Relative Seriality Research Articles

Poster - Thur Eve - 73: Prediction of risks of cardiac mortality and secondary cancers after radiotherapy for Hodgkin's lymphoma, non-Hodgkin's lymphoma, and breast cancer.

To predict the risks of late, radiation-induced effects for young patients with Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), or breast cancer (BC) if treated with intensity modulated proton therapy (IMPT) compared to 3D conformal photon radiotherapy (3D-CRT). Late effects considered were cardiac mortality and secondary cancer in the lungs and breasts (for female patients). Patient data were acquired for twenty-six patients (ages 12-29) who were treated with 3D-CRT for HL, NHL, or BC in 2010. Original CT simulation images were used to re-plan the patients with IMPT using commercially-available treatment planning software. The contours of the organs at risk were reviewed by a single physician and modified for consistency. The dose-volume data of the 3D-CRT plans and the new IMPT plans were analyzed to model the risks of late effects. The relative seriality model was used to predict excess risk of cardiac mortality at fifteen years post-irradiation. A modified linear quadratic model was used to predict the Excess Absolute Risk (EAR) for induction of lung cancer and breast cancer at thirty years post-irradiation. For 3D-CRT and IMPT respectively, the mean excess risks of cardiac mortality were 0.9% and 0.5%. Mean EARs for lung cancer were 17.5 cases per 10,000 persons per year (PY) and 10.1 PY. Mean EARs for breast cancer were 8.2 PY and 2.8 PY. IMPT may significantly reduce the risks of radiation-induced cardiac mortality and secondary cancer in the lungs and breasts of young patients receiving radiotherapy for HL, NHL, or breast cancer.

SU‐C‐BRB‐03: Modeling of Radiation‐Induced Sensorineural Hearing Loss from IMRT and Chemotherapy for Nasopharyngeal Carcinoma

Purpose: To model and predict radiation‐induced Sensorineural Hearing Loss (SNHL) from intensity modulated radiation therapy (IMRT) and cisplatin‐based chemotherapy for patients with nasopharyngeal carcinoma (NPC). Methods: Audiometry data of 53 patients (106 ears) treated with the chemoradiation therapy were collected with a median follow‐up time of 60 (28–84) months. Among them, 15 SNHL cases were observed. The correlation of the SNHL data with the dose volume histograms (DVH) of both inner ear and cochlea, chemotherapy dose and patient age for each patient were analyzed using the Lyman‐Kutcher‐Burman (LKB) model and relative seriality (RS) model with a modification to include the impacts from the cisplatin dose and patient age. There are 5 parameters in each model which were determined by a maximal likelihood fitting of the clinical data. Results: Both models fit the data reasonably well, indicating that SNHL is correlated to the volume and radiation dose to cochlea, thus, to inner ear. This correlation is modified by chemotherapy dose and patient age. TD50(1) is approximately 300 Gy when only radiation is considered and is 72 Gy when patient aging and the cisplatin dose are included. The parameter n and m in the LKB model and s and γ in the SR model were obtained to be n=0.035±0.010, m=0.45±0.11 and s=2.05±1.75, γ =0.71±0.15 averaged over those obtained using DVHs of the cochlea and inner ear. A multivariate analysis found that the normal tissue toxicity probability (NTCP) calculated by the models is a statistically significant factor to predict the ototoxicity rate. The modeling results show that both inner ear and cochlea have the characteristics of a serial organ in terms of radiation dose response. Conclusions: The biophysical models derived in this study can predict the incidence of SNHL and may be used to optimize radiation treatment plans to reduce SNHL.

