B.J.M. Heijmen

Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study

The feasibility, toxicity and tumor response of stereotactic body radiation therapy (SBRT) for treatment of primary and metastastic liver tumors was investigated. From October 2002 until June 2006, 25 patients not suitable for other local treatments were entered in the study. In total 45 lesions were treated, 34 metastases and 11 hepatocellular carcinoma (HCC). Median follow-up was 12.9 months (range 0.5–31). Median lesion size was 3.2 cm (range 0.5–7.2) and median volume 22.2 cm3 (range 1.1–322). Patients with metastases, HCC without cirrhosis, and HCC < 4 cm with cirrhosis were mostly treated with 3×12.5 Gy. Patients with HCC ≥4cm and cirrhosis received 5×5 Gy or 3×10 Gy. The prescription isodose was 65%. Acute toxicity was scored following the Common Toxicity Criteria and late toxicity with the SOMA/LENT classification. Local failures were observed in two HCC and two metastases. Local control rates at 1 and 2 years for the whole group were 94% and 82%. Acute toxicity grade ≥3 was seen in four patients; one HCC patient with Child B developed a liver failure together with an infection and died (grade 5), two metastases patients presented elevation of gamma glutamyl transferase (grade 3) and another asthenia (grade 3). Late toxicity was observed in one metastases patient who developed a portal hypertension syndrome with melena (grade 3). SBRT was feasible, with acceptable toxicity and encouraging local control. Optimal dose-fractionation schemes for HCC with cirrhosis have to be found. Extreme caution should be used for patients with Child B because of a high toxicity risk.

Clinical accuracy of the respiratory tumor tracking system of the cyberknife: assessment by analysis of log files.

PURPOSE To quantify the clinical accuracy of the respiratory motion tracking system of the CyberKnife treatment device. METHODS AND MATERIALS Data in log files of 44 lung cancer patients treated with tumor tracking were analyzed. Errors in the correlation model, which relates the internal target motion with the external breathing motion, were quantified. The correlation model error was compared with the geometric error obtained when no respiratory tracking was used. Errors in the prediction method were calculated by subtracting the predicted position from the actual measured position after 192.5 ms (the time lag to prediction in our current system). The prediction error was also measured for a time lag of 115 ms and a new prediction method. RESULTS The mean correlation model errors were less than 0.3 mm. Standard deviations describing intrafraction variations around the whole-fraction mean error were 0.2 to 1.9 mm for cranio-caudal, 0.1 to 1.9 mm for left-right, and 0.2 to 2.5 mm for anterior-posterior directions. Without the use of respiratory tracking, these variations would have been 0.2 to 8.1 mm, 0.2 to 5.5 mm, and 0.2 to 4.4 mm. The overall mean prediction error was small (0.0 +/- 0.0 mm) for all directions. The intrafraction standard deviation ranged from 0.0 to 2.9 mm for a time delay of 192.5 ms but was halved by using the new prediction method. CONCLUSIONS Analyses of the log files of real clinical cases have shown that the geometric error caused by respiratory motion is substantially reduced by the application of respiratory motion tracking.

Accuracy of tumor motion compensation algorithm from a robotic respiratory tracking system: a simulation study.

The Synchrony Respiratory Tracking System (RTS) is a treatment option of the CyberKnife robotic treatment device to irradiate extra-cranial tumors that move due to respiration. Advantages of RTS are that patients can breath normally and that there is no loss of linac duty cycle such as with gated therapy. Tracking is based on a measured correspondence model (linear or polynomial) between internal tumor motion and external (chest/abdominal) marker motion. The radiation beam follows the tumor movement via the continuously measured external marker motion. To establish the correspondence model at the start of treatment, the 3D internal tumor position is determined at 15 discrete time points by automatic detection of implanted gold fiducials in two orthogonal x-ray images; simultaneously, the positions of the external markers are measured. During the treatment, the relationship between internal and external marker positions is continuously accounted for and is regularly checked and updated. Here we use computer simulations based on continuously and simultaneously recorded internal and external marker positions to investigate the effectiveness of tumor tracking by the RTS. The Cyberknife does not allow continuous acquisition of x-ray images to follow the moving internal markers (typical imaging frequency is once per minute). Therefore, for the simulations, we have used data for eight lung cancer patients treated with respiratory gating. All of these patients had simultaneous and continuous recordings of both internal tumor motion and external abdominal motion. The available continuous relationship between internal and external markers for these patients allowed investigation of the consequences of the lower acquisition frequency of the RTS. With the use of the RTS, simulated treatment errors due to breathing motion were reduced largely and consistently over treatment time for all studied patients. A considerable part of the maximum reduction in treatment error could already be reached with a simple linear model. In case of hysteresis, a polynomial model added some extra reduction. More frequent updating of the correspondence model resulted in slightly smaller errors only for the few recordings with a time trend that was fast, relative to the current x-ray update frequency. In general, the simulations suggest that the applied combined use of internal and external markers allow the robot to accurately follow tumor motion even in the case of irregularities in breathing patterns.

