Maunu Pitkänen

Quality Assurance in Radiotherapy of Breast Cancer Variability in Planning Target Volume Delineation

The inter-physician and inter-patient variability in planning target volume delineation for the radiotherapy of breast cancer after conservative surgery is presented. Eleven experienced radiation oncologists determined the planning target volume (PTV) for four breast cancer patients. Delineation was based on CT slices taken at intervals of 15 mm. The variability in target volume delineation was determined by measuring the volumes in units of cc and the position of the drawn PTVs. Statistical analysis was based on X/R-charts and on Pareto chart and analysis. The maximum range in PTV for one patient was from 670 to 1,200 cc. The observations of three physicians were in excess of the warning limit altogether 18 times. The methods used in this study clearly reveal inter-physician variability in PTV delineation and widest variations found are not acceptable. Training targeted to some physicians and more detailed and unambiguous protocols for PTV delineation are needed.The inter-physician and inter-patient variability in planning target volume delineation for the radiotherapy of breast cancer after conservative surgery is presented. Eleven experienced radiation oncologists determined the planning target volume (PTV) for four breast cancer patients. Delineation was based on CT slices taken at intervals of 15 mm. The variability in target volume delineation was determined by measuring the volumes in units of cc and the position of the drawn PTVs. Statistical analysis was based on X/R-charts and on Pareto chart and analysis. The maximum range in PTV for one patient was from 670 to 1200 cc. The observations of three physicians were in excess of the warning limit altogether 18 times. The methods used in this study clearly reveal inter-physician variability in PTV delineation and widest variations found are not acceptable. Training targeted to some physicians and more detailed and unambiguous protocols for PTV delineation are needed.

Performance of dose calculation algorithms from three generations in lung SBRT: comparison with full Monte Carlo-based dose distributions

The accuracy of dose calculation is a key challenge in stereotactic body radiotherapy (SBRT) of the lung. We have benchmarked three photon beam dose calculation algorithms — pencil beam convolution (PBC), anisotropic analytical algorithm (AAA), and Acuros XB (AXB) — implemented in a commercial treatment planning system (TPS), Varian Eclipse. Dose distributions from full Monte Carlo (MC) simulations were regarded as a reference. In the first stage, for four patients with central lung tumors, treatment plans using 3D conformal radiotherapy (CRT) technique applying 6 MV photon beams were made using the AXB algorithm, with planning criteria according to the Nordic SBRT study group. The plans were recalculated (with same number of monitor units (MUs) and identical field settings) using BEAMnrc and DOSXYZnrc MC codes. The MC‐calculated dose distributions were compared to corresponding AXB‐calculated dose distributions to assess the accuracy of the AXB algorithm, to which then other TPS algorithms were compared. In the second stage, treatment plans were made for ten patients with 3D CRT technique using both the PBC algorithm and the AAA. The plans were recalculated (with same number of MUs and identical field settings) with the AXB algorithm, then compared to original plans. Throughout the study, the comparisons were made as a function of the size of the planning target volume (PTV), using various dose‐volume histogram (DVH) and other parameters to quantitatively assess the plan quality. In the first stage also, 3D gamma analyses with threshold criteria 3%/3 mm and 2%/2 mm were applied. The AXB‐calculated dose distributions showed relatively high level of agreement in the light of 3D gamma analysis and DVH comparison against the full MC simulation, especially with large PTVs, but, with smaller PTVs, larger discrepancies were found. Gamma agreement index (GAI) values between 95.5% and 99.6% for all the plans with the threshold criteria 3%/3 mm were achieved, but 2%/2 mm threshold criteria showed larger discrepancies. The TPS algorithm comparison results showed large dose discrepancies in the PTV mean dose (D50%), nearly 60%, for the PBC algorithm, and differences of nearly 20% for the AAA, occurring also in the small PTV size range. This work suggests the application of independent plan verification, when the AAA or the AXB algorithm are utilized in lung SBRT having PTVs smaller than 20‐25 cc. The calculated data from this study can be used in converting the SBRT protocols based on type ‘a’ and/or type ‘b’ algorithms for the most recent generation type ‘c’ algorithms, such as the AXB algorithm. PACS numbers: 87.55.‐x, 87.55.D‐, 87.55.K‐, 87.55.kd, 87.55.Qr

Radiological pulmonary findings after breast cancer irradiation: A prospective study

