripherally located, Stage IA non-small-cell lung cancer. A steep dose-response curve between 40 and 48 Gy using a daily dose of 12 Gy delivered within 1 week was identified for Stage IB non-small-cell lung cancer in stereotactic body radiotherapy using real-time tumor tracking radiotherapy.     

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.     

肾上腺转移癌的立体定向放射治疗

目的探讨立体定向放射治疗肾上腺转移癌的临床可行性与近期疗效。方法采用OUR-QGD型立体定向体部伽玛射线放射治疗系统,治疗肾上腺转移癌43例,根据肿瘤的位置、临床靶体积、患者的身体状况与治疗目的,制定放疗计划及调整剂量分布。肿瘤体积7~1362 cm3,等剂量曲线50%~80%,周边照射总剂量3100~3600 cGy,分割处方剂量400~600 cGy,重复治疗6~9次,隔日治疗。结果治疗前腰背部疼痛28例,治疗结束后1~6个月,症状完全消失16例(57.1%),部分缓解10例(35.7%),2例无效(7.1%),疼痛缓解有效率为92.9%;43例肾上腺转移癌,共53个治疗病灶,治疗后3个月复查CT、MR或PET,肿瘤消失17例(32.1%),缩小27例(50.9%),无变化7例(13.2%),增大2例(3.8%),总有效率96.2%。结论立体定向放射治疗肾上腺转移癌临床效果确切,不良反应较轻。     

Conformal three-dimensional photon radiotherapy for paranasal sinus tumors.

BACKGROUND: Tumors in the nasal cavity and paranasal sinus are difficult to treat with radiotherapy. Usually, in addition to a two- or three-field photon technique, an interorbital electron field is required. This may result, however, in severe over- or underdosage, the latter being especially detrimental when occurring in the main tumor bulk. METHODS AND RESULTS: We present a conformal three-dimensional treatment technique that provides sufficient interorbital dose with photons only while sparing the eyes, optic nerves and chiasm, and may be considered for selected tumors in this region.     

Postoperative radiotherapy for malignant tumors of the submandibular gland.

PURPOSE: This retrospective study assessed the outcome and patterns of failure for patients with malignant submandibular tumors treated with surgery and postoperative radiation. METHODS AND MATERIALS: Between 1965 and 1995, 83 patients aged 11-83 years old received postoperative radiotherapy after resection of submandibular gland carcinomas. The most common radiation technique was an appositional field to the submandibular gland bed using electrons either alone or mixed with photons. Primary tumor bed doses ranged from 50 to 69 Gy (median, 60 Gy). Regional lymph nodes (ipsilateral Levels I-IV) were irradiated in 66 patients to a median dose of 50 Gy. Follow-up time ranged from 5 to 321 months (median, 82 months). RESULTS: Actuarial locoregional control rates were 90%, 88%, and 88% at 2, 5, and 10 years, respectively. The corresponding disease-free survival rates were 76%, 60%, and 53%, because 27 of 74 patients (36%) who attained locoregional control developed distant metastases. Adenocarcinoma, high-grade histology, and treatment during the earlier years of the study were associated with worse locoregional control and disease-free survival. The median survival times for patients with and without locoregional control were 183 months and 19 months, respectively. Actuarial 2-, 5-, and 10-year survival rates were 84%, 71%, and 55%, respectively. Late complications occurred in 8 patients (osteoradionecrosis, 5 patients). CONCLUSIONS: High-risk cancers of the submandibular gland have a historic control rate of approximately 50% when treated with surgery alone. In the current series, locoregional control rates for high-risk patients with submandibular gland cancers treated with surgery and postoperative radiotherapy were excellent, with an actuarial locoregional control rate of 88% at 10 years.     

Charged particle radiotherapy of paraspinal tumors.

Between 1976 and 1987, 52 patients with tumors adjacent to and/or involving the cervical, thoracic, or lumbar spinal cord were treated with charged particles at the University of California Lawrence Berkeley Laboratory. The histologies included chordoma and chondrosarcoma (24 pts), other bone and soft tissue sarcoma (14 pts), and metastatic or unusual histology tumors (14 pts). Radiation doses ranged from 29 to 80 Gray-equivalent (GyE), with a median dose of 70 GyE. Twenty-one patients received a portion of their treatment with photons. Median followup was 28 months. For 36 previously untreated patients, local control was achieved in 21/36 patients and the 3-year actuarial survival was 61%. Of 16 patients treated for recurrent disease, 7/16 were locally controlled and the 3-year actuarial survival was 51%. For patients treated for chordoma and chondrosarcoma, probability of local control was influenced by tumor volume (less than 100 cc or greater than 150 cc) and whether disease was recurrent or previously untreated. Complications occurred in 6/52 patients, including one spinal cord injury, one cauda equina and one brachial plexus injury, and three instances of skin or subcutaneous fibrosis. Charged particle radiotherapy can safely deliver high tumor doses to paraspinal tumors with good local control.     

Three-dimensional intrafractional movement of prostate measured during real-time tumor-tracking radiotherapy in supine and prone treatment positions

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.

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.

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.

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.     

Basal-cell tumors of the lumbar skin after radiotherapy for arthrosis.

Twenty-three cases of basal-cell tumor of the skin arising in the lumbar-sacral region after repeated irradiations in anti-inflammatory doses for arthrosis are discussed. The involved cutaneous region had been submitted to a number of roentgenotherapy cycles, varying from a minimum of 2 to a maximum of 10. The total dose absorbed at skin level varied between 14.4 and 72.0 Gy, administered over 2 to 6 years. Thirteen to 30 years (median, 19) had elapsed since the end of the irradiations. This observation compels a critical re-evaluation to be made concerning certain radiotherapy indications. The treatment of these lesions involves some problems: radiotherapy is made difficult by the coexistence of often serious dystrophic lesions on the surrounding skin, and surgery is often unsuccessful. The topic application of 5-fluorouracil ointment seems to achieve good results.