Investigation of 90Y-avidin for prostate cancer brachytherapy: a dosimetric model for a phase I-II clinical study.

PURPOSE: A novel method for prostate irradiation is investigated. Similarly to (125)I or (103)Pd seed brachytherapy, (90)Y-avidin could be injected via the perineum under ultrasound image guidance. This study inspects the theoretical feasibility with a dosimetric model based on Monte Carlo simulation. METHODS: A geometrical model of the prostate, urethra and rectum was designed. The linear-quadratic model was applied to convert (125)I absorbed dose prescription/constraints into (90)Y dose through biological effective dose (BED) calculation. The optimal (90)Y-avidin injection strategy for the present model was obtained. Dose distribution was calculated by Monte Carlo simulation (PENELOPE,GEANT4). Dose volume histograms (DVH) for the prostate, urethra and rectum were compared to typical DVHs of (125)I seed brachytherapy, used routinely in our institute. RESULTS: With (90)Y-avidin, at least 95% of the prostate must receive more than 70 Gy. The absorbed dose to 10% of the urethra (D(10%_urethra)) and the maximum absorbed dose to the rectum (D(max_rectum)) must be lower than 122 Gy. For the present model, the optimum strategy consists in multiple injections of (90)Y-avidin 50 µl drops, for a total volume of 3.1 ml. The minimum activity to deliver the prescribed absorbed dose is 0.7 GBq, which also fully respects urethral and rectal constraints. The resulting dose map has a maximum in the central region with a sharp decrease towards the urethra and the prostate edge. Notably, D(10%_urethra) is 95 Gy and D(max_rectum) is below 2 Gy. Prostate absorbed dose is higher with (90)Y-avidin than (125)I seeds, although the total volume receiving the prescribed absorbed dose is 1-2% lower. Urethral DVH strictly depends on the (90)Y distribution, to be optimized according to prostate shape; in our model, BED(30%_urethra) is 90 Gy with (90)Y-avidin, whereas for patients receiving (125)I seeds it ranges between 150 and 230 Gy. The rectal DVH is always more favourable with (90)Y. CONCLUSION: The methodology is theoretically feasible and can deliver an effective treatment in T1-T2 prostate cancer. Pharmacokinetic and biodistribution studies in prostate cancer patients are needed for validation.

3D dosimetry in patients with early breast cancer undergoing Intraoperative Avidination for Radionuclide Therapy (IART) combined with external beam radiation therapy.

PURPOSE: Intraoperative Avidination for Radionuclide Therapy (IART) is a novel targeted radionuclide therapy recently used in patients with early breast cancer. It is a radionuclide approach with (90)Y-biotin combined with external beam radiotherapy (EBRT) to release a boost of radiation in the tumour bed. Two previous clinical trials using dosimetry based on the calculation of mean absorbed dose values with the hypothesis of uniform activity distribution (MIRD 16 method) assessed the feasibility and safety of IART. In the present retrospective study, a voxel dosimetry analysis was performed to investigate heterogeneity in distribution of the absorbed dose. The aim of this work was to compare dosimetric and radiobiological evaluations derived from average absorbed dose vs. voxel absorbed dose approaches. METHODS: We evaluated 14 patients who were injected with avidin into the tumour bed after conservative surgery and 1 day later received an intravenous injection of 3.7 GBq of (90)Y-biotin (together with 185 MBq (111)In-biotin for imaging). Sequential images were used to estimate the absorbed dose in the target region according to the standard dosimetry method (SDM) and the voxel dosimetry method (VDM). The biologically effective dose (BED) distribution was also evaluated. Dose/volume and BED volume histograms were generated to derive equivalent uniform BED (EUBED) and equivalent uniform dose (EUD) values. RESULTS: No "cold spots" were highlighted by voxel dosimetry. The median absorbed-dose in the target region was 20 Gy (range 15-27 Gy) by SDM, and the median EUD was 20.4 Gy (range 16.5-29.4 Gy) by the VDM; SDM and VDM estimates differed by about 6 %. The EUD/mean voxel absorbed dose ratio was >0.9 in all patients, indicative of acceptable uniformity in the target. The median BED and EUBED values were 21.8 Gy (range 15.9-29.3 Gy) and 22.8 Gy (range 17.3-31.8 Gy), respectively. CONCLUSION: VDM highlighted the absence of significant heterogeneity in absorbed dose in the target. The EUD/mean absorbed dose ratio indicated a biological efficacy comparable to that of uniform distribution of absorbed dose. The VDM is recommended for improving accuracy, taking into account actual activity distribution in the target region. The radiobiological model applied allowed us to compare the effects of IART® with those of EBRT and to match the two irradiation modalities.

A bonding technique for fixed maxillary retainers.

