D. Verellen

Innovations in image-guided radiotherapy

The limited ability to control for the location of a tumour compromises the accuracy with which radiation can be delivered to tumour-bearing tissue. The resultant requirement for larger treatment volumes to accommodate target uncertainty restricts the radiation dose because more surrounding normal tissue is exposed. With image-guided radiotherapy (IGRT) these volumes can be optimized and tumoricidal doses can be delivered, achieving maximal tumour control with minimal complications. Moreover, with the ability of high-precision dose delivery and real-time knowledge of the target volume location, IGRT has initiated the exploration of new indications for radiotherapy, some of which were previously considered infeasible.

Quality assurance of a system for improved target localization and patient set-up that combines real-time infrared tracking and stereoscopic X-ray imaging

BACKGROUND AND PURPOSE The aim of this study is to investigate the positional accuracy of a prototype X-ray imaging tool in combination with a real-time infrared tracking device allowing automated patient set-up in three dimensions. MATERIAL AND METHODS A prototype X-ray imaging tool has been integrated with a commercially released real-time infrared tracking device. The system, consisting of two X-ray tubes mounted to the ceiling and a centrally located amorphous silicon detector has been developed for automated patient positioning from outside the treatment room prior to treatment. Two major functions are supported: (a) automated fusion of the actual treatment images with digitally reconstructed radiographs (DRRs) representing the desired position; (b) matching of implanted radio opaque markers. Measurements of known translational (up to 30.0mm) and rotational (up to 4.0 degrees ) set-up errors in three dimensions as well as hidden target tests have been performed on anthropomorphic phantoms. RESULTS The systems accuracy can be represented with the mean three-dimensional displacement vector, which yielded 0.6mm (with an overall SD of 0.9mm) for the fusion of DRRs and X-ray images. Average deviations between known translational errors and calculations varied from -0.3 to 0.6mm with a standard deviation in the range of 0.6-1.2mm. The marker matching algorithm yielded a three-dimensional uncertainty of 0.3mm (overall SD: 0.4mm), with averages ranging from 0.0 to 0.3mm and a standard deviation in the range between 0.3 and 0.4mm. CONCLUSIONS The stereoscopic X-ray imaging device integrated with the real-time infrared tracking device represents a positioning tool allowing for the geometrical accuracy that is required for conformal radiation therapy of abdominal and pelvic lesions, within an acceptable time-frame.

Risk assessment of radiation-induced malignancies based on whole-body equivalent dose estimates for IMRT treatment in the head and neck region

BACKGROUND AND PURPOSE Intensity modulated radiation therapy (IMRT) has been introduced in our department for treatment of the head and neck region with the intention of reducing complications without compromising treatment outcome. However, these new treatment modalities inevitably require a substantial increase in monitor units per target dose yielding an increased risk of secondary malignancies induced by the treatment. This study aims at assessing the increased risk by means of in vivo measurements of the whole-body equivalent dose of both the conventional and the IMRT treatment techniques for head and neck lesions. MATERIAL AND METHODS A conventional technique using parallel opposed, wedged treatment fields has been compared with a slice-by-slice arc rotation technique for IMRT. Both techniques were used to treat head and neck lesions with a 6-MV photon beam. Thermoluminescent badges and neutron bubble detectors designed for personnel monitoring have been applied to obtain the estimated whole-body equivalent dose on three patients for each treatment technique. The nominal probability coefficient for a lifetime risk of excess fatal cancer, recommended by the ICRP 60 has been used for risk estimates based on the estimated dose values. RESULTS An estimated whole-body equivalent dose per monitor unit equal to 1.2 x 10(-2) mSv/MU and 1.6 x 10(-2) mSv/MU have been obtained with the conventional and IMRT technique, respectively. Applying the average amount of MU necessary to realize a 70 Gy target dose the estimated whole-body equivalent dose for both treatment techniques becomes 242 mSv (conventional) and 1969 mSv (IMRT), yielding an increase in the risk for secondary malignancies with a factor 8. CONCLUSIONS Historically the risk of secondary malignancies has been accepted to take advantage of the possible benefits of improved local control and treatment outcome. However, the introduction of new and sophisticated treatment techniques will also increase the risk of radiation induced malignancies. Therefore, these risk estimates become important to assess whether the benefits of the treatment technique outweigh the possible risks.

