Radiation treatment monitoring with DCE-US in CWR22 prostate tumor xenografts.

BACKGROUND: Longitudinal monitoring of potential radiotherapy treatment effects can be determined by dynamic contrast-enhanced ultrasound (DCE-US). PURPOSE: To assess functional parameters by means of DCE-US in a murine subcutaneous model of human prostate cancer, and their relationship to dose deposition and time-frame after treatment. A special focus has been placed to evaluate the vascular heterogeneity of the tumor and on the most suitable data analysis approach that reflects this heterogeneity. MATERIAL AND METHODS: In vivo DCE-US was acquired 24 h and 48 h after radiation treatment with a single dose of 7.5 Gy and 10 Gy, respectively. Tumor vasculature was characterized pixelwise using the Brix pharmacokinetic analysis of the time-intensity curves. RESULTS: Longitudinal changes were detected ( P < 0.001) at 24 h and 48 h after treatment. At 48 h, the eliminating rate constant of the contrast agent from the plasma, kel, was correlated ( P ≤ 0.05) positively with microvessel density (MVD; rτ = 0.7) and negatively with necrosis (rτ = -0.6) for the treated group. Furthermore, Akep, a parameter related to transcapillary transport properties, was also correlated to MVD (rτ = 0.6, P ≤ 0.05). CONCLUSION: DCE-US has been shown to detect vascular changes at a very early stage after radiotherapy, which is a great advantage since DCE-US is non-invasive, available at most hospitals, and is low in cost compared to other techniques used in clinical practice.

Radiation treatment monitoring using multimodal functional imaging: PET/CT ((18)F-Fluoromisonidazole & (18)F-Fluorocholine) and DCE-US.

BACKGROUND: This study aims to assess the effect of radiation treatment on the tumour vasculature and its downstream effects on hypoxia and choline metabolism using a multimodal approach in the murine prostate tumour model CWR22. Functional parameters derived from Positron Emission Tomography (PET)/Computer Tomography (CT) with (18)F-Fluoromisonidazole ((18)F-FMISO) and (18)F-Fluorocholine ((18)F-FCH) as well as Dynamic Contrast-Enhanced Ultrasound (DCE-US) were employed to determine the relationship between metabolic parameters and microvascular parameters that reflect the tumour microenvironment. Immunohistochemical analysis was employed for validation. METHODS: PET/CT and DCE-US were acquired pre- and post-treatment, at day 0 and day 3, respectively. At day 1, radiation treatment was delivered as a single fraction of 10 Gy. Two experimental groups were tested for treatment response with (18)F-FMISO and (18)F-FCH. RESULTS: The maximum Standardized Uptake Values (SUVmax) and the mean SUV (SUVmean) for the (18)F-FMISO group were decreased after treatment, and the SUVmean of the tumour-to-muscle ratio was correlated to microvessel density (MVD) at day 3. The kurtosis of the amplitude of the contrast uptake A was significantly decreased for the control tumours in the (18)F-FCH group. Furthermore, the eliminating rate constant of the contrast agent from the plasma k el derived from DCE-US was negatively correlated to the SUVmean of tumour-to-muscle ratio, necrosis and MVD. CONCLUSIONS: The present study suggests that the multimodal approach using (18)F-FMISO PET/CT and DCE-US seems reliable in the assessment of both microvasculature and necrosis as validated by histology. Thus, it has valuable diagnostic and prognostic potential for early non-invasive evaluation of radiotherapy.

Vascular responses to radiotherapy and androgen-deprivation therapy in experimental prostate cancer.

BACKGROUND: Radiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC. METHODS: Using mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI. RESULTS: Compared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density (VD), and vessel area fraction (VF) from qIHC. Although total hypoxic fractions ( HF) did not change, estimated acute hypoxia scores (AHS)--the proportion of hypoxia staining within 50 µm from perfusion staining--were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve (AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size (VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after pharmacokinetic modeling. Interestingly, such modeling also detected tumor necrosis very strongly. CONCLUSIONS: DCE MRI reliably allows non-invasive assessment of tumors' vascular function. The findings of increased tumor vascularization after ADT encourage further studies into whether these changes are beneficial for combined RT, or if treatment with anti-angiogenic therapy may be a strategy to improve the therapeutic efficacy of ADT in advanced PC.