The aim of this study was to evaluate radiation-induced pulmonary abnormalities of breast cancer patients. Altogether 202 consecutive patients receiving postoperative radiotherapy entered the study. Plain chest radiographs taken at entry and 3, 6 and 12 months after radiotherapy were evaluated according to modified Arriagada classification. In addition, pulmonary symptoms were recorded. Supplementary high-resolution computed tomography (HRCT) was employed in a subgroup of patients (n = 15). Plain radiographs were interpreted by a radiologist, and uncertain findings were re-evaluated by a radiologist together with a radiation oncologist. Grade 2 pneumonitis was the most common abnormality. The proportion of patients yielding a grade 2 finding was 22.5%, 28.1%, and 16.0% at three, six, and twelve months, respectively. There were 2 normal findings in HRCTscans, and 8 in plain radiographs of the same patients. Radiological lung abnormalities are common after radiotherapy, but they are usually reversible, and their significance for the patients well-being is minor. No correlation between symptoms and lung or pleural reactions was seen.

Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy.

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al and Gagliardi et al parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.

The accuracy of Acuros XB algorithm for radiation beams traversing a metallic hip implant — comparison with measurements and Monte Carlo calculations

In this study, the clinical benefit of the improved accuracy of the Acuros XB (AXB) algorithm, implemented in a commercial radiotherapy treatment planning system (TPS), Varian Eclipse, was demonstrated with beams traversing a high‐Z material. This is also the first study assessing the accuracy of the AXB algorithm applying volumetric modulated arc therapy (VMAT) technique compared to full Monte Carlo (MC) simulations. In the first phase the AXB algorithm was benchmarked against point dosimetry, film dosimetry, and full MC calculation in a water‐filled anthropometric phantom with a unilateral hip implant. Also the validity of the full MC calculation used as reference method was demonstrated. The dose calculations were performed both in original computed tomography (CT) dataset, which included artifacts, and in corrected CT dataset, where constant Hounsfield unit (HU) value assignment for all the materials was made. In the second phase, a clinical treatment plan was prepared for a prostate cancer patient with a unilateral hip implant. The plan applied a hybrid VMAT technique that included partial arcs that avoided passing through the implant and static beams traversing the implant. Ultimately, the AXB‐calculated dose distribution was compared to the recalculation by the full MC simulation to assess the accuracy of the AXB algorithm in clinical setting. A recalculation with the anisotropic analytical algorithm (AAA) was also performed to quantify the benefit of the improved dose calculation accuracy of type ‘c’ algorithm (AXB) over type ‘b’ algorithm (AAA). The agreement between the AXB algorithm and the full MC model was very good inside and in the vicinity of the implant and elsewhere, which verifies the accuracy of the AXB algorithm for patient plans with beams traversing through high‐Z material, whereas the AAA produced larger discrepancies. PACS numbers: 87.55.‐x, 87.55.D‐, 87.55.K‐, 87.55.kd, 87.55.Qr

Quality control in health care: an experiment in radiotherapy planning for breast cancer patients after mastectomy.

PURPOSE The importance of evaluating and improving quality in clinical practice is now generally acknowledged. In this study we estimated different sources of variation in radiotherapy planning for breast cancer patients after mastectomy and sought to test the applicability of a reproducibility and repeatability (R&R) study in a clinical context. METHODS Eleven radiation oncologists planned radiotherapy three times for three different kinds of breast cancer patients without knowing they were handling the same patient three times. Variation was divided into different components: physicians as operators, patients as parts, and repeated measurements as trials. Variation due to difference across trials (repeatability), that across the physicians (reproducibility), and that across the patients (variability) were estimated, as well as interactions between physicians and patients. Calculation was based on the sum of squares, and analysis was supported by various graphical presentations such as range charts and box plots. RESULTS Some parts of the planning process were characterized by higher and different kinds of variation than the others. Interphysician variation (i.e., reproducibility) was not high but there were some clearly outlying physicians. The highest variation was in repeatability (= intraphysician variation). The major part of the variation was, however, that from patient to patient: 33% of the total in Parameter 1 and 85% of the total in Parameter 2. CONCLUSIONS R&R studies are applicable and are needed to evaluate and improve quality in clinical practice. This kind of analysis provides opportunities to establish which kinds of patients require particularly careful attention, which points in the process are most critical for variation, which are the most difficult aspects for each physician and call for more careful description in documents, and which physicians need further training.

Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy.

