Dirk Van den Berge

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.

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.

Clinical use of stereoscopic X-ray positioning of patients treated with conformal radiotherapy for prostate cancer.

PURPOSE To evaluate accuracy and time requirements of a stereoscopic X-ray-based positioning system in patients receiving conformal radiotherapy to the prostate. METHODS AND MATERIALS Setup errors of the isocenter with regard to the bony pelvis were measured by means of orthogonal verification films and compared to conventional positioning (using skin drawings and lasers) and infrared marker (IR) based positioning in each of 261 treatments. In each direction, the random error represents the standard deviation and the systematic error the absolute value of the mean position. Time measurements were done in 75 treatments. RESULTS Random errors with the X-ray positioning system in the anteroposterior (AP), lateral, and longitudinal direction were (average +/- 1 standard deviation) 2 +/- 0.6 mm, 1.7 +/- 0.6 mm, and 2.4 +/- 0.7 mm. The corresponding values of conventional as well as IR positioning were significantly higher (p < 0.01). Systematic errors for X-ray positioning were 1.1 +/- 1.2 mm AP, 0.6 +/- 0.5 mm laterally, and 1.5 +/- 1.6 mm longitudinally. Conventional and IR marker-based positioning showed significantly larger systematic errors AP and laterally, but longitudinally, the difference was not significant. Depending on the axis looked at, errors of >or=5 mm occurred in 2%-14% of treatments after X-ray positioning, 13%-29% using IR markers, and 28%-53% with conventional positioning. Total linac time for one treatment session was 14 min 51 s +/- 4 min 18 s, half of which was used for the X-ray-assisted positioning procedure. CONCLUSION X-ray-assisted patient positioning significantly improves setup accuracy, at the cost of an increased treatment time.

Assessment of the uncertainties in dose delivery of a commercial system for linac-based stereotactic radiosurgery

PURPOSE Linac-based stereotactic radiosurgery (SRS) was introduced in our department in 1992, and since then, more than 200 patients have been treated with this method. An in-house-developed algorithm for target localization and dose calculation has recently been replaced with a commercially available system. In this study, both systems have been compared, and positional accuracy, as well as dose calculation, have been verified experimentally. METHODS AND MATERIALS The in-house-developed software for target localization and dose calculation is an extension to George Sherouses GRATIS(R) software for radiotherapy treatment planning, and has been replaced by a commercial (BrainSCAN version 3.1; BrainLAB, Germany) treatment planning system (TPS) for SRS. The positional accuracy for the entire SRS procedure (from image acquisition to treatment) has been investigated by treatment of simulated targets in the form of 0.2-cm lead beads inserted into an anthropomorphic phantom. Both dose calculation algorithms have been verified against manual calculations (based on basic beam data and CT data from phantom and patients), and measurements with the anthropomorphic phantom applying ionization chamber, thermoluminescent detectors, and radiographic film. This analysis has been performed on a variety of experimental situations, starting with static beams and simple one-arc treatments, to more complex and clinical relevant applications. Finally, 11 patients have been evaluated with both TPS in parallel for comparison and continuity of clinical experience. RESULTS Phantom studies evaluating the entire SRS procedure have shown that a target, localized by CT, can be irradiated with a positional accuracy of 0.08 cm in any direction with 95% confidence. Neglecting the influence of dose perturbation when the beam passes through bone tissue or air cavities, the calculated dose values obtained from both TPSs agreed within 1% (SD 1%) for phantom and patient studies. The application of a one-dimensional path length correction for tissue heterogeneity influences the treatment prescription 4% on average (SD 1%), which is in compliance with theoretical predictions. The phantom measurements confirmed the predicted dose at isocenter within uncertainty for the different treatment schedules in this study. CONCLUSION The full SRS procedure applied to an anthropomorphic phantom has been used as a comprehensive method to assess the uncertainties involved in dose delivery and target positioning. The results obtained with both TPSs are in agreement with AAPM Report 54, TG 42 and clinical continuity is assured. However, the use of a one-dimensional path length correction will result in an increase of 4% in dose prescription, which is slightly more than that predicted in the literature.

3D conformal intensity-modulated radiotherapy planning: interactive optimization by constrained matrix inversion.

BACKGROUND AND PURPOSE This paper presents a method for interactive optimization of 3D conformal intensity-modulated radiotherapy plans employing a quadratic objective that also contains dose limitations in the organs at risk. This objective function is minimized by constrained matrix inversion (CMI) that follows the same approach as the gradient technique using matrix notation. MATERIALS AND METHODS Sherouses GRATIS radiotherapy design system is used to determine the outlines of the target volume and the organs at risk and to input beam segments which are given by the beam segmentation technique. This technique defines the beam incidences and the beam segmentation. The weights of the segments are then calculated using a quadratic objective function and CMI. The objective function to be minimized consists of two components based on the planning target volume (PTV) and the organ at risk (OAR) with an importance factor w associated with the OAR. RESULTS Optimization is tested for concave targets in the head and neck region wrapping around the spinal cord. For a predefined w-value, segment weights are optimized within a few seconds on a DEC Alpha 3000. In practice, 5-10 w-values have to be tested, making optimization a less than 5 min procedure. This optimization procedure predicts the possibility of target dose escalation for a tumour in the lower neck to 120-150 Gy without exceeding the spinal cord tolerance, whereas human planners could not increase the dose above 65-80 Gy. CONCLUSIONS Treatment plans optimized using a quadratic objective function and the CMI algorithm are superior to those which are generated by human planners. The optimization algorithm is very fast and allows interactive use. Quadratic optimization by CMI is routinely used by clinicians at the Division of Radiotherapy, U.Z.-Gent.