Liposomal doxorubicin improves radiotherapy response in hypoxic prostate cancer xenografts.

BACKGROUND: Tumor vasculature frequently fails to supply sufficient levels of oxygen to tumor tissue resulting in radioresistant hypoxic tumors. To improve therapeutic outcome radiotherapy (RT) may be combined with cytotoxic agents. METHODS: In this study we have investigated the combination of RT with the cytotoxic agent doxorubicin (DXR) encapsulated in pegylated liposomes (PL-DXR). The PL-DXR formulation Caelyx was administered to male mice bearing human, androgen-sensitive CWR22 prostate carcinoma xenografts in a dose of 3.5 mg DXR/kg, in combination with RT (2 Gy/day × 5 days) performed under normoxic and hypoxic conditions. Hypoxic RT was achieved by experimentally inducing tumor hypoxia by clamping the tumor-bearing leg five minutes prior to and during RT. Treatment response evaluation consisted of tumor volume measurements and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) with subsequent pharmacokinetic analysis using the Brix model. Imaging was performed pre-treatment (baseline) and 8 days later. Further, hypoxic fractions were determined by pimonidazole immunohistochemistry of excised tumor tissue. RESULTS: As expected, the therapeutic effect of RT was significantly less effective under hypoxic than normoxic conditions. However, concomitant administration of PL-DXR significantly improved the therapeutic outcome following RT in hypoxic tumors. Further, the pharmacokinetic DCE MRI parameters and hypoxic fractions suggest PL-DXR to induce growth-inhibitory effects without interfering with tumor vascular functions. CONCLUSIONS: We found that DXR encapsulated in liposomes improved the therapeutic effect of RT under hypoxic conditions without affecting vascular functions. Thus, we propose that for cytotoxic agents affecting tumor vascular functions liposomes may be a promising drug delivery technology for use in chemoradiotherapy.

Early prediction of response to radiotherapy and androgen-deprivation therapy in prostate cancer by repeated functional MRI: a preclinical study.

BACKGROUND: In modern cancer medicine, morphological magnetic resonance imaging (MRI) is routinely used in diagnostics, treatment planning and assessment of therapeutic efficacy. During the past decade, functional imaging techniques like diffusion-weighted (DW) MRI and dynamic contrast-enhanced (DCE) MRI have increasingly been included into imaging protocols, allowing extraction of intratumoral information of underlying vascular, molecular and physiological mechanisms, not available in morphological images. Separately, pre-treatment and early changes in functional parameters obtained from DWMRI and DCEMRI have shown potential in predicting therapy response. We hypothesized that the combination of several functional parameters increased the predictive power. METHODS: We challenged this hypothesis by using an artificial neural network (ANN) approach, exploiting nonlinear relationships between individual variables, which is particularly suitable in treatment response prediction involving complex cancer data. A clinical scenario was elicited by using 32 mice with human prostate carcinoma xenografts receiving combinations of androgen-deprivation therapy and/or radiotherapy. Pre-radiation and on days 1 and 9 following radiation three repeated DWMRI and DCEMRI acquisitions enabled derivation of the apparent diffusion coefficient (ADC) and the vascular biomarker Ktrans, which together with tumor volumes and the established biomarker prostate-specific antigen (PSA), were used as inputs to a back propagation neural network, independently and combined, in order to explore their feasibility of predicting individual treatment response measured as 30 days post-RT tumor volumes. RESULTS: ADC, volumes and PSA as inputs to the model revealed a correlation coefficient of 0.54 (p < 0.001) between predicted and measured treatment response, while Ktrans, volumes and PSA gave a correlation coefficient of 0.66 (p < 0.001). The combination of all parameters (ADC, Ktrans, volumes, PSA) successfully predicted treatment response with a correlation coefficient of 0.85 (p < 0.001). CONCLUSIONS: We have in a preclinical investigation showed that the combination of early changes in several functional MRI parameters provides additional information about therapy response. If such an approach could be clinically validated, it may become a tool to help identifying non-responding patients early in treatment, allowing these patients to be considered for alternative treatment strategies, and, thus, providing a contribution to the development of individualized cancer therapy.