Acute morbidity reduction using 3DCRT for prostate carcinoma : A randomized study

PURPOSE To study the effects on gastrointestinal and urological acute morbidity, a randomized toxicity study, comparing conventional and three-dimensional conformal radiotherapy (3DCRT) for prostate carcinoma was performed. To reveal possible volume effects, related to the observed toxicity, dose-volume histograms (DVHs) were used. METHODS AND MATERIALS From June 1994 to March 1996, 266 patients with prostate carcinoma, stage T1-4N0M0 were enrolled in the study. All patients were treated to a dose of 66 Gy (ICRU), using the same planning procedure, treatment technique, linear accelerator, and portal imaging procedure. However, patients in the conventional treatment arm were treated with rectangular, open fields, whereas conformal radiotherapy was performed with conformally shaped fields using a multileaf collimator. All treatment plans were made with a 3D planning system. The planning target volume (PTV) was defined to be the gross target volume (GTV) + 15 mm. Acute toxicity was evaluated using the EORTC/RTOG morbidity scoring system. RESULTS Patient and tumor characteristics were equally distributed between both study groups. The maximum toxicity was 57% grade 1 and 26% grade 2 gastrointestinal toxicity; 47% grade 1, 17% grade 2, and 2% grade > 2 urological toxicity. Comparing both study arms, a reduction in gastrointestinal toxicity was observed (32% and 19% grade 2 toxicity for conformal and conventional radiotherapy, respectively; p = 0.02). Further analysis revealed a marked reduction in medication for anal symptoms: this accounts for a large part of the statistical difference in gastrointestinal toxicity (18% vs. 14% [p = ns] grade 2 rectum/sigmoid toxicity and 16% vs. 8% [p < 0.0001] grade 2 anal toxicity for conventional and conformal radiotherapy, respectively). A strong correlation between exposure of the anus and anal toxicity was found, which explained the difference in anal toxicity between both study arms. No difference in urological toxicity between both treatment arms was found, despite a relatively large difference in bladder DVHs. CONCLUSIONS The reduction in gastrointestinal morbidity was mainly accounted for by reduced toxicity for anal symptoms using 3DCRT. The study did not show a statistically significant reduction in acute rectum/sigmoid and bladder toxicity.

Portal dose measurement in radiotherapy using an electronic portal imaging device (EPID)

Physical characteristics of a commercially available electronic portal imaging device (EPID), relevant to dosimetric applications in high-energy photon beams, have been investigated. The EPID basically consists of a fluorescent screen, mirrors and a CCD camera. Image acquisition for portal dose measurement has been performed with a special procedure, written in the command language that comes with the system. The observed day-to-day variation in local EPID responses, i.e. measured grey scale value (EPID signal) per unit of delivered portal dose, is 0.4% (1 SD); day-to-day variation in relative EPID responses (e.g. normalized to the on-axis response) are within 0.2% (1 SD). Measured grey scale values are linearly proportional to transmitted portal doses with a proportionality constant which is independent of the thickness of a flat, water-equivalent absorber in the beam, but which does significantly depend on the size of the applied x-ray beam. It is shown that the observed increased in EPID response with increasing field size is mainly due to contributions to the EPID signals from scattered light: visible photons produced by the x-ray beam in a point of the fluorescent screen not only generate a grey scale value in the corresponding point of the EPID image, but also lead (due to scatter from components of the EPID structure onto the CCD chip) to an increased grey scale value at all other points of the image. A point spread function, derived from measured data and describing the increase in EPID response at the beam axis due to off-axis irradiation of the fluorescent screen, has been successfully applied to connect portal doses with grey scale values measured with the EPID.