The European Society of Therapeutic Radiology and Oncology-European Institute of Radiotherapy (ESTRO-EIR) report on 3D CT-based in-room image guidance systems: a practical and technical review and guide.

The past decade has provided many technological advances in radiotherapy. The European Institute of Radiotherapy (EIR) was established by the European Society of Therapeutic Radiology and Oncology (ESTRO) to provide current consensus statement with evidence-based and pragmatic guidelines on topics of practical relevance for radiation oncology. This report focuses primarily on 3D CT-based in-room image guidance (3DCT-IGRT) systems. It will provide an overview and current standing of 3DCT-IGRT systems addressing the rationale, objectives, principles, applications, and process pathways, both clinical and technical for treatment delivery and quality assurance. These are reviewed for four categories of solutions; kV CT and kV CBCT (cone-beam CT) as well as MV CT and MV CBCT. It will also provide a framework and checklist to consider the capability and functionality of these systems as well as the resources needed for implementation. Two different but typical clinical cases (tonsillar and prostate cancer) using 3DCT-IGRT are illustrated with workflow processes via feedback questionnaires from several large clinical centres currently utilizing these systems. The feedback from these clinical centres demonstrates a wide variability based on local practices. This report whilst comprehensive is not exhaustive as this area of development remains a very active field for research and development. However, it should serve as a practical guide and framework for all professional groups within the field, focussed on clinicians, physicists and radiation therapy technologists interested in IGRT.

Conformal Arc Radiotherapy for Prostate Cancer: Increased Biochemical Failure in Patients With Distended Rectum on the Planning Computed Tomogram Despite Image Guidance by Implanted Markers

PURPOSE To evaluate the effect of rectal distention on the planning computed tomogram on freedom from biochemical failure (FFBF) of prostate cancer patients treated with image-guided conformal arc radiotherapy. METHODS AND MATERIALS The outcomes of 238 patients with T1-T3N0M0 tumors were analyzed, with a median follow-up of 53 months (range, 24-93 months). In 213 patients, daily co-registration of X-rays and digitally reconstructed radiographs was used for positioning, whereas in 25 patients positioning was done using direct prostate visualization with implanted markers. The rectal average cross-sectional area was determined on the planning computed tomogram. RESULTS The 5-year freedom from Grade 3 to 4 late gastrointestinal and urinary side effect, according to the Radiation Therapy Oncology Group criteria, was 100% and 99.4% respectively. The 5-year FFBF was 88.4%. On multivariate analysis the following variables were significantly related to worse FFBF: risk group according to the National Comprehensive Cancer Network (high- to very high risk vs. intermediate- to low-risk), dose (70 vs. 78 Gy), average cross-sectional area (> or =16 vs. <16 cm(2)) and, unexpectedly, the use of implanted markers as opposed to bony structures for patient positioning. In retrospect, the margins around the clinical target volume appeared to be inadequate in the cases in which markers were used. CONCLUSION Overall, the outcome of patients treated with image-guided conformal arc radiotherapy is excellent. We were able to confirm the negative prognostic impact of a distended rectum on the planning computed tomogram described by others. The study illustrates the potential danger of image guidance techniques as to margin reduction around the clinical target volume.