Maintaining incisor alignment is an important goal of orthodontic retention and can only be guaranteed by placement of an intact, passive and permanent fixed retainer. Here we describe a reliable technique for bonding maxillary retainers and demonstrate all the steps necessary for both technician and clinician. The importance of increasing the surface roughness of the wire and teeth to be bonded, maintaining passivity of the retainer, especially during bonding, the use of a stiff wire and correct placement of the retainer are all discussed. Examples of adverse tooth movement from retainers with twisted and multistrand wires are shown.

Physical and clinical implications of radiotherapy treatment of prostate cancer using a full bladder protocol.

PURPOSE: To assess the dosimetric and clinical implication when applying the full bladder protocol for the treatment of the localized prostate cancer (PCA). PATIENTS AND METHODS: A total of 26 consecutive patients were selected for the present study. Patients underwent two series of CT scans: the day of the simulation and after 40 Gy. Each series consisted of two consecutive scans: (1) full bladder (FB) and (2) empty bladder (EB). The contouring of clinical target volumes (CTVs) and organs at risk (OAR) were compared to evaluate organ motion. Treatment plans were compared by dose distribution and dose-volume histograms (DVH). RESULTS: CTV shifts were negligible in the laterolateral and superior-inferior directions (the maximum shift was 1.85 mm). Larger shifts were recorded in the anterior-posterior direction (95% CI, 0.83-4.41 mm). From the dosimetric point of view, shifts are negligible: the minimum dose to the CTV was 98.5% (median; 95%CI, 95-99%). The potential advantage for GU toxicity in applying the FB treatment protocol was measured: the ratio between full and empty bladder dose-volume points (selected from our protocol) is below 0.61, excluding the higher dose region where DVHs converge. CONCLUSION: Having a FB during radiotherapy does not affect treatment effectiveness, on the contrary it helps achieve a more favorable DVH and lower GU toxicities.

Use of machine learning methods for prediction of acute toxicity in organs at risk following prostate radiotherapy.

PURPOSE: The goal of this study is to investigate the advantages of large scale optimization methods vs conventional classification techniques in predicting acute toxicity for urinary bladder and rectum due to prostate irradiation. METHODS: Clinical and dosimetric data of 321 patients undergoing prostate conformal radiotherapy were recorded. Gastro-intestinal and genito-urinary acute toxicities were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale. Patients were classified in two categories to separate mild (Grade < 2) from severe toxicity levels (Grade > 2). Machine learning methods at different complexity were implemented to predict toxicity as a function of multiple variables. The first approach consisted of a large scale optimization method, based on genetic algorithms (GAs) and artificial neural networks (ANN). The second approach was a binary classifier based on support vector machines (SVM). RESULTS: The ANN and SVM-based solutions showed comparable prediction accuracy, exhibiting an area under the receiver operating characteristic (ROC) curve of 0.7. Different sensitivity and specificity features were measured for the two approaches. The ANN algorithm showed enhanced sensitivity if combined with appropriate classification criteria. CONCLUSIONS: The results demonstrate that high sensitivity in toxicity prediction can be achieved with optimized ANNs, that are put forward to represent a valuable support in medical decisions. Future studies will be focused on enlarging the available patient database to increase the reliability of toxicity prediction algorithms and to define optimal classification criteria.

Sentinel lymph node biopsy in pregnant patients with breast cancer.

PURPOSE: Sentinel lymph node biopsy (SLNB) is currently not recommended in pregnant patients with breast cancer due to radiation concerns. METHODS: Twelve pregnant patients with breast cancer received low-dose (10 MBq on average) lymphoscintigraphy using (99m)Tc human serum albumin nanocolloids. RESULTS: The sentinel lymph node (SLN) was identified in all patients. Of the 12 patients, 10 had pathologically negative SLN. One patient had micrometastasis in one of four SLN. One patient had metastasis in the SLN and underwent axillary clearance. From the 12 pregnancies, 11 healthy babies were born with no malformations and normal weight. One baby, whose mother underwent lymphatic mapping during the 26th week of gestation, was operated on at the age of 3 months for a ventricular septal defect and at 43 months was in good health. This malformation was suspected at the morphological US examination during week 21, well before lymphoscintigraphy, and was confirmed a posteriori by a different observer based on videotaped material. No overt axillary recurrence appeared in the patients with negative SLNs after a median follow-up of 32 months. CONCLUSION: Our experience supports the safety of SLNB in pregnant patients with breast cancer, when performed with a low-dose lymphoscintigraphic technique.

Evaluation of late rectal toxicity after conformal radiotherapy for prostate cancer: a comparison between dose-volume constraints and NTCP use.