TH‐C‐213AB‐06: Risk of Radiation‐Induced Cardiotoxicity and Secondary Cancers in Hodgkin's Lymphoma Patients

Purpose: To evaluate the potential reduction of risk of late radiation‐ induced effects for young patients with Hodgkin's lymphoma treated with intensity modulated proton therapy (IMPT) as compared to 3D conformal involved‐field photon radiotherapy. The late effects considered were cardiac mortality and secondary cancer in the lungs and breasts (for female patients). Methods: Patient data was acquired for eleven patients who were under thirty years of age and were treated with radiotherapy for Hodgkin's lymphoma in Quebec in 2010. The original CT simulation images were used to re‐plan the patients with IMPT using commercially‐available treatment planning software. The contours of the critical organs of interest were reviewed for each patient by a physician and modified when necessary for consistency. The dose‐volume matrices of the original photon plans and the new proton plans were analyzed using radiobiological models to assess the risk of late effects. The relative seriality model was utilized to predict excess risk of fatal cardiotoxicity. The organ equivalent dose concept was utilized in conjunction with a modified linear quadratic model to predict the excess absolute risk for induction of lung cancer and breast cancer. Parameters for each model were derived from retrospective studies in the literature. Results: Mean excess risk of fatal cardiotoxicity was 0.9% for photon plans and 0.6% for proton plans. Mean excess absolute risk of developing lung cancer thirty years post‐treatment was 11.9/10,000 patients per year (PY) for photons and 6.9/10,000 PY for protons. Mean excess absolute risk of developing breast cancer thirty years post‐treatment was 6.0/10,000 PY for photons and 2.1/10,000 PY for protons. Conclusions: IMPT has the potential to reduce the risk of fatal, radiation‐induced late cardiotoxicity as well as the risk of radiation‐induced secondary cancers in the lungs and breasts of young patients receiving radiotherapy for Hodgkin's lymphoma. This work has been funded in part by a grant from the Fonds de recherche Santé Quebec (FRSQ).

Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with α/β = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D(50) estimated from the models was approximately 44 Gy. The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication.

The Benefits of Including Clinical Factors in Rectal Normal Tissue Complication Probability Modeling After Radiotherapy for Prostate Cancer

To study the impact of clinical predisposing factors on rectal normal tissue complication probability modeling using the updated results of the Dutch prostate dose-escalation trial. Toxicity data of 512 patients (conformally treated to 68 Gy [n = 284] and 78 Gy [n = 228]) with complete follow-up at 3 years after radiotherapy were studied. Scored end points were rectal bleeding, high stool frequency, and fecal incontinence. Two traditional dose-based models (Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) and a logistic model were fitted using a maximum likelihood approach. Furthermore, these model fits were improved by including the most significant clinical factors. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminating ability of all fits. Including clinical factors significantly increased the predictive power of the models for all end points. In the optimal LKB, RS, and logistic models for rectal bleeding and fecal incontinence, the first significant (p = 0.011-0.013) clinical factor was "previous abdominal surgery." As second significant (p = 0.012-0.016) factor, "cardiac history" was included in all three rectal bleeding fits, whereas including "diabetes" was significant (p = 0.039-0.048) in fecal incontinence modeling but only in the LKB and logistic models. High stool frequency fits only benefitted significantly (p = 0.003-0.006) from the inclusion of the baseline toxicity score. For all models rectal bleeding fits had the highest AUC (0.77) where it was 0.63 and 0.68 for high stool frequency and fecal incontinence, respectively. LKB and logistic model fits resulted in similar values for the volume parameter. The steepness parameter was somewhat higher in the logistic model, also resulting in a slightly lower D(50). Anal wall DVHs were used for fecal incontinence, whereas anorectal wall dose best described the other two endpoints. Comparable prediction models were obtained with LKB, RS, and logistic NTCP models. Including clinical factors improved the predictive power of all models significantly.