Initial experience with intensity-modulated conformal radiation therapy for treatment of the head and neck region

PURPOSE The efficacy of a conventional, noninvasive fixation technique in combination with a commercially available system for conformal radiotherapy by intensity modulation of the treatment beam has been studied. METHODS AND MATERIALS A slice-by-slice arc-rotation approach was used to deliver a conformal dose to the target and patient fixation was performed by means of thermoplastic casts. Eleven patients have been treated, of which 9 were for tumors of the head and neck region and 2 were for intracranial lesions. A procedure for target localization and verification of patient positioning suitable for this particular treatment technique has been developed based on the superposition of digitized portals with plots generated from the treatment-planning system. A dosimetric verification of the treatment procedure was performed with an anthropomorphic phantom: both absolute dose measurements (alanine and thermoluminescent detectors) and relative dose distribution measurements (film dosimetry) have been applied. The dose delivered outside the target has also been investigated. RESULTS The dose verification with the anthropomorphic phantom yielded a ratio between measured and predicted dose values of 1.0 for different treatment schedules and the calculated dose distribution agreed with the measured dose distribution. Day-to-day variations in patient setup of 0.3 cm (translations) and 2.0 degrees (rotations) were considered acceptable for this particular patient population, whereas the verification protocol allowed detection of 0.1 cm translational errors and 1.0 rotational errors. CONCLUSIONS The noninvasive fixation technique in combination with an adapted verification protocol proved to be acceptable for conformal treatment of the head and neck region. Dose measurements, in turn, confirmed the predicted dose values to the target and organs at risk within uncertainty. Daily monitoring becomes mandatory if an accuracy superior to 0.1 cm and 1.0 degree is required for patient setup.

Electronic Portal Imaging with On-Line Correction of Setup Error in Thoracic Irradiation: Clinical Evaluation

PURPOSE To analyze setup errors and the feasibility of their on-line correction using electronic portal imaging in the irradiation of lung tumors. METHODS AND MATERIALS Sixteen patients with lung cancer were irradiated through opposed anteroposterior fields. Localization images of anteroposterior fields were recorded with an electronic portal imaging device (EPID). Using an in-house developed algorithm for on-line comparison of portal images setup errors were measured and a correction of table position was performed with a remote couch control prior to treatment. In addition, residual errors were measured on the EPID verification image. Global and individual mean and standard deviation of setup errors were calculated and compared. The feasibility of the procedure was assessed measuring intra- and interobserver variability, influence of organ movement, reproducibility of error measurement, the extra time fraction needed for measuring and adjusting and the fraction of dose needed for imaging. RESULTS In two setups the procedure could not be finished normally due to problems inherent to the procedure. The reproducibility, intraobserver variability, and influence of organ movements were each described by a distribution with a mean value less than or equal to 1 mm and a standard deviation (SD) of less than 1.5 mm. The interobserver variability showed to be a little bit larger (mean: 0.3 mm, SD: 1.7 mm). The mean time to perform the irradiation of the anteroposterior field was 4 +/- 1 min. The mean time for the measurement and correction procedure approximated 2.5 min. The mean extra time fraction was 65 +/- 24% (1 SD) with more than half of this coming from the error measurement. The dose needed for generation of EPID images was 5.9 +/- 1.4% of total treatment dose. The mean and SD of setup errors were, respectively, 0.1 and 4.5 mm for longitudinal and -2.0 and 5.7 mm for transversal errors. Of 196 measured translational errors 120 (61%) exceeded the adjustment criteria. For individual patients systematic and random setup errors can be as high as, respectively, 15.8 and 7.5 mm. Mean residual error and SD were for longitudinal direction 0.08 and 1.2 mm and for transversal direction -0.9 and 1.0 mm (pooled data). For individuals, the mean residual errors were smaller than 1 mm, with a typical SD per patient of less than 2 mm. CONCLUSION Setup errors in thoracic radiation therapy are clinically important. On-line correction can be performed accurately with an objective measurement tool, although this prolongs the irradiation procedure for one field with 65%.

Interactive use of on-line portal imaging in pelvic radiation.