Ischemic heart disease after mantlefield irradiation for Hodgkin's disease in long-term follow-up

BACKGROUND AND PURPOSE In patients with Hodgkins disease treated by radiotherapy with a moderate total dose and a low (mean) fraction dose to the heart, the risk of ischemic heart disease was investigated during long-term follow-up. MATERIALS AND METHODS The medical records of 258 patients treated in the period 1965-1980 with radiotherapy alone as the primary treatment were reviewed. The median follow-up was 14.2 years (range 0.7-26.2). The mean total dose and fraction dose to the heart were 37.2 Gy (SD 2.9) and 1.64 Gy (SD 0.09), respectively. The impact on the development of ischemic heart disease of treatment-related parameters, such as the applied (fraction) dose, irradiation technique (one or two fields per day), and chemotherapy in case of a relapse, was investigated. The incidence of ischemic heart disease in this patient population was compared with the expected incidence based on gender, age and calendar period-specific data for the Dutch population. RESULTS Thirty-one patients (12%) experienced ischemic heart disease (actuarial risk at 20-25 years: 21.2% (95% C.I. 15-30). Twenty-five of them were hospitalized. When compared with the expected incidence, the relative risk (RR) of hospital admission for ischemic heart disease was 2.7 (95% C.I. 1.7-4.0). There were 12 deaths (4.7%) due to ischemic myocardial or sudden death (actuarial risk at 25 years: 10.2% (95% C.I. 5.3-19), compared to 2.3 cases that were expected to have died from these causes, yielding a standardized mortality ratio (SMR) of 5.3 (95% C.I. 2.7-9.3). Gender (male), pretreatment cardiac medical history and increasing age appeared to be the only significant factors for the development of ischemic heart disease. CONCLUSIONS Despite the moderate total dose and the low (mean) fraction dose to the heart, the observed incidence of ischemic heart disease is high, especially after long follow-up periods. Treatment related cardiac disease in patients treated for Hodgkins disease has only been reported for doses above 30 Gy. Although the optimum curative dose is still under debate, some studies recommend a dose as low as 32.5 Gy. The observed high rate of severe heart complications in this study advocates a dose reduction to this level, particularly in the regions where the coronary arteries are located.

iCycle: Integrated, multicriterial beam angle, and profile optimization for generation of coplanar and noncoplanar IMRT plans

PURPOSE To introduce iCycle, a novel algorithm for integrated, multicriterial optimization of beam angles, and intensity modulated radiotherapy (IMRT) profiles. METHODS A multicriterial plan optimization with iCycle is based on a prescription called wish-list, containing hard constraints and objectives with ascribed priorities. Priorities are ordinal parameters used for relative importance ranking of the objectives. The higher an objective priority is, the higher the probability that the corresponding objective will be met. Beam directions are selected from an input set of candidate directions. Input sets can be restricted, e.g., to allow only generation of coplanar plans, or to avoid collisions between patient/couch and the gantry in a noncoplanar setup. Obtaining clinically feasible calculation times was an important design criterium for development of iCycle. This could be realized by sequentially adding beams to the treatment plan in an iterative procedure. Each iteration loop starts with selection of the optimal direction to be added. Then, a Pareto-optimal IMRT plan is generated for the (fixed) beam setup that includes all so far selected directions, using a previously published algorithm for multicriterial optimization of fluence profiles for a fixed beam arrangement Breedveld et al. [Phys. Med. Biol. 54, 7199-7209 (2009)]. To select the next direction, each not yet selected candidate direction is temporarily added to the plan and an optimization problem, derived from the Lagrangian obtained from the just performed optimization for establishing the Pareto-optimal plan, is solved. For each patient, a single one-beam, two-beam, three-beam, etc. Pareto-optimal plan is generated until addition of beams does no longer result in significant plan quality improvement. Plan generation with iCycle is fully automated. RESULTS Performance and characteristics of iCycle are demonstrated by generating plans for a maxillary sinus case, a cervical cancer patient, and a liver patient treated with SBRT. Plans generated with beam angle optimization did better meet the clinical goals than equiangular or manually selected configurations. For the maxillary sinus and liver cases, significant improvements for noncoplanar setups were seen. The cervix case showed that also in IMRT with coplanar setups, beam angle optimization with iCycle may improve plan quality. Computation times for coplanar plans were around 1-2 h and for noncoplanar plans 4-7 h, depending on the number of beams and the complexity of the site. CONCLUSIONS Integrated beam angle and profile optimization with iCycle may result in significant improvements in treatment plan quality. Due to automation, the plan generation workload is minimal. Clinical application has started.