SU-E-T-594: Estimation of the Clinical Impact of Dwell Time Modulation Restriction in HIPO Optimized HDR Prostate Brachytherapy Implants

Purpose: In HDR brachytherapy planning, one of the issues that have to be accounted for is the selective existence of high dose volumes around some few dominating dwell positions. This effect can be eliminated by limiting the free dwell time modulation. This possibility can be offered by an inverse treatment plan optimization algorithm such as HIPO. Methods: The dose distributions of 12 clinical HDR brachytherapy implants for prostate that were produced by HIPO with and without modulation restriction (MR) are compared. Common dose‐volume indices were used to examine the clinical effectiveness of the different dose distributions. The response probabilities of the prostate tumors and organs at risk (OARs) were calculated using the Poisson and the relative seriality models. In treatment plan evaluation and comparison, the complication‐free tumor control probability, P+ and the biologically effective uniform dose ( ) were also used. Results: HIPO with a MR of 0.1–0.2 can produce high quality treatment plans which are practically equivalent to those that are produced by HIPO without MR. However, a considerable variation between the different plans could be indicated by the radiobiological indices. The HIPO with MR treatment plans demonstrated a statistically significant (p=0.002) lower total dwell time by a mean of 1.4% compared to the HIPO without MR plans. Furthermore, due to a better sparing of the OARs by 1.0%, the HIPO with MR plans produced a higher P+ by 0.5%. Conclusions: The present analysis shows that on average the HIPO with MR and without MR treatment plan optimizations give similar results regarding common dosimetric indices and widely known radiobiological measures. It appears that the examined dwell time regularization technique can introduce a minor only improvement in the effectiveness of the optimized HDR dose distributions.

Comparison of Dose Response Models for Predicting Normal Tissue Complications from Cancer Radiotherapy: Application in Rat Spinal Cord

Seven different radiobiological dose-response models have been compared with regard to their ability to describe experimental data. The first four models, namely the critical volume, the relative seriality, the inverse tumor and the critical element models are mainly based on cell survival biology. The other three models: the Lyman (Gaussian distribution), the parallel architecture and the Weibull distribution models are semi-empirical and rather based on statistical distributions. The maximum likelihood estimation was used to fit the models to experimental data and the χ2-distribution, AIC criterion and F-test were applied to compare the goodness-of-fit of the models. The comparison was performed using experimental data for rat spinal cord injury. Both the shape of the dose-response curve and the ability of handling the volume dependence were separately compared for each model. All the models were found to be acceptable in describing the present experimental dataset (p > 0.05). For the white matter necrosis dataset, the Weibull and Lyman models were clearly superior to the other models, whereas for the vascular damage case, the Relative Seriality model seems to have the best performance although the Critical volume, Inverse tumor, Critical element and Parallel architecture models gave similar results. Although the differences between many of the investigated models are rather small, they still may be of importance in indicating the advantages and limitations of each particular model. It appears that most of the models have favorable properties for describing dose-response data, which indicates that they may be suitable to be used in biologically optimized intensity modulated radiation therapy planning, provided a proper estimation of their radiobiological parameters had been performed for every tissue and clinical endpoint.

Influence of dose calculation algorithms on the predicted dose distributions and NTCP values for NSCLC patients

To investigate differences in calculated doses and normal tissue complication probability (NTCP) values between different dose algorithms. Six dose algorithms from four different treatment planning systems were investigated: Eclipse AAA, Oncentra MasterPlan Collapsed Cone and Pencil Beam, Pinnacle Collapsed Cone and XiO Multigrid Superposition, and Fast Fourier Transform Convolution. Twenty NSCLC patients treated in the period 2001-2006 at the same accelerator were included and the accelerator used for treatments were modeled in the different systems. The treatment plans were recalculated with the same number of monitor units and beam arrangements across the dose algorithms. Dose volume histograms of the GTV, PTV, combined lungs (excluding the GTV), and heart were exported and evaluated. NTCP values for heart and lungs were calculated using the relative seriality model and the LKB model, respectively. Furthermore, NTCP for the lungs were calculated from two different model parameter sets. Calculations and evaluations were performed both including and excluding density corrections. There are found statistical significant differences between the calculated dose to heart, lung, and targets across the algorithms. Mean lung dose and V20 are not very sensitive to change between the investigated dose calculation algorithms. However, the different dose levels for the PTV averaged over the patient population are varying up to 11%. The predicted NTCP values for pneumonitis vary between 0.20 and 0.24 or 0.35 and 0.48 across the investigated dose algorithms depending on the chosen model parameter set. The influence of the use of density correction in the dose calculation on the predicted NTCP values depends on the specific dose calculation algorithm and the model parameter set. For fixed values of these, the changes in NTCP can be up to 45%. Calculated NTCP values for pneumonitis are more sensitive to the choice of algorithm than mean lung dose and V20 which are also commonly used for plan evaluation. The NTCP values for heart complication are, in this study, not very sensitive to the choice of algorithm. Dose calculations based on density corrections result in quite different NTCP values than calculations without density corrections. It is therefore important when working with NTCP planning to use NTCP parameter values based on calculations and treatments similar to those for which the NTCP is of interest.