Predicted risk of radiation-induced cancers after involved field and involved node radiotherapy with or without intensity modulation for early-stage hodgkin lymphoma in female patients.

PURPOSE: To assess the excess relative risk (ERR) of radiation-induced cancers (RIC) in female patients with Hodgkin lymphoma (HL) female patients treated with conformal (3DCRT), intensity modulated (IMRT), or volumetric modulated arc (RA) radiation therapy. METHODS AND MATERIALS: Plans for 10 early-stage HL female patients were computed for 3DCRT, IMRT, and RA with involved field RT (IFRT) and involvednode RT (INRT) radiation fields. Organs at risk dose--volume histograms were computed and inter-compared for IFRT vs. INRT and 3DCRT vs. IMRT/RA, respectively. The ERR for cancer induction in breasts, lungs, and thyroid was estimated using both linear and nonlinear models. RESULTS: The mean estimated ERR for breast, lung, and thyroid were significantly lower (p < 0.01) with INRT than with IFRT planning, regardless of the radiation delivery technique used, assuming a linear dose-risk relationship. We found that using the nonlinear model, the mean ERR values were significantly (p < 0.01) increased with IMRT or RA compared to those with 3DCRT planning for the breast, lung, and thyroid, using an IFRT paradigm. After INRT planning, IMRT or RA increased the risk of RIC for lung and thyroid only. CONCLUSIONS: In this comparative planning study, using a nonlinear dose--risk model, IMRT or RA increased the estimated risk of RIC for breast, lung, and thyroid for HL female patients. This study also suggests that INRT planning, compared to IFRT planning, may reduce the ERR of RIC when risk is predicted using a linear model. Observing the opposite effect, with a nonlinear model, however, questions the validity of these biologically parameterized models.

Preclinical dynamic 18F-FDG PET - tumor characterization and radiotherapy response assessment by kinetic compartment analysis.

BACKGROUND: Non-invasive visualization of tumor biological and molecular processes of importance to diagnosis and treatment response is likely to be critical in individualized cancer therapy. Since conventional static (18)F-FDG PET with calculation of the semi-quantitative parameter standardized uptake value (SUV) may be subject to many sources of variability, we here present an approach of quantifying the (18)F-FDG uptake by analytic two-tissue compartment modeling, extracting kinetic tumor parameters from dynamic (18)F-FDG PET. Further, we evaluate the potential of such parameters in radiotherapy response assessment. MATERIAL AND METHODS: Male, athymic mice with prostate carcinoma xenografts were subjected to dynamic PET either untreated (n=8) or 24 h post-irradiation (7.5 Gy single dose, n=8). After 10 h of fasting, intravenous bolus injections of 10-15 MBq (18)F-FDG were administered and a 1 h dynamic PET scan was performed. 4D emission data were reconstructed using OSEM-MAP, before remote post-processing. Individual arterial input functions were extracted from the image series. Subsequently, tumor (18)F-FDG uptake was fitted voxel-by-voxel to a compartment model, producing kinetic parameter maps. RESULTS: The kinetic model separated the (18)F-FDG uptake into free and bound tracer and quantified three parameters; forward tracer diffusion (k(1)), backward tracer diffusion (k(2)), and rate of (18)F-FDG phosphorylation, i.e. the glucose metabolism (k(3)). The fitted kinetic model gave a goodness of fit (r(2)) to the observed data ranging from 0.91 to 0.99, and produced parametrical images of all tumors included in the study. Untreated tumors showed homogeneous intra-group median values of all three parameters (k(1), k(2) and k(3)), whereas the parameters significantly increased in the tumors irradiated 24 h prior to (18)F-FDG PET. CONCLUSIONS: This study demonstrates the feasibility of a two-tissue compartment kinetic analysis of dynamic (18)F-FDG PET images. If validated, extracted parametrical maps might contribute to tumor biological characterization and radiotherapy response assessment.

