Dietmar Georg

Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer

Background To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT) ± chemotherapy (ChT). Methods Treatment schedule was EBRT with 45–50.4 Gy ± concomitant cisplatin chemotherapy plus 4 × 7 Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90 > 85 Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75 Gy for rectum and sigmoid and 90 Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. Findings One hundred and fifty-six consecutive patients (median age 58 years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5 cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42 months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93 ± 13 Gy, D2cc 86 ± 17 Gy for bladder, 65 ± 9 Gy for rectum and 64 ± 9 Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3 years was 95%; 98% for tumours 2–5 cm, and 92% for tumours >5 cm (p = 0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3 years was overall 74%, 83% for tumours 2–5 cm, 70% for tumours >5 cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3 years was in total 68%, 72% for tumours 2–5 cm, 65% for tumours >5 cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1 + 2 and 11 grade 3 + 4 late events were observed in 143 patients. G1 + 2/G3 + 4 events for bladder were n = 32/3, for rectum n = 14/5, for bowel (including sigmoid) n = 3/0, for vagina n = 128/2, respectively. Interpretation 3D conformal radiotherapy ± chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3 years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings.

Current status and future perspective of flattening filter free photon beams

PURPOSE Flattening filters (FFs) have been considered as an integral part of the treatment head of a medical accelerator for more than 50 years. The reasons for the longstanding use are, however, historical ones. Advanced treatment techniques, such as stereotactic radiotherapy or intensity modulated radiotherapy have stimulated the interest in operating linear accelerators in a flattening filter free (FFF) mode. The current manuscript reviews treatment head physics of FFF beams, describes their characteristics and the resulting potential advantages in their medical use, and closes with an outlook. METHODS A number of dosimetric benefits have been determined for FFF beams, which range from increased dose rate and dose per pulse to favorable output ratio in-air variation with field size, reduced energy variation across the beam, and reduced leakage and out-of-field dose, respectively. Finally, the softer photon spectrum of unflattened beams has implications on imaging strategies and radiation protection. RESULTS The dosimetric characteristics of FFF beams have an effect on treatment delivery, patient comfort, dose calculation accuracy, beam matching, absorbed dose determination, treatment planning, machine specific quality assurance, imaging, and radiation protection. When considering conventional C-arm linacs in a FFF mode, more studies are needed to specify and quantify the clinical advantages, especially with respect to treatment plan quality and quality assurance. CONCLUSIONS New treatment units are already on the market that operate without a FF or can be operated in a dedicated clinical FFF mode. Due to the convincing arguments of removing the FF, it is expected that more vendors will offer dedicated treatment units for advanced photon beam therapy in the near future. Several aspects related to standardization, dosimetry, treatment planning, and optimization need to be addressed in more detail in order to facilitate the clinical implementation of unflattened beams.

Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma.

PURPOSE To determine the potential improvements in patients with paranasal sinus carcinoma by comparing proton and intensity-modulated radiotherapy (IMRT) with conventional and conformal photon treatment planning techniques. METHODS AND MATERIALS In 5 patients, comparative treatment planning was performed by comparing proton plans and related conventional, conformal, and IMRT photon plans. The evaluations analyzed dose-volume histogram findings of the target volumes and organs at risk (OARs, i.e., pituitary gland, optical pathway structures, brain, nontarget tissue). RESULTS The mean and maximal doses, dose inhomogeneities, and conformity indexes for the planning target volumes were comparable for all techniques. Photon plans resulted in greater volumes of irradiated nontarget tissues at the 10-70% dose level compared with the corresponding proton plans. The volumes thereby increased by a factor of 1.3-3.1 for conventional, 1.1-3.8 for conformal, and 1.1-3.7 for IMRT. Compared with conventional techniques, conformal and IMRT photon treatment planning options similarly reduced the mean dose to the OARs. The use of protons further reduced the mean dose to the OARs by up to 65% and 62% compared with the conformal and IMRT technique, respectively. CONCLUSION Compared with conventional treatment techniques, conformal RT and IMRT similarly enabled dose reductions to the OARs. Additional improvements were obtained using proton-based treatment planning modalities.