Response-probability volume histograms and iso-probability of response charts in treatment plan evaluation

This study aims at demonstrating a new method for treatment plan evaluation and comparison based on the radiobiological response of individual voxels. This is performed by applying them on three different cancer types and treatment plans of different conformalities. Furthermore, their usefulness is examined in conjunction with traditionally applied radiobiological and dosimetric treatment plan evaluation criteria. Three different cancer types (head and neck, breast and prostate) were selected to quantify the benefits of the proposed treatment plan evaluation method. In each case, conventional conformal radiotherapy (CRT) and intensity modulated radiotherapy (IMRT) treatment configurations were planned. Iso-probability of response charts was produced by calculating the response probability in every voxel using the linear-quadratic-Poisson model and the dose-response parameters of the corresponding structure to which this voxel belongs. The overall probabilities of target and normal tissue responses were calculated using the Poisson and the relative seriality models, respectively. The 3D dose distribution converted to a 2 Gy fractionation, D2(GY) and iso-BED distributions are also shown and compared with the proposed methodology. Response-probability volume histograms (RVH) were derived and compared with common dose volume histograms (DVH). The different dose distributions were also compared using the complication-free tumor control probability, P+, the biologically effective uniform dose, D, and common dosimetric criteria. 3D Iso-probability of response distributions is very useful for plan evaluation since their visual information focuses on the doses that are likely to have a larger clinical effect in that particular organ. The graphical display becomes independent of the prescription dose highlighting the local radiation therapy effect in each voxel without the loss of important spatial information. For example, due to the exponential nature of the Poisson distribution, cold spots in the target volumes or hot spots in the normal tissues are much easier to be identified. Response-volume histograms, as DVH, can also be derived and used for plan comparison. RVH are advantageous since by incorporating the radiobiological properties of each voxel they summarize the 3D distribution into 2D without the loss of relevant information. Thus, more clinically relevant radiobiological objectives and constraints could be defined and used in treatment planning optimization. These measures become increasingly important when dose distributions need to be designed according to the microscopic biological properties of tumor and normal tissues. The proposed methods do not aim to replace quantifiers like the probabilities of total tissue response, which ultimately are the quantities of interest to evaluate treatment success. However, iso-probability of response charts and response-probability volume histograms illustrates more clearly the difference in effectiveness between different treatment plans than the information provided by alternative dosimetric data. The use of 3D iso-probability of response distributions could serve as a good descriptor of the effectiveness of a dose distribution indicating primarily the regions in a tissue that dominate its response.