CT density in lung cancer patients after radiotherapy sensitized by metoclopramide. A subgroup analysis of a randomized trial.

PURPOSE: To investigate the lung tissue response measured with computed tomography (CT) after radiotherapy (RT) combined with metoclopramide. PATIENTS AND METHODS: Patients with non-small cell lung cancer (tumor stage IIIA and IIIB), included in a multicenter, randomized phase III trial investigating the use of metoclopramide as a radiosensitizing agent, were examined with repetitive post-RT CT scans. The analysis comprised data up to 100 days after RT for a subgroup of 16 patients treated with a total dose of 60 Gy given in 1.82 Gy per fraction. RESULTS: Large radiation doses to subvolumes were associated with denser lung tissue measured with CT (p < 0.001). Opposed to this finding, the volume of lung tissue irradiated with significant doses (V(40Gy)) was negatively correlated with the average increase in lung tissue density (p = 0.003). Patients randomized to metoclopramide injections also experienced less increase in lung tissue density (p = 0.01). CONCLUSION: There was an increase in the density of irradiated lung tissue with radiation dose and time after RT. Metoclopramide and significant radiation doses to larger lung volumes (V(40Gy)) seemed to protect against fibrosis development.

Dynamic contrast enhanced magnetic resonance imaging of bladder cancer and implications for biological image-adapted radiotherapy.

PURPOSE: To assess the role of image parameters derived from dynamic contrast enhanced magnetic resonance imaging (DCEMRI) in bladder cancer staging, and to investigate the potential use of such parameter images in biological image-adapted radiotherapy (RT). MATERIALS AND METHODS: High-resolution volumetric interpolated breath-hold (VIBE) DCEMRI of 26 patients diagnosed with bladder cancer was performed. DCEMRI parameters derived from tumor and muscle contrast uptake curves were extracted and subjected to correlation analysis with tumor volume as well as clinical, pathological, histological and T2-weighted MR tumor stage. For parameters showing a significant correlation with tumor stage, 3D malignancy maps were generated. As an initial step towards delivery of biologically adapted intensity modulated radiotherapy (IMRT) it was hypothesized that the malignancy map could be used as a RT dose prescription map. Simulating IMRT delivery with multi-leaf collimators (MLCs), idealized dose distributions, constituted by dose cubes, were adapted to the prescription map. The size of the dose cubes were varied to mimic MLCs of varying leaf width. The difference between the adapted and prescribed dose distributions was quantified by the root mean square deviation (RMSD). RESULTS: No significant relationships were found between tumor volume and extracted DCEMRI parameters. The normalized area between tumor and muscle contrast uptake curves (nABC) evaluated from 0-180 seconds (nABC(180)) and 0-480 s (nABC(480)) correlated significantly with tumor stage (p=0.047 and p=0.035, respectively). Dose prescription maps for 10 patients were generated from the nABC(480). The RMSD between the prescribed and adapted dose distribution decreased with decreasing size of the dose cubes. Large interpatient variations in the RMSD and in the dependence of the RMSD on different dose cube sizes were found. CONCLUSIONS: The nABC(180) and nABC(480) may provide added value in staging of bladder cancer. High-resolution IMRT is required for some patients for optimal adapted RT.

Radiological and functional assessment of radiation-induced pulmonary damage following breast irradiation.