Imaging in radiotherapy

Radiotherapy, more then any other treatment modality, relies heavily and often exclusively on medical imaging to determine the extent of disease and the spatial relation between target region and neighbouring healthy tissues. Radically new approaches to radiation delivery are inspired on CT scanning and treat patients in a slice-by-slice fashion using intensity modulated megavoltage fan beams. For quality assurance of complex 3-D dose distributions, MR based 3-D verificative dosimetry on irradiated phantoms has been described. As treatment delivery becomes increasingly refined, the need for accurate target definition increases as well and sophisticated imaging tools like image fusion and 3-D reconstruction are routinely used for treatment planning. While in the past patients were positioned on the treatment machines based exclusively on surface topography and the well-known skin marks, such approach is no longer sufficient for high-accuracy radiotherapy and special imaging tools like on-line portal imaging are used to verify and correct target positioning. Much of these applications rely on digital image processing, transmission and storage, and the development of standards, like DICOM and PACS have greatly contributed to these applications. Digital imaging plays an increasing role in many areas in radiotherapy and has been fundamental in new developments that have demonstrated impact on patient care.

Lipid a radiosensitizes hypoxic EMT-6 tumor cells: role of the NF-κB signaling pathway

PURPOSE Lipid A has shown promising immunostimulatory effects in both experimental tumor models and advanced stage cancer patients. This study examines whether lipid A may directly modulate the radioresponse of tumor cells by activating inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2) through nuclear factor-kappaB (NF-kappaB) signaling. METHODS AND MATERIALS Hypoxic EMT-6 tumor cells were exposed to lipid A and analyzed for the level of COX-2 and iNOS by Western blotting and enzymatic assays. The hypoxic radioresponse of EMT-6 cells was estimated by clonogenic survival. The activation of NF-kappaB was examined by immunostaining of its p65 subunit and by luciferase reporter gene assay. RESULTS Lipid A dose-dependently increased the expression and activity of iNOS with a maximal effect at plasma achievable concentrations of 3-30 micro g/mL. The COX-2 mediated production of prostaglandin E2 was constitutively high and further upregulated by lipid A. The radiosensitivity of hypoxic EMT-6 cells was increased up to 2.5 times and counteracted by the iNOS inhibitor aminoguanidine but not by the COX-2 inhibitor NS-398. The mechanism of radiosensitization was linked to NF-kappaB signaling, because its inhibition by phenylarsine oxide impaired both iNOS activation and radioresponse. CONCLUSION Lipid A is an efficient hypoxic cell radiosensitizer at plasma relevant concentrations, which provides a rationale to combine lipid A with radiotherapy in further studies.

IFN-γ+ CD8+ T Lymphocytes: Possible Link Between Immune and Radiation Responses in Tumor-Relevant Hypoxia

Activated T lymphocytes are known to kill tumor cells by triggering cytolytic mechanisms; however, their ability to enhance radiation responses remains unclear. This study examined the radiosensitizing potential of mouse CD8+ T cells, obtained by T-cell-tailored expansion and immunomagnetic purification. Activated CD8+ T cells displayed an interferon (IFN)-gamma+ phenotype and enhanced by 1.8-fold the radiosensitivity of EMT-6 tumor cells in 1% oxygen, which modeled tumor-relevant hypoxia. Radiosensitization was counteracted by neutralizing IFN-gamma or by blocking the inducible isoform of nitric oxide synthase, thus delineating the immune-tumor cell interaction through the IFN-gamma secretion pathway. Reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and fluorescence-activated cell sorter data in agreement detected downregulation of the IFN-gamma gene by hypoxia, which caused IFN-gamma deficiency next to radioresistance. Therefore, immune and radiation responses are likely to be allied in the hypoxic tumor microenvironment, and CD8+ T cells may bridge immunostimulatory and radiosensitizing strategies.

Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species.

Auranofin (AF) is an anti-arthritic drug considered for combined chemotherapy due to its ability to impair the redox homeostasis in tumor cells. In this study, we asked whether AF may in addition radiosensitize tumor cells by targeting thioredoxin reductase (TrxR), a critical enzyme in the antioxidant defense system operating through the reductive protein thioredoxin. Our principal findings in murine 4T1 and EMT6 tumor cells are that AF at 3–10 μM is a potent radiosensitizer in vitro, and that at least two mechanisms are involved in TrxR-mediated radiosensitization. The first one is linked to an oxidative stress, as scavenging of reactive oxygen species (ROS) by N-acetyl cysteine counteracted radiosensitization. We also observed a decrease in mitochondrial oxygen consumption with spared oxygen acting as a radiosensitizer under hypoxic conditions. Overall, radiosensitization was accompanied by ROS overproduction, mitochondrial dysfunction, DNA damage and apoptosis, a common mechanism underlying both cytotoxic and antitumor effects of AF. In tumor-bearing mice, a simultaneous disruption of the thioredoxin and glutathione systems by the combination of AF and buthionine sulfoximine was shown to significantly improve tumor radioresponse. In conclusion, our findings illuminate TrxR in cancer cells as an exploitable radiobiological target and warrant further validation of AF in combination with radiotherapy.

Microprocessor controlled limitation system for a stand-alone freely movable treatment couch.

Because of the capability of free movement in the treatment room, we recently introduced a Hercules treatment couch on one of our linear accelerators. One of the advantages of this couch is that it allows for a more flexible way of patient setup and that it can be moved entirely out of the way to enable treatment with a hospital bed. A disadvantage, however, is that the couch can hit a wall or a cover of the accelerator accidentally. A limitation system has been developed to protect both the table and the accelerator against such collisions.