PURPOSE: To analyze the reliability of different methods used in evaluating the risk of late rectal toxicity. PATIENTS AND METHODS: The treatment plans of 57 patients treated at the authors' institute between September 1999 and September 2000 for localized prostate cancer using three-dimensional conformal radiotherapy (3D-CRT) were analyzed retrospectively. The expected rate of late rectal toxicity was analyzed (a) by means of the dose-volume histogram (DVH) constraints; (b) by calculating the normal-tissue complication probability (NTCP) using the Lyman-Kutcher-Burman (LKB) model with the radiobiological parameters of either Emami (1991; for toxicity of grade >or= 2) or Rancati (2004; for toxicity of grade >or= 2 and >or= 3). Patients were divided into high-/low-risk (HR/LR) groups and the results were compared to the clinical outcome. RESULTS: (a) The HR percentages were 24% and 5% for radical and postsurgical 3D-CRT, respectively. When applying high-dose constraints only, HR percentages were 18% and 5%, respectively. (b) In the case of the NTCP (grade >or= 2), Emami (1991) HR rates were 16% and 11%, and Rancati (2004) HR rates 29% and 11%, for radical and postsurgical treatment, respectively. Only one case with higher-grade toxicity was found. The reported clinical toxicity was 17.8% and 6.7% for grade >or= 2 toxicity, and 3.7% and 0.7% for grade >or= 3 toxicity, for radical and postsurgical treatment, respectively. CONCLUSION: This study demonstrated that there is an agreement between the toxicity rate evaluated by DVH constraints and by the LKB model and the clinical outcome. In this case, the use of the LKB model can be as reliable as the use of DVH constraints.

Radiation survey around a Liac mobile electron linear accelerator for intraoperative radiation therapy.

The aim of this study was to perform a detailed analysis of the air kerma values around a Liac mobile linear accelerator working in a conventional operating room (OR) for IORT. The Liac delivers electron beams at 4, 6, 8 and 10 MeV. A radiation survey to determine photon leakage and scatter consisted of air kerma measurements on a spherical surface of 1.5 m radius, centered on the titanium exit window of the accelerating structure. Measurements were taken using a 30 cm3 calibrated cylindrical ion chamber in three orthogonal planes, at the maximum electron energy. For each point, 10 Gy was delivered. At selected points, the quality of x-ray radiation was determined by using lead sheets, and measurements were performed for all energies to investigate the energy dependence of stray radiation. The photon scatter contribution from the metallic internal patient-shielding in IORT, used to protect normal tissues underlying the target, was also evaluated. At seven locations outside the OR, the air kerma values derived from in-room measurements were compared to measurements directly performed using a survey meter. The results, for a delivered dose of 10 Gy, showed that the air kerma values ranged from approximately 6 microGy (upper and rear sides of the Liac) to 320 microGy (lateral to beam stopper) in the two orthogonal vertical planes, while values lower than 18 microGy were found in the horizontal plane. At 10 MeV, transmission behind 1 cm lead shield was found to be 42%. The use of internal shielding appeared to increase the photon scatter only slightly. Air kerma values outside the OR were generally lower than 1 mGy for an annual workload of 200 patients. Thus, the Liac can safely work in a conventional OR, while the need for additional shielding mainly depends on patient workload. Our data can be useful for centers planning to implement an IORT program using a mobile linear accelerator, permitting radiation safety personnel to estimate in advance the shielding required for a particular workload.

Radioembolisation with 90Y-microspheres: dosimetric and radiobiological investigation for multi-cycle treatment.

INTRODUCTION: Radioembolisation with (90)Y-microspheres is a new locoregional treatment of hepatic lesions, usually applied as single cycle. Multi-cycle treatments might be considered as a strategy to improve the risk-benefit balance. With the aim to derive suitable information for patient tailored therapy, available patients' dosimetric data were reviewed according to the linear-quadratic model and converted into biological effective dose (BED) values. Single vs. multi-cycle approaches were compared through radiobiological perspective. MATERIALS AND METHODS: Twenty patients with metastatic lesions underwent radioembolisation. The (90)Y-administered activity (AA) was established in order to respect a precautionary limit dose (40 Gy) for the non-tumoral liver (NTL). BED was calculated setting alpha/beta = 2.5 Gy (NTL), 10 Gy (tumours); T (1/2,eff) = T (1/2,phys) = 64.2 h; T (1/2,rep) = 2.5 h (NTL), 1.5 h (tumours). The BED to NTL was considered as a constraint for multi-cycle approach. The AA for two cycles and the percent variations of AA, tumour dose, BED were estimated. RESULTS: In one-cycle, for a prescribed BED to NTL of 64 Gy (NTL dose = 40 Gy), AA was 1.7 (0.9-3.2) GBq, tumour dose was 130 (65-235) Gy, and tumour BED was 170 (75-360) Gy. Considering two cycles, approximately 15% increase was found for AA and dose to NTL, with unvaried BED for NTL. Tumour dose increase was 20 (10-35) Gy; tumour BED increase was 10 (3-11) Gy. In different protocols allowing 80 Gy to NTL, the BED sparing estimated was approximately 50 Gy (two cycles) and 65 Gy (three cycles). CONCLUSIONS: From a radiobiological perspective, multi-cycle treatments would allow administering higher activities with increased tumour irradiation and preserved radiation effects on NTL. Trials comparing single vs. multiple cycles are suggested.