PURPOSE: The purpose of this study was to compare late radiation-induced radiological abnormalities of the lung with spirometric observations. Radiological abnormalities were also related to theoretical calculations, in order to predict late effects based on dose-volume histograms. PATIENTS AND METHODS: Sixty-one breast cancer patients who had received postoperative radiotherapy were included. During a follow-up examination 3 years or more after start of radiotherapy, computed tomography (CT) scans and pulmonary function tests were performed. Grading of radiological abnormalities (fibrosis) was performed based on CT images. Based on the dose volume histograms of the lung, effective dose was calculated. RESULTS: There was a positive correlation between the effective radiation dose and the fraction of patients that developed radiation induced fibrosis. No significant association was found between the normalized forced vital capacity (FVC) and the radiological abnormality score or the effective radiation dose. CONCLUSION: In this study we found no correlation between local radiation-induced changes in the lung tissue and overall lung function. The effective dose was a better predictive factor for radiation induced fibrosis than for overall lung function.

Quality assurance of dosimetry and the impact on sample size in randomized clinical trials.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the impact of appropriate dosimetry quality assurance (QA) on patient number required in radiotherapy randomized control trials (RCT). MATERIALS AND METHODS: The steepness of clinical dose-response curves, gamma(clin.), was calculated by a convoluting a biological dose-response distribution and the distribution of technical and dosimetrical factors. Population size calculation was performed taking into account gamma(clin.) and expected difference in outcome between two arms of an RCT, for different levels of variation in dose to the patient population. RESULTS: Uncertainties in dose reduces gamma(clin.) to the largest extent when the initial gamma-value is high and less so for low gamma-value. Reduced uncertainty in dose led to a significant reduction in the number of patients required in an RCT if the expected difference between the experimental and conventional arm is small. The reduction in patient numbers is less when the differences between the conventional and experimental arm is larger. CONCLUSION: The number of patients required in an RCT may be reduced by introducing appropriate dosimetry QA as the risk of under-powering the study is minimized. Dosimetry QA in clinical studies is therefore cost-effective.

Analysis of normal tissue complication probability of the lung using a reliability model.

The volume effect of normal tissues and organs is an important factor for predicting normal tissue complication probability (NTCP) following partial, heterogeneous irradiation of organs at risk, and reducing the late sequela by conformal radiation therapy. We have previously developed a reliability model for calculation of NTCP, assuming a parallel architecture of functional subunits (FSU), where a critical number (k) out of the total number of FSUs (N) must be intact for the organ to maintain its function. Published data on radiation-induced lethal pneumonitis and altered breathing rate following partial volume irradiation of the mouse lung were analysed, and critical fraction and corresponding spatial density distribution of FSUs were estimated using this model. The critical fraction (k/N) seemed to be similar for the two endpoints, and a value of 0.7 was found to provide good fit to the experimental data. The critical fraction did not vary throughout the lung, and variation in volume effect cannot therefore be attributed to heterogeneous tissue architecture. On the other hand, our analysis revealed that the observed variation in volume effect of mouse lung may be attributed to heterogeneous spatial distribution in FSU density or also the spatial variation in inactivation probability of the FSUs.

Fluctuations in pO2 in poorly and well-oxygenated spontaneous canine tumors before and during fractionated radiation therapy.

BACKGROUND AND PURPOSE: The spatial heterogeneity in oxygen tension (pO2) in tumor tissue has been studied extensively, whereas, the information about the temporal heterogeneity is sparse. The purpose of the present study was to search for pO2 fluctuations in untreated and irradiated spontaneous canine tumors, and to investigate whether there is a relationship between overall tumor oxygenation status and pO2 fluctuation pattern. PATIENTS AND METHODS: Six dogs scheduled for radiation therapy of head and neck cancer were included in the study. The primary tumors were irradiated with 18 fractions of 3 Gy. Eppendorf polarographic electrodes and OxyLite fluorescence probes were used to measure overall oxygenation status and pO2 fluctuation pattern, respectively. Tissue pO2 was recorded at three subsequent days prior to treatment, and immediately before radiation fraction 4, 7, and 10. RESULTS: Overall oxygenation status differed substantially among the tumors. Radiation therapy had no consistent effect on overall oxygenation status. Fluctuations in pO2 were detected in untreated as well as irradiated tumors, and independent of whether the tumors were poorly or well oxygenated. CONCLUSIONS: Fluctuations in pO2 can occur in untreated and irradiated spontaneous canine tumors. There is no correlation between pO2 fluctuation pattern and overall tumor oxygenation status.