Dosimetric verification of intensity modulated beams produced with dynamic multileaf collimation using an electronic portal imaging device.

Dose distributions can often be significantly improved by modulating the two-dimensional intensity profile of the individual x-ray beams. One technique for delivering intensity modulated beams is dynamic multileaf collimation (DMLC). However, DMLC is complex and requires extensive quality assurance. In this paper a new method is presented for a pretreatment dosimetric verification of these intensity modulated beams utilizing a charge-coupled devicecamera based fluoroscopic electronic portal imaging device(EPID). In the absence of the patient, EPIDimages are acquired for all beams produced with DMLC. These images are then converted into two-dimensional dose distributions and compared with the calculated dose distributions. The calculations are performed with a pencil beam algorithm as implemented in a commercially available treatment planning system using the same absolute beam fluence profiles as used for calculation of the patient dose distribution. The method allows an overall verification of (i) the leaf trajectory calculation (including the models to incorporate collimator scatter and leaf transmission), (ii) the correct transfer of the leaf sequencing file to the treatment machine, and (iii) the mechanical and dosimetrical performance of the treatment unit. The method was tested for intensity modulated 10 and 25 MV photon beams; both model cases and real clinical cases were studied. Dose profiles measured with the EPID were also compared with ionization chamber measurements. In all cases both predictions and EPID measurements and EPID and ionization chamber measurements agreed within 2% (1σ). The study has demonstrated that the proposed method allows fast and accurate pretreatment verification of DMLC.

Stereotactic body radiation therapy for colorectal liver metastases

Stereotactic body radiation therapy (SBRT) is a treatment option for colorectal liver metastases. Local control, patient survival and toxicity were assessed in an experience of SBRT for colorectal liver metastases.

Analysis and reduction of 3D systematic and random setup errors during the simulation and treatment of lung cancer patients with CT-based external beam radiotherapy dose planning

PURPOSE To determine the magnitude of the errors made in (a) the setup of patients with lung cancer on the simulator relative to their intended setup with respect to the planned treatment beams and (b) in the setup of these patients on the treatment unit. To investigate how the systematic component of the latter errors can be reduced with an off-line decision protocol for setup corrections. METHODS AND MATERIALS For 39 patients with CT planning, digitally-reconstructed radiographs (DRRs) were calculated for anterior-posterior and lateral beams. Retrospectively, the position of the visible anatomy relative to the planned isocenter was compared with the corresponding position on the digitized simulator radiographs using contour match software. The setup accuracy at the treatment unit relative to the simulator setup was measured for 40 patients for at least 5 fractions per patient in 2 orthogonal beams with the aid of an electronic portal imaging device (EPID). Setup corrections were applied, based on an off-line decision protocol, with parameters derived from knowledge of the random setup errors in the studied patient group. RESULTS The standard deviations (SD) of the simulator setup errors relative to the CT planning setup in the lateral, longitudinal, and anterior-posterior directions were 4.0, 2.8, and 2.5 mm, respectively. The SD of rotations around the anterior-posterior axis was 1.6 degrees and around the left-right axis 1.3 degrees. The setup error at the treatment unit had a small random component in all three directions (1 SD = 2 mm). The systematic components were larger, particularly in the longitudinal direction (1 SD = 3.6 mm), but were reduced with the decision protocol to 1 SD < 2 mm with, on average, 0.6 setup correction per patient. CONCLUSION Setup errors at the simulator, which become systematic errors if the simulation defines the reference setup, were comparable to the systematic setup errors at the treatment unit in case no off-line protocol would have been applied. Hence, the omission of a separate simulation step can reduce systematic errors as efficiently as the application of an off-line correction protocol during treatment. The random errors were sufficiently small to make an off-line protocol feasible.