Planning combined treatments of external beam radiation therapy and molecular radiotherapy.

Molecular radiotherapy (MRT) with radiolabeled molecules has being constantly evolving, leading to notable results in cancer treatment. In some cases, the absorbed doses delivered to tumors by MRT are sufficient to obtain complete responses; in other cases, instead, to be effective, MRT needs to be combined with other therapeutic approaches. Recently, several studies proposed the combination of MRT with external beam radiation therapy (EBRT). Some describe the theoretical basis within radiobiological models, others report the results of clinical phase I-II studies aimed to assess the feasibility and tolerability. The latter includes the treatment of various tumors, such as meningiomas, paragangliomas, non-Hodgkin's lymphomas, bone, brain, hepatic, and breast lesions. The underlying principle of combined MRT and EBRT is the possibility of exploiting the full potential of each modality, given the different organs at risk. Target tissues can indeed receive a higher irradiation, while respecting the threshold limits of more than one critical tissue. Nevertheless, clinical trials are empirical and optimization is still a theoretical issue. This article describes the state of the art of combined MRT and EBRT regarding the rationale and the results of clinical studies, with special focus on the possibility of treatment improvement.

Application of failure mode and effects analysis to intraoperative radiation therapy using mobile electron linear accelerators.

PURPOSE: Failure mode and effects analysis (FMEA) represents a prospective approach for risk assessment. A multidisciplinary working group of the Italian Association for Medical Physics applied FMEA to electron beam intraoperative radiation therapy (IORT) delivered using mobile linear accelerators, aiming at preventing accidental exposures to the patient. METHODS AND MATERIALS: FMEA was applied to the IORT process, for the stages of the treatment delivery and verification, and consisted of three steps: 1) identification of the involved subprocesses; 2) identification and ranking of the potential failure modes, together with their causes and effects, using the risk probability number (RPN) scoring system, based on the product of three parameters (severity, frequency of occurrence and detectability, each ranging from 1 to 10); 3) identification of additional safety measures to be proposed for process quality and safety improvement. RPN upper threshold for little concern of risk was set at 125. RESULTS: Twenty-four subprocesses were identified. Ten potential failure modes were found and scored, in terms of RPN, in the range of 42-216. The most critical failure modes consisted of internal shield misalignment, wrong Monitor Unit calculation and incorrect data entry at treatment console. Potential causes of failure included shield displacement, human errors, such as underestimation of CTV extension, mainly because of lack of adequate training and time pressures, failure in the communication between operators, and machine malfunctioning. The main effects of failure were represented by CTV underdose, wrong dose distribution and/or delivery, unintended normal tissue irradiation. As additional safety measures, the utilization of a dedicated staff for IORT, double-checking of MU calculation and data entry and finally implementation of in vivo dosimetry were suggested. CONCLUSIONS: FMEA appeared as a useful tool for prospective evaluation of patient safety in radiotherapy. The application of this method to IORT lead to identify three safety measures for risk mitigation.

Evaluation of the efficacy of a bismuth shield during CT examinations.

PURPOSE: The purpose of the study was to evaluate the efficacy of a bismuth shield (Attenurad F&L Medical Products, Vandergrift, PA) in reducing the dose to surface organs during Computed Tomography (CT) examinations. The shield was evaluated for reduction of the dose to breast during chest examinations and reduction of the dose to the lens of the eye during brain examinations. MATERIALS AND METHODS: The dose was measured on patients (10 for the eye and 30 for the breast), and on an anthropomorphic phantom (Alderson Rando). The reduction of image quality was evaluated both qualitatively by an expert radiologist, and in terms of increased noise on the phantom images (Rando). RESULTS: The use of the protective device reduced the dose by 34% to the breast and 50% to the lens. These figures are confirmed by the measurements taken both on patients and on the anthropomorphic phantom. The protective device reduced image quality in the regions immediately beneath it, but in the cases considered, those regions were of no diagnostic interest, while in the brain and lung regions, the quality is only slightly reduced, always allowing a correct diagnostic evaluation. Numerical analysis also led to the conclusion that a modest increase in noise is only statistically significant for the anterior portions of the lung. When present, the artifacts appeared outside the field of clinical interest. That is mainly due to the use of a foam pad (0.7 - 1 cm thick) to protect the breast. DISCUSSION AND CONCLUSIONS: The protection proved effective both in the case of breast and of lens, leading to a significant reduction in dose, without excessively affecting image quality. The shield proved easy to use, and did not increase the examination time.