Geometric and Dosimetric Approach to Determine Probability of Late Cardiac Mortality in Left Tangential Breast Irradiation: Comparison Between Wedged Beams and Field-in-Field Technique

To evaluate the probability of late cardiac mortality resulting from left breast irradiation planned with tangential fields and to compare this probability between the wedged beam and field-in-field (FIF) techniques and to investigate whether some geometric/dosimetric indicators can be determined to estimate the cardiac mortality probability before treatment begins. For 30 patients, differential dose-volume histograms were calculated for the wedged beam and FIF plans, and the corresponding cardiac mortality probabilities were determined using the relative seriality model. As a comparative index of the dose distribution uniformity, the planning target volume (PTV) percentages involved in 97-103% of prescribed dose were determined for the two techniques. Three geometric parameters were measured for each patient: the maximal length, indicates how much the heart contours were displaced toward the PTV, the angle subtended at the center of the computed tomography slice by the PTV contour, and the thorax width/thickness ratio. Evaluating the differential dose-volume histograms showed that the gain in uniformity between the two techniques was about 1.5. With the FIF technique, the mean dose sparing for the heart, the left anterior descending coronary artery, and the lung was 15% (2.5 Gy vs. 2.2 Gy), 21% (11.3 Gy vs. 9.0 Gy), and 42% (8.0 Gy vs. 4.6 Gy) respectively, compared with the wedged beam technique. Also, the cardiac mortality probability decreased by 40% (from 0.9% to 0.5%). Three geometric parameters, the maximal length, angle subtended at the center of the computed tomography slice by the PTV contour, and thorax width/thickness ratio, were the determining factors (p = .06 for FIF, and p = .10 for wedged beam) for evaluating the cardiac mortality probability. The FIF technique seemed to yield a lower cardiac mortality probability than the conventional wedged beam technique. However, although our study demonstrated that FIF technique improved the dose coverage of the PTV, the restricted number of patients enrolled and the short follow-up did not allow us to evaluate and compare the breast cancer survival rates of the patients.

On the use of published radiobiological parameters and the evaluation of NTCP models regarding lung pneumonitis in clinical breast radiotherapy

In this study we sought to evaluate and accent the importance of radiobiological parameter selection and implementation to the normal tissue complication probability (NTCP) models. The relative seriality (RS) and the Lyman-Kutcher-Burman (LKB) models were studied. For each model, a minimum and maximum set of radiobiological parameter sets was selected from the overall published sets applied in literature and a theoretical mean parameter set was computed. In order to investigate the potential model weaknesses in NTCP estimation and to point out the correct use of model parameters, these sets were used as input to the RS and the LKB model, estimating radiation induced complications for a group of 36 breast cancer patients treated with radiotherapy. The clinical endpoint examined was Radiation Pneumonitis. Each model was represented by a certain dose-response range when the selected parameter sets were applied. Comparing the models with their ranges, a large area of coincidence was revealed. If the parameter uncertainties (standard deviation) are included in the models, their area of coincidence might be enlarged, constraining even greater their predictive ability. The selection of the proper radiobiological parameter set for a given clinical endpoint is crucial. Published parameter values are not definite but should be accompanied by uncertainties, and one should be very careful when applying them to the NTCP models. Correct selection and proper implementation of published parameters provides a quite accurate fit of the NTCP models to the considered endpoint.

Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models

Normal tissue complication probability (NTCP) of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. Model parameters from literature were used in this evaluation. The treatment techniques included external (standard fractionated, hypofractionated, and dose-escalated) three-dimensional conformal radiotherapy (3D-CRT), low-dose-rate (LDR) brachytherapy (I-125 seeds), and high-dose-rate (HDR) brachytherapy (Ir-192 source). Dose-volume histograms (DVHs) of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences in radiation treatment modality and fractionation schedule. Results indicated that with hypofractionated 3D-CRT (20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy), NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique (32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy) and dose-escalated 3D-CRT. Rectal and bladder NTCPs (5.2% and 6.6%, respectively) following the dose-escalated four-field 3D-CRT (2 Gy/fraction to total dose of 74 Gy) were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues.