Dosimetric characterization of GafChromic EBT film and its implication on film dosimetry quality assurance

The suitability of radiochromic EBT film was studied for high-precision clinical quality assurance (QA) by identifying the dose response for a wide range of irradiation parameters typically modified in highly-conformal treatment techniques. In addition, uncertainties associated with varying irradiation conditions were determined. EBT can be used for dose assessment of absorbed dose levels as well as relative dosimetry when compared to absolute absorbed dose calibrated using ionization chamber results. For comparison, a silver halide film (Kodak EDR-2) representing the current standard in film dosimetry was included. As an initial step a measurement protocol yielding accurate and precise results was established for a flatbed transparency scanner (Epson Expression 1680 Pro) that was utilized as a film reading instrument. The light transmission measured by the scanner was found to depend on the position of the film on the scanner plate. For three film pieces irradiated with doses of 0 Gy, approximately 1 Gy and approximately 7 Gy, the pixel values measured in portrait or landscape mode differed by 4.7%, 6.2% and 10.0%, respectively. A study of 200 film pieces revealed an excellent sheet-to-sheet uniformity. On a long time scale, the optical development of irradiated EBT film consisted of a slow but steady increase of absorbance which was not observed to cease during 4 months. Sensitometric curves of EBT films obtained under reference conditions (SSD = 95 cm, FS = 5 x 5 cm(2), d = 5 cm) for 6, 10 and 25 MV photon beams did not show any energy dependence. The average separation between all curves was only 0.7%. The variation of the depth d (range 2-25 cm) in the phantom did not affect the dose response of EBT film. Also the influence of the radiation field size (range 3 x 3-40 x 40 cm(2)) on the sensitometric curve was not significant. For EDR-2 films maximum differences between the calibration curves reached 7-8% for X6MV and X25MV. Radiochromic EBT film, in combination with a flatbed scanner, presents a versatile system for high-precision dosimetry in two dimensions, provided that the intrinsic behaviour of the film reading device is taken into account. EBT film itself presents substantial improvements on formerly available models of radiographic and a radiochromic film and its dosimetric characteristics allow us to measure absorbed dose levels in a large variety of situations with a single calibration curve.

Dose Effect Relationship for Late Side Effects of the Rectum and Urinary Bladder in Magnetic Resonance Image-Guided Adaptive Cervix Cancer Brachytherapy

PURPOSE To establish dose-response relationships for late side effects of the rectum and bladder in cervix cancer patients after magnetic resonance image-guided adaptive brachytherapy (IGABT). METHODS AND MATERIALS A cohort of 141 patients was treated with 45 to 50.4 Gy with or without cisplatin plus 4 fractions of 7 Gy IGABT. Doses for the most exposed 2, 1, and 0.1-cm(3) (D(2 cc), D(1 cc), D(0.1 cc)) volumes of the rectum and bladder were converted into the equivalent dose in 2 Gy fractions (EQD2), using a linear quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed (using late effects in normal tissues subjective, objective, management and analytic [LENT SOMA]) scales. Dose-response relationships were determined by logit analyses. RESULTS Eleven patients developed rectal side effects, and 23 patients had urinary side effects. A significant dose effect was found for all rectal dose-volume histogram (DVH) parameters for patients with side effect grades of 1 to 4 but was only significant for D(2 cc) and D(1 cc) for grades ≥ 2. The ED10 values for D(2 cc) were 73 Gy for grades 1 to 4 and 78 Gy for grades 2 to 4 rectal morbidity. For bladder side effects, a significant dose effect was shown for all DVH parameters for complication grades ≥ 2; the respective ED10 was 101 Gy. CONCLUSIONS Well-defined dose-response curves could be established for D(2 cc) in the rectum and the urinary bladder.