Telemedicine in radiotherapy: a study exploring remote treatment planning, supervision and economics.

In January 2002, the departments of radiotherapy at the University Hospital of North Norway and the Norwegian Radium Hospital were connected through a 2 Mbit/s digital telecommunication line. The treatment planning systems at the two institutions were connected and videoconferencing units were installed. We explored the feasibility of remote treatment planning, supervision, second opinions and education. Tests involved two dummy cases and six patients. Remote simulation procedures were carried out for five patients. A cost-minimization analysis was performed. Treatment planning was not completely successful as the software could not handle plans including bolus or weighting between the fields. Remote supervision was possible. A common patient record and radiotherapy system, including digital imaging, digital prescription and approval forms and digital signature, were felt to be desirable. The threshold (break-even point) comparing the costs of telemedicine with those of transportation by air was 12 patients/year. Telemedicine in radiotherapy appears to be feasible, but some limitations must be overcome.

Tumor-line specific pO(2) fluctuations in human melanoma xenografts.

PURPOSE: A large number of studies have demonstrated that tumors are heterogeneous in oxygen tension (pO(2)) and may develop regions with chronically or acutely hypoxic cells during growth. In the present study, it was investigated whether experimental tumors of different lines may show characteristic pO(2) fluctuation patterns and hence may differ with respect to the kinetics of acute hypoxia. METHODS AND MATERIALS: A total of 70 xenografted tumors of two human melanoma lines (A-07 and R-18) were included in the study. Tissue pO(2) was measured simultaneously in two positions in each tumor for periods of at least 60 min using a two-channel fiberoptic oxygen-sensing device (OxyLite 2000, Oxford Optronix, Oxford, UK). RESULTS: The mean pO(2) was calculated for each pO(2) trace, and this parameter was significantly greater in A-07 than in R-18 tumors (p <0.000001). Fluctuations in pO(2) around 3, 5, or 10 mm Hg were seen in a large fraction of the tumors of both lines. The pO(2) fluctuation frequency differed among individual traces from 0 to 20/h (A-07) and from 0 to 12/h (R-18) and was significantly greater in A-07 than in R-18 tumors (p = 0.0026). The absolute amplitude of the pO(2) fluctuations ranged from 1 to 16 mm Hg (A-07) and 1 to 33 mm Hg (R-18) and did not differ between the tumor lines. The relative amplitude was significantly higher in R-18 than in A-07 tumors (p <0.000001). The pO(2) values recorded simultaneously in the same tumor were in general not temporally coordinated. CONCLUSION: Experimental tumors of different lines may show individual and characteristic pO(2) fluctuation patterns. The pO(2) fluctuations may result in regions with acutely hypoxic cells. The kinetics of the acute hypoxia may differ among tumors of different lines, individual tumors of the same line, and different regions within the same tumor.

Changes in treatment volume of hormonally treated and untreated cancerous prostate and its impact on rectal dose.

Late chronic side effects of the rectum constitute one of the principal limiting factors for curative radiation therapy in patients with prostate cancer. The purpose of the study was to determine the impact of immediate androgen deprivation (IAD) prior to conformal radiotherapy on rectal volume exposed to high doses, as compared with a deferred treatment strategy (DAD). Twenty-five patients (13 in the IAD group and 12 in the DAD group) with bulky tumours of the prostate, T3pN1-2M0 from the prospective EORTC trial 30846 were analysed. Three-dimensional conformal radiation treatment plans (3DCRT) using a 4-field box technique were generated based on the digitized computed tomographic or magnetic resonance findings acquired during the first 9 months after inclusion in the EORTC trial. Dose-volume histograms (DVHs) were calculated for the prostate and rectum. In the DAD group, there was no obvious alteration in the mean size of the prostate or other evaluated structures. In the IAD patients, a statistically significant reduction of approximately 40% of the gross tumour volume (GTV) was reached after a 6 months' course of hormonal treatment (p < 0.001). High-dose rectal volume was correlated with the volume changes of the GTV (p < 0.001). Mean rectal volume receiving 95% or more of the target dose was significantly reduced by 20%. Our study confirms the effect of downsizing of locally advanced prostate tumours following AD treatment and demonstrates the interdependence of the high-dose rectal volume with the volume changes of the GTV. However, the mean beneficial sparing of rectal volume was outweighed in some patients by considerable inter-patient variations.