Radiobiological evaluation of forward and inverse IMRT using different fractionations for head and neck tumours

PurposeTo quantify the radiobiological advantages obtained by an Improved Forward Planning technique (IFP) and two IMRT techniques using different fractionation schemes for the irradiation of head and neck tumours. The conventional radiation therapy technique (CONVT) was used here as a benchmark.MethodsSeven patients with head and neck tumours were selected for this retrospective planning study. The PTV1 included the primary tumour, PTV2 the high risk lymph nodes and PTV3 the low risk lymph nodes. Except for the conventional technique where a maximum dose of 64.8 Gy was prescribed to the PTV1, 70.2 Gy, 59.4 Gy and 50.4 Gy were prescribed respectively to PTV1, PTV2 and PTV3. Except for IMRT2, all techniques were delivered by three sequential phases. The IFP technique used five to seven directions with a total of 15 to 21 beams. The IMRT techniques used five to nine directions and around 80 segments. The first, IMRT1, was prescribed with the conventional fractionation scheme of 1.8 Gy per fraction delivered in 39 fractions by three treatment phases. The second, IMRT2, simultaneously irradiated the PTV2 and PTV3 with 59.4 Gy and 50.4 Gy in 28 fractions, respectively, while the PTV1 was boosted with six subsequent fractions of 1.8 Gy. Tissue response was calculated using the relative seriality model and the Poisson Linear-Quadratic-Time model to simulate repopulation in the primary tumour.ResultsThe average probability of total tumour control increased from 38% with CONVT to 80% with IFP, to 85% with IMRT1 and 89% with IMRT2. The shorter treatment time and larger dose per fraction obtained with IMRT2 resulted in an 11% increase in the probability of control in the PTV1 with respect to IFP and 7% relatively to IMRT1 (p < 0.05). The average probability of total patient complications was reduced from 80% with CONVT to 61% with IFP and 31% with IMRT. The corresponding probability of complications in the ipsilateral parotid was 63%, 42% and 20%; in the contralateral parotid it was 50%, 20% and 9%; in the oral cavity it was 2%, 15% and 4% and in the mandible it was 1%, 5% and 3%, respectively.ConclusionsA significant improvement in treatment outcome was obtained with IMRT compared to conventional radiation therapy. The practical and biological advantages of IMRT2, employing a shorter treatment time, may outweigh the small differences obtained in the organs at risk between the two IMRT techniques. This technique is therefore presently being used in the clinic for selected patients with head and neck tumours. A significant improvement in the quality of the dose distribution was obtained with IFP compared to CONVT. Thus, this beam arrangement is used in the clinical routine as an alternative to IMRT.

Dose–response relations for stricture in the proximal oesophagus from head and neck radiotherapy

Background and purpose Determination of the dose–response relations for oesophageal stricture after radiotherapy of the head and neck. Material and methods In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5 cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992–2000 and 2001–2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model. Results For the treatment period 1992–2005, the mean doses were 49.8 and 33.4 Gy, respectively, for the cases and the controls. For the period 1992–2000, the mean doses for the cases and the controls were 49.9 and 45.9 Gy and for the period 2001–2005 were 49.8 and 21.4 Gy. For the period 2001–2005 the best estimates of the dose–response parameters are D 50 = 61.5 Gy (52.9–84.9 Gy), γ = 1.4 (0.8–2.6) and s = 0.1 (0.01–0.3). Conclusions Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001–2005. However, no dose response relation was found for the complete material.

Investigation of source position uncertainties &amp; balloon deformation in MammoSite brachytherapy on treatment effectiveness