The choice of the appropriate model and parameter set in determining the relation between the incidence of radiation pneumonitis and dose distribution in the lung is of great importance, especially in the case of breast radiotherapy where the observed incidence is fairly low. From our previous study based on 150 breast cancer patients, where the fits of dose-volume models to clinical data were estimated (Tsougos et al 2005 Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy Phys. Med. Biol. 50 3535-54), one could get the impression that the relative seriality is significantly better than the LKB NTCP model. However, the estimation of the different NTCP models was based on their goodness-of-fit on clinical data, using various sets of published parameters from other groups, and this fact may provisionally justify the results. Hence, we sought to investigate further the LKB model, by applying different published parameter sets for the very same group of patients, in order to be able to compare the results. It was shown that, depending on the parameter set applied, the LKB model is able to predict the incidence of radiation pneumonitis with acceptable accuracy, especially when implemented on a sub-group of patients (120) receiving [see text]|EUD higher than 8 Gy. In conclusion, the goodness-of-fit of a certain radiobiological model on a given clinical case is closely related to the selection of the proper scoring criteria and parameter set as well as to the compatibility of the clinical case from which the data were derived.

Action of Recombinant Interferons and Interleukin 2 in Modulating Radiation Effects on Viability and Cytotoxicity of Large Granular Lymphocytes

We have evaluated in vitro the modulating effect of interferon (IFN) alpha, beta and gamma as well as interleukin 2 (IL-2) on the radiosensitivity of large granular lymphocytes (LGL) having natural killer cell activity. LGL were treated with IFNs or IL-2 in concentrations from 1 to 1000 U/ml before or after a single or a split dose of irradiation. The viability of LGL was measured by intracellular ATP, and cytotoxicity by a 51Cr release assay. Both viability and cytotoxicity were clearly higher when IFNs and IL-2 were used before irradiation. Some IFNs were slightly radiosensitizing in ATP studies. Only IFN gamma in a concentration of 1000 U/ml was significantly radioprotective in cytotoxicity tests when used before irradiation. IL-2 had a significant concentration-dependent radioprotective effect in cytotoxicity when used before or after irradiation, and in the viability of preincubated LGL. No combination of IFNs and IL-2 was more radioprotective than IL-2 used alone. IL-2 retarded the time dependent decrease of ATP and 51Cr release levels after irradiation. According to our results, IL-2 is a radioprotective substance for LGL.

Post-irradiation viability and cytotoxicity of natural killer cells isolated from human peripheral blood using different methods

Abstract Purpose We compared the pre- and post-irradiation viability and cytotoxicity of human peripheral natural killer cell (NK) populations obtained using different isolation methods. Material and methods Three methods were used to enrich total NK cells from buffy coats: (I) a Ficoll-Paque gradient, plastic adherence and a nylon wool column; (II) a discontinuous Percoll gradient; or (III) the Dynal NK cell isolation kit. Subsequently, CD16+ and CD56+ NK cell subsets were collected using (IV) flow cytometry or (V) magnetic-activated cell sorting (MACS) NK cell isolation kits. The yield, viability, purity and cytotoxicity of the NK cell populations were measured using trypan blue exclusion, flow cytometry using propidium iodide and 51Cr release assays after enrichments as well as viability and cytotoxicity after a single radiation dose. Results The purity of the preparations, as measured by the CD16+ and CD56+ cell content, was equally good between methods I–III (p = 0.323), but the content of CD16+ and CD56+ cells using these methods was significantly lower than that using methods IV and V (p = 0.005). The viability of the cell population enriched via flow cytometry (85.5%) was significantly lower than that enriched via other methods (99.4–98.0%, p = 0.003). The cytotoxicity of NK cells enriched using methods I–III was significantly higher than that of NK cells enriched using methods IV and V (p = 0.000). In vitro the NK cells did not recover cytotoxic activity following irradiation. In addition, we detected considerable inter-individual variation in yield, cytotoxicity and radiation sensitivity between the NK cells collected from different human donors. Conclusions The selection of the appropriate NK cell enrichment method is very important for NK cell irradiation studies. According to our results, the Dynal and MACS NK isolation kits best retained the killing capacity and the viability of irradiated NK cells.

Comparison of performance standards for radiation beam uniformity characteristics of a linear accelerator

The recent international standards published by the International Electrotechnical Commission (IEC) on the performance of medical electron accelerators describe suggested test procedures for the performance of radiotherapy accelerators. The recommendations of the Nordic Association of Clinical Physics for testing of the radiation beam characteristics include test conditions, methods and suggested tolerances that are different from those of the IEC. In this work the two publications were compared for acceptance testing of a Philips SL25 linear accelerator. It is important to gain experience on the practical use of these standards.