Dose-volume histogram parameters and late side effects in magnetic resonance image-guided adaptive cervical cancer brachytherapy.

PURPOSE To evaluate the predictive value of dose-volume histogram (DVH) parameters for late side effects of the rectum, sigmoid colon, and bladder in image-guided brachytherapy for cervix cancer patients. METHODS AND MATERIALS A total of 141 patients received external-beam radiotherapy and image-guided brachytherapy with or without chemotherapy. The DVH parameters for the most exposed 2, 1, and 0.1 cm(3) (D(2cc), D(1cc), and D(0.1cc)) of the rectum, sigmoid, and bladder, as well as International Commission on Radiation Units and Measurements point doses (D(ICRU)) were computed. Total doses were converted to equivalent doses in 2 Gy by applying the linear-quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed using the Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic score. The following patient groups were defined: Group 1: no side effects (Grade 0); Group 2: side effects (Grade 1-4); Group 3: minor side effects (Grade 0-1); and Group 4: major side effects (Grade 2-4). RESULTS The median follow-up was 51 months. The overall 5-year actuarial side effect rates were 12% for rectum, 3% for sigmoid, and 23% for bladder. The mean total D(2cc) were 65 ± 12 Gy for rectum, 62 ± 12 Gy for sigmoid, and 95 ± 22 Gy for bladder. For rectum, statistically significant differences were observed between Groups 1 and 2 in all DVH parameters and D(ICRU). Between Groups 3 and 4, no difference was observed for D(0.1cc). For sigmoid, significant differences were observed for D(2cc) and D(1cc), but not for D(0.1cc) in all groups. For bladder, significant differences were observed for all DVH parameters only comparing Groups 3 and 4. No differences were observed for D(ICRU). CONCLUSIONS The parameters D(2cc) and D(1cc) have a good predictive value for rectal toxicity. For sigmoid, no prediction could be postulated because of limited data. In bladder, DVH parameters were predictive only for major toxicity.

Dosimetric characteristics of 6 and 10 MV unflattened photon beams

PURPOSE To determine dosimetric properties of unflattened megavoltage photon beams. MATERIALS AND METHODS Dosimetric data including depth dose, profiles, output factors and phantom scatter factors from three different beam qualities provided by Elekta Precise linacs, operated with and without flattening filter were examined. Additional measurements of leaf transmission, leakage radiation and surface dose were performed. In flattening filter free (FFF) mode a 6-mm thick copper filter was placed into the beam to stabilize it. RESULTS Depths of dose maxima for flattened and unflattened beams did not deviate by more than 2mm and penumbral widths agreed within 1mm. In FFF mode the collimator exchange effect was found to be on average 0.3% for rectangular fields. Between maximum and minimum field size head scatter factors of unflattened beams showed on average 40% and 56% less variation for 6 and 10MV beams than conventional beams. Phantom scatter factors for FFF beams differed up to 4% from the published reference data. For field sizes smaller than 15cm, surface doses relative to the dose at d(max) increased for unflattened beams with maximum differences of 7% at 6MV and 25% at 10MV for a 5x5cm(2) field. For a 30x30cm(2) field, relative surface dose decreased by about 10% for FFF beams. Leaf transmission on the central axis was 0.3% and 0.4% lower for unflattened 6 and 10MV beams, respectively. Leakage radiation was reduced by 52% for 6MV and by 65% for 10MV unflattened beams. CONCLUSIONS The results of the study were independently confirmed at two radiotherapy centres. Phantom scatter reference data need to be reconsidered for medical accelerators operated without a flattening filter.