Modeling volume effects of experimental brachytherapy in the rat rectum: uncovering the limitations of a radiobiologic concept.

PURPOSE: To analyze the significance of volume effects in experimental brachytherapy, based on modeling normal tissue complication probability. METHODS AND MATERIALS: Experimental brachytherapy in the rat rectum was based on an eight-step 2.5-mm step size source configuration for 192Ir, afterloaded into an unshielded polystyrene applicator. Volume effects were studied using a half-circumferential lead-shielded applicator and a shorter (two-step) source configuration. The main end point was rectal stenosis. RESULTS: Rectal stenosis was always caused by a radiation ulcer. With the shielded configuration, single-dose ED50 (50% incidence of rectal stenosis) increased from 23 Gy to 36.5 Gy. Single-dose ED50 for the short configuration was 77.9 Gy. The data showed a reasonable fit to a three-parameter version of the biophysical model described by Jackson et al. (1995). This model assumes that organs consist of a large number of radiobiologically independent subunits and that radiation causes a complication if the fraction of the organ damaged is greater than its functional reserve. The fraction of the organ damaged is calculated summing over fractions of the organ damaged at each dose level. The calculated mean functional reserve (nu50) of the rat rectum, assuming a cumulative functional reserve distribution in the group of experimental rats, was 0.53. CONCLUSIONS: The volume effect observed within small brachytherapy volumes agreed well with clinical experience of large tolerance doses in contact X-ray therapy. However, the nu50 value was comparable to the high functional reserve value reported for liver. Experimental volume effects probably reflect repair processes originating in the areas adjacent to small radiation fields of brachytherapy more than the radiobiologic characteristics of the cells in the irradiated volume.

Side effects and quality of life after inadvertent radiation overdosage in brachytherapy of head-and-neck cancer.

PURPOSE: By comparing our old (DP5, in use from 1978 to 1994) and new (Plato, Nucletron) dose planning system, we found that the old system underestimated doses by 20-25%. To study the possible consequences for the patients treated between 1978 and 1994, all who were still alive were invited to undergo an examination with respect to side effects and quality of life (QOL). MATERIALS AND METHODS: The degree of overdosage was calculated by comparing the isodose distribution generated on the two dose planning systems. Eighty-four patients were then invited to undergo an examination with respect to side effects and QOL. The side effects were scored according to the LENT SOMA system and QOL according to European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), and EORTC Quality of Life Questionnaire-Head & Neck 35 (QLQ-H&N35). RESULTS: The mean overdosage of brachytherapy was 19.3%. No association was found between overdosage and side effects or QOL. For implants in the lateral border of the tongue, we found a statistically significant correlation between osteoradionecrosis and the following parameters: linear activity, total activity, dose rate, and extrapolated response dose. By multivariate analysis, only total implanted activity and the use of lead protection during brachytherapy were found to be of prognostic significance with respect to development of osteoradionecrosis. CONCLUSION: The incidence of side effects after brachytherapy at the Norwegian Radium Hospital seems to have been somewhat higher in the period under investigation than at other institutions. There may be several explanations, including the use of external beam radiotherapy before brachytherapy and departure from the Paris system among others. However, the side effects were not associated with the overdosage that was the basis for the study. As opposed to the general consensus of opinion, long-term QOL was found to be worse after brachytherapy than after external beam radiotherapy. This calls for increased awareness and a systematic prospective registration of the long-term side effects of brachytherapy.