The MammoSite breast high dose rate brachytherapy is used in treatment of early-stage breast cancer. The tumour bed volume is irradiated with high dose per fraction in a relatively small number of fractions. Uncertainties in the source positioning and MammoSite balloon deformation will alter the prescribed dose within the treated volume. They may also expose the normal tissues in balloon proximity to excessive dose. The purpose of this work is to explore the impact of these two uncertainties on the MammoSite dose distribution in the breast using dose volume histograms and Monte Carlo simulations. The Lyman-Kutcher and relative seriality models were employed to estimate the normal tissues complications associated with the MammoSite dose distributions. The tumour control probability was calculated using the Poisson model. This study gives low probabilities for developing heart and lung complications. The probability of complications of the skin and normal breast tissues depends on the location of the source inside the balloon and the volume receiving high dose. Incorrect source position and balloon deformation had significant effect on the prescribed dose within the treated volume. A 4 mm balloon deformation resulted in reduction of the tumour control probability by 24%. Monte Carlo calculations using EGSnrc showed that a deviation of the source by 1 mm caused approximately 7% dose reduction in the treated target volume at 1 cm from the balloon surface. In conclusion, accurate positioning of the (192)Ir source at the balloon centre and minimal balloon deformation are critical for proper dose delivery with the MammoSite brachytherapy applicator. On the basis of this study, we suggest that the MammoSite treatment protocols should allow for a balloon deformation of < or = 2 mm and a maximum source deviation of < or = 1 mm.

Dose convolution filter: Incorporating spatial dose information into tissue response modeling

A model is introduced to integrate biological factors such as cell migration and bystander effects into physical dose distributions, and to incorporate spatial dose information in plan analysis and optimization. The model consists of a dose convolution filter (DCF) with single parameter sigma. Tissue response is calculated by an existing NTCP model with DCF-applied dose distribution as input. The authors determined sigma of rat spinal cord from published data. The authors also simulated the GRID technique, in which an open field is collimated into many pencil beams. After applying the DCF, the NTCP model successfully fits the rat spinal cord data with a predicted value of sigma = 2.6 +/- 0.5 mm, consistent with 2 mm migration distances of remyelinating cells. Moreover, it enables the appropriate prediction of a high relative seriality for spinal cord. The model also predicts the sparing of normal tissues by the GRID technique when the size of each pencil beam becomes comparable to sigma. The DCF model incorporates spatial dose information and offers an improved way to estimate tissue response from complex radiotherapy dose distributions. It does not alter the prediction of tissue response in large homogenous fields, but successfully predicts increased tissue tolerance in small or highly nonuniform fields.

Probabilities of Pulmonary and Cardiac Complications and Radiographic Parameters in Breast Cancer Radiotherapy

Purpose: To evaluate the relationship between the normal tissue complication probability (NTCP) of 3- dimensional (3-D) radiotherapy and the radiographic parameters of 2-dimensional (2-D) radiotherapy such as central lung distance (CLD) and maximal heart distance (MHD). Materials and Methods: We analyzed 110 patients who were treated with postoperative radiotherapy for breast cancer. A two-field tangential technique, a three-field technique, and the reverse hockey stick method were used. The radiation dose administered to whole breast or the chest wall was 50.4 Gy, whereas a 45 Gy was administered to the supraclavicular field. The NTCPs of the hea rt and lung were calculated by the modified Lyman model and the relative seriality model. Results : For all patients, the NTCPs of radiation-induced pneumonitis and cardiac mortality were 0.5% and 0.7%, respectively. The NTCP of radiation-induced pneumonitis was higher in patients treated with the reverse hockey stick method than in those treated by other two techniques (0.0%, 0.0%, 3.1%, p <0.001). The NTCP of radiation-induced pneumonitis increased with CLD. The NTCP of cardiac mortality increased with MHD (R 2 =0.808). Conclusion : We found a close correlation between the NTCP of 3-D radiothe rapy and 2-D radiographic parameters. Our results are useful to reanalyze the previous 2- D based clinical reports about breast radiation therapy complications as a viewpoint of NTCP.

Radiobiological evaluation of the influence of dwell time modulation restriction in HIPO optimized HDR prostate brachytherapy implants.