Interpretation and evaluation of the γ index and the γ index angle for the verification of IMRT hybrid plans

In IMRT, the method for a quantitative comparison of two-dimensional dose distributions is still under development. The γ evaluation method proposed by Low et al is the most accepted approach and has been adapted by many groups. Based on the concept of Low et al we developed a software tool with an intelligent search algorithm to minimize the calculation time. For the interpretation of deviations a γ angle distribution and other tools (dose difference map, profiles, γ area histograms, etc) are integrated in the software package. Ten hybrid plans are included in the verification study containing 6 IMRT head and neck cases, 2 IMRT prostate cases and one IMRT paravertebral case as well as a standard uniform intensity conformal 4 field box treatment for comparison. IMRT plans are realized with a segmental MLC delivery technique. The fields of a hybrid plan are applied at once and dose distributions are measured with films in three planes of a verification phantom. All γ vector calculations are based on a 3% dose criterion and a 3 mm DTA acceptance criterion. The mean value γmean (mean value in the γ distribution) of the various IMRT plans is 0.45 ± 0.10 (1 SD). On average, the percentage of points exceeding the acceptance criteria of γ ≤ 1 (γ>1) is 5.8 ± 5.4% (1 SD). The mean value of γ1% (1% of points have an equal or higher γ value) is 1.47 ± 0.59 (1 SD) for IMRT plans. In 5 out of 27 planes, γ>1 is substantially larger than the average. This is also indicated in γ area histograms. Planes with large areas outside the tolerance criteria were further evaluated using γ angle distributions. This additional information indicates that the large areas with high γ values are dominated by the dose difference. It is shown that the deviations are influenced by tongue and groove effects. From the statistical evaluation of γ values (e.g. γ area histogram), acceptance criteria for IMRT hybrid plans can be defined. For the interpretation of the γ maps, distributions of the γ angle and traditional evaluation methods, such as dose profiles, are still very useful.

IMAGE-GUIDED RADIOTHERAPY FOR CERVIX CANCER: HIGH-TECH EXTERNAL BEAM THERAPY VERSUS HIGH-TECH BRACHYTHERAPY

PURPOSE Many studies comparing external-beam therapy (EBT) and brachytherapy (BT) are biased because advanced EBT is compared with conventional BT. This study compares high-tech EBT against high-tech BT. METHODS AND MATERIALS Nine patients were selected with locally advanced cervix cancer, representing typical clinical situations according to initial tumor extension and response after EBT. Patients were treated either with intracavitary, combined interstitial/intracavitary, or complex interstitial BT. Gross tumor volume, high-risk clinical target volume (CTV), intermediate-risk CTV, bladder, rectum, and sigmoid were delineated. Magnetic resonance-guided BT planning was manually optimized with respect to organ dose limits. Margins (3 and 5 mm) were added to BT CTVs to construct planning target volumes (PTVs) for EBT. Inversely planned EBT with photons (IMRT) and protons (IMPT) was challenged to deliver the highest possible doses to PTVs while respecting D(1cc) and D(2cc) limits from BT, assuming the same fractionation (4 x 7 Gy). The D90 for target structures and normal tissue volumes receiving fractionated doses between 3 and 7 Gy were compared. RESULTS High-risk CTV doses depended on the clinical situation and radiation quality. If IMRT was limited to D(2cc) and D(1cc) from BT, the D90 for high-risk PTV and intermediate-risk PTV was mostly lower. Volumes receiving 60 Gy (in equivalent dose in 20 Gy fractions) were approximately twice as large for IMRT compared with BT. For IMPT, this volume ratio was lower. Planning target volume doses of IMPT plans with 3-mm margins were comparable to those with BT. Gross tumor volume doses were mostly lower for both IMRT and IMPT. CONCLUSION For benchmarking high-tech EBT, high-tech BT techniques have to be used. For cervix cancer boost treatments, both IMRT and IMPT seem to be inferior to advanced BT.

Dose-response characteristics of an amorphous silicon EPID.

Electronic portal imaging devices(EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector’sdose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous siliconEPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV . The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac’s changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output characteristics of the accelerator. If ghosting is prevented from affecting the results and all dose-response effects are properly corrected for, the EPID signal becomes independent of dose rate, dose, and exposure time.