We have evaluated a fluoroscopic on-line portal imaging system in routine clinical radiotherapy, involving the treatment of 566 pelvic fields on 13 patients. The image was typically generated by delivering a radiation dose of 6-8 cGy. Comparison between portal image and simulator film was done by eye and all visible errors were corrected before continuing irradiation. If possible, these corrections were performed from outside the treatment room by moving the patient couch by remote control or by changing collimator parameters. Adjustments were performed on 289/530 (54.5%) evaluable fields or 229/278 (82.4%) evaluable patient set-ups. The lateral couch position was most frequently adjusted (n = 254). The absolute values of the adjustments were 6.8 mm mean (SD 6.6 mm) with a maximum of 40 mm. All absolute values of adjustments exceeding 25 mm were recorded in one patient and those exceeding 15 mm were observed in two patients. Both patients were obese females. Adjustments exceeding 5 mm were observed in all 13 patients. Related to the use of on-line portal imaging, treatment time was increased by a median of 36.5% (mean 45.8%; SD 42.1%). The range was 7.7 to 442%. The fraction of the total treatment time to perform corrections was 22.7% median (mean: 26.0; SD: 11.8%). Statistically significant systematic in-plane errors were found in 7/13 patients. A systematic error was detected on the lateral position of the field in five patients. In one patient a systematic error of the longitudinal field position and in one patient a rotational error was detected. For adjustments in the lateral direction the present method does not allow to detect lateral shifts of less than 2 mm. For adjustments in the longitudinal direction the sensitivity could not be estimated but the available data suggest that 80% of errors < or = 5 mm were not adjusted. In obese patients, random errors may be surprisingly large.

Hypoxic tumor cell radiosensitization through nitric oxide

Hypoxia is a principal signature of the tumor microenvironment and is considered to be the most important cause of clinical radioresistance and local failure. Oxygen is so far the best radiosensitizer, but tumor oxygenation protocols are compromised by its metabolic consumption and therefore limited diffusion inside tumors. Many chemical radiosensitizers can selectively target hypoxic tumor cells, but their systemic toxicity compromises their adequate clinical use. NO is an efficient hypoxic radiosensitizer, as it may mimic the effects of oxygen on fixation of radiation-induced DNA damage, but the required levels cannot be obtained in vivo because of vasoactive complications. Our laboratory explored whether this problem may be overcome by endogenous production of NO inside tumors. We demonstrated that iNOS, activated by pro-inflammatory cytokines, is capable of radiosensitizing tumor cells through endogenous production of NO, at non-toxic extracellular concentrations. We observed that this radiosensitizing effect is transcriptionally controlled by hypoxia and by NF-kappaB. Tumor-associated immune cells may contribute to the iNOS-mediated radiosensitization by the generation of pro-inflammatory cytokines and NO, which may diffuse towards bystander tumor cells. Our findings indicate a rationale for combining immunostimulatory and radiosensitizing strategies in the future.

Initial clinical experience with infrared-reflecting skin markers in the positioning of patients treated by conformal radiotherapy for prostate cancer

PURPOSE To evaluate an infrared (IR) marker-based positioning system in patients receiving conformal radiotherapy for prostate cancer. METHODS AND MATERIALS During 553 treatments, the ability of the IR system to automatically position the isocenter was recorded. Setup errors were measured by means of orthogonal verification films and compared to conventional positioning (using skin drawings and lasers) in 184 treatments. RESULTS The standard deviation of anteroposterior (AP) and lateral setup errors was significantly reduced with IR marker positioning compared to conventional: 2 vs. 4.8 mm AP (p < 0.01) and 1.6 vs. 3.5 mm laterally (p < 0.01). Longitudinally, the difference was not significant (3.5 vs. 3.0 mm). Systematic errors were on the average smaller AP and laterally for the IR method: 4.1 vs. 7.8 mm AP (p = 0.01) and 3.1 vs. 5.6 mm lateral (p = 0.07). Longitudinally, the IR system resulted in somewhat larger systematic errors: 5.0 vs. 3.4 mm for conventional positioning (p = 0.03). The use of an off-line correction protocol, based on the average deviation measured over the first four fractions, allowed virtual elimination of systematic errors. Inability of the IR system to correctly locate the markers, leading to an executional failure, occurred in 21% of 553 fractions. CONCLUSION IR marker-assisted patient positioning significantly improves setup accuracy along the AP and lateral axes. Executional failures need to be reduced.