PurposeOne of the issues that a planner is often facing in HDR brachytherapy is the selective existence of high dose volumes around some few dominating dwell positions. If there is no information available about its necessity (e.g. location of a GTV), then it is reasonable to investigate whether this can be avoided. This effect can be eliminated by limiting the free modulation of the dwell times. HIPO, an inverse treatment plan optimization algorithm, offers this option. In treatment plan optimization there are various methods that try to regularize the variation of dose non-uniformity using purely dosimetric measures. However, although these methods can help in finding a good dose distribution they do not provide any information regarding the expected treatment outcome as described by radiobiology based indices.Material and methodsThe quality of 12 clinical HDR brachytherapy implants for prostate utilizing HIPO and modulation restriction (MR) has been compared to alternative plans with HIPO and free modulation (without MR). All common dose-volume indices for the prostate and the organs at risk have been considered together with radiobiological measures. The clinical effectiveness of the different dose distributions was investigated by calculating the response probabilities of the tumors and organs-at-risk (OARs) involved in these prostate cancer cases. The radiobiological models used are the Poisson and the relative seriality models. Furthermore, the complication-free tumor control probability, P+ and the biologically effective uniform dose () were used for treatment plan evaluation and comparison.ResultsOur results demonstrate that HIPO with a modulation restriction value of 0.1-0.2 delivers high quality plans which are practically equivalent to those achieved with free modulation regarding the clinically used dosimetric indices. In the comparison, many of the dosimetric and radiobiological indices showed significantly different results. The modulation restricted clinical plans demonstrated a lower total dwell time by a mean of 1.4% that was proved to be statistically significant (p = 0.002). The HIPO with MR treatment plans produced a higher P+ by 0.5%, which stemmed from a better sparing of the OARs by 1.0%.ConclusionsBoth the dosimetric and radiobiological comparison shows that the modulation restricted optimization gives on average similar results with the optimization without modulation restriction in the examined clinical cases. Concluding, based on our results, it appears that the applied dwell time regularization technique is expected to introduce a minor improvement in the effectiveness of the optimized HDR dose distributions.

A Comparison of Dose–Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulated salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD(50) in these models was approximately 39 Gy. The mean dose model was preferred for describing the dose-response relationship of the parotid gland.

BIOSUITE, NEW SOFTWARE FOR RADIOBIOLOGICAL CUSTOMISATION OF DOSE AND FRACTON SIZE IN EBRT

Purpose: BioSuite is a program developed to help clinicians to identify cases eligible for escalation and/or altered fractionation and to quantify this potential using biological models of normal tissue and tumour response to EBRT. Materials: BioSuite consists in a single executable file developed in C++. The input data are DVHs from a TPS (Philips Pinnacle) as well as a more general DVH format. Plans are defined by parameters such as the number of fractions or a default prescription dose. These DVHs are in turn associated with an endpoint defined by a biological model and a set of parameters. From these models (LKB, Relative Seriality and enhanced LQ Poisson TCP), evaluation of NTCP or TCP can be performed forwardly or inversely. The forward evaluation is made in real-time as the operator modifies plan or endpoint parameters. The inverse evaluation (or optimisation) finds the dose multiplication factor (DMP) rescaling the DVH or number of fractions of a given size which take the complication risk to a prior set level. An isotoxic can also be done, which consists of computing for a fraction-number range the highest DMP (and thus TCP) for a constant NTCP. An upper TCP limit can be set (e.g. 99%) to avoid excessive doses in particular cases. The operator can finally generate dose-response curves to visually assess plan quality. Isotoxic optimisation was applied to 33 plans from our institution whose DVHs were exported to BIOSUITE. Results: For most of these plans, scope for escalation and/or altered fractionation was found, suggesting these patients were undertreated. In cases with a very small tumour and consequently small volume of irradiated normal tissue, the models implemented in BioSuite suggested treatments very similar to those currently done in SBRT i.e. TCP close to 100% for as low as 3 fractions. Serial organ DVHs in the plan can drastically affect the BIOSUITE fractionation strategy, making hypofractionation no longer viable.