Dosimetry in Peptide radionuclide receptor therapy: a review.

The potential of targeted therapy with radiolabeled peptides has been reported in several clinical trials. Although there have been many improvements in dose estimation, a general and reliable dosimetric approach in peptide receptor radionuclide therapy (PRRT) is still a matter of debate. This article reviews the methods for PRRT dosimetry and the results presented in the literature. Radiopharmaceutical characteristics, data processing, dosimetric outcomes, and methods to protect critical organs are reported. The biological effective dose, based on the linear quadratic model, is also described.

Radiation protection in radionuclide therapies with (90)Y-conjugates: risks and safety.

PURPOSE: The widespread interest in (90)Y internal radionuclide treatments has drawn attention to the issue of radiation protection for staff. Our aim in this study was to identify personnel at risk and to validate the protection devices used. METHODS: (90)Y-MoAb (Zevalin, 15 cases, 1.1 GBq/patient) and (90)Y-peptide ((90)Y-DOTATOC) systemic (i.v., 50 cases, 3.0 GBq/patient) and locoregional (l.r., 50 cases, 0.4 GBq/patient) treatments were considered. Radiolabelling was carried out in a dedicated hot cell. Tele-tongs, shielded (PMMA: polymethylmethacrylate) syringes/vials and an automatic dose fractionating system were used. Operators wore anti-X-ray and anti-contamination gloves, with TLD dosimeters placed over the fingertips. For i.v. administration, activity was administered by a dedicated system; for l.r. administration, during activity infusion in the brain cavity, tongs were used and TLDs were placed over the fingertips. The air kerma-rate was measured around the patients. RESULTS: The use of devices provided a 75% dose reduction, with mean fingertip doses of 2.9 mGy (i.v. MoAbs), 0.6 mGy (i.v. peptides)/radiolabelling procedure and 0.5 mGy/l.r. administration. The mean effective dose to personnel was 5 microSv/patient. The air kerma-rate around the patients administered i.v. (90)Y-peptides were 3.5 (1 h) and 1.0 (48 h) microGy/h at 1 m. Patient hospitalisation of 6 h (l.r.)/48 h (i.v.) guaranteed that the recommended limits of 3 mSv/year to family members and 0.3 mSv/year to the general population (Council Directive 97/43/Euratom) were respected. CONCLUSIONS: When specific procedures are adopted, a substantial improvement in (90)Y manipulation is attainable, reducing doses and increasing safety. For the widespread clinical use of (90)Y-conjugates, a completely automatic labelling procedure is desirable.

CT image fusion as a tool for measuring in 3D the setup errors during conformal radiotherapy for prostate cancer.

AIMS AND BACKGROUND: The importance of optimal daily patient positioning has been stressed in order to ensure treatment reproducibility and gain in accuracy and precision. We report our data on the 3D setup uncertainty during radiation therapy for prostate cancer using the CT image fusion technique. METHODS: Ten consecutive patients scheduled for radiation therapy for prostate cancer underwent 5 prone position CT scans using an individualized immobilization cast. These different setups were analyzed using the image fusion module of the ERGO 3D-Line Medical System (Milan, Italy) treatment planning system. The isocenter and the body marker displacements were measured. RESULTS: The 3D isocenter dislocations were quantified: systematic error was sigma(3D) = 3.9 mm, whereas random error was sigma(3D) = 1 mm. The mean of the minimum displacements was 0.2 +/- 1 mm showing that the immobilization device used allows an accurate setup to be obtained. Single direction errors were also measured showing systematic errors, sigma(AP), = 2.6 mm, sigma(LL) = 0.6 mm, SigmaSI = 3 mm in the anterior-posterior, latero-lateral, superior-inferior direction, respectively. Related random errors were sigma(AP), = 1 mm, sigma(LL) = 0.6 mm, sigma(SI) = 1.2 mm. In terms of accuracy, our uncertainties are similar to those reported in the literature. CONCLUSIONS: By applying the CT image fusion technique, a 3D study on setup accuracy was performed. We demonstrated that the use of an individualized immobilization system for prostate treatment is adequate to obtain good setup accuracy, as long as a high-quality positioning control method, such as the stereoscopic X-ray-based positioning system, is used.

Radiation exposure after permanent prostate brachytherapy.

BACKGROUND AND PURPOSE: Limited information is available on the true radiation exposure and associated risks for the relatives of the patients submitted to prostate brachytherapy with permanent implant of radioactive sources and for any other people coming into contact with them. In order to provide appropriate information, we analyzed the radiation exposure data from 216 prostate cancer patients who underwent (125)I or (103)Pd implants at the European Institute of Oncology of Milan, Italy. PATIENTS AND METHODS: Between October 1999 and October 2004, 216 patients with low risk prostate carcinoma were treated with (125)I (200 patients) or (103)Pd (16 patients) permanent seed implantation. One day after the procedure, radiation exposure measurements around the patients were performed using an ionization chamber survey meter (Victoreen RPO-50) calibrated in dose rate at an accredited calibration center (calibration Centre SIT 104). RESULTS: The mean dose rate at the posterior skin surface (gluteal region) following (125)I implants was 41.3 microSv/h (range: 6.2-99.4 microSv/h) and following (103)Pd implants was 18.9 microSv/h (range 5.0-37.3 microSv/h). The dose rate at 50 cm from the skin decreased to the mean value of 6.4 microSv/h for the (125)I implants and to the mean value of 1.7 microSv/h for the (103)Pd implants. Total times required to reach the annual dose limit (1 mSv/year) recommended for the general population by the European Directive 96/29/Euratom and by the Italian law (Decreto Legislativo 241/2000) at a distance of 50 cm from the posterior skin surface of the implanted patient would be 7.7 and 21.6 days for (125)I and for (103)Pd. Good correlation between the measured dose rates and both the total implanted activity and the distance between the most posteriorly implanted seed and the skin surface of the patients was found. CONCLUSIONS: Our data show that the dose rates at 50 cm away from the prostate brachytherapy patients are very low and that the doses possibly absorbed by the relatives and other members of the general population coming into contact with the treated patients are well below the dose limit set by the European Directive and by the Italian regulation. However, in order to meet the recommendation of the ALARA principle (As Low As Reasonably/Readily Achievable), some advice to the patients should be given, such as to maintain a minimum distance from the patient of 1m, at least for a period equal to one half life of used radionuclide (60 days for (125)I and 15 days for (103)Pd).

Dosimetric model for locoregional treatments of brain tumors with 90Y-conjugates: clinical application with 90Y-DOTATOC.

UNLABELLED: Locoregional (LR) administration of (90)Y-conjugates after surgical debulking is a promising therapeutic option of gliomas. Dosimetry is highly recommended, as patient-specific parameters influence the absorbed dose to target and normal tissues. After tumor resection, the absorbed dose must be carefully evaluated in the rim of tissue surrounding the resected area. The aim of this study was to calculate and provide the S values, according to the MIRD concept, for dosimetry of LR brain treatments with several (90)Y-labeled compounds. The S values thus obtained have been clinically applied in 12 patients treated with (90)Y-labeled [DOTA(0),D-Phe(1),Tyr(3)]octreotide ((90)Y-DOTATOC). METHODS: An anthropomorphic model for Monte Carlo simulations was developed to evaluate absorbed doses in brain-adjacent tissue (BAT) and in normal brain. To adapt the model to single patients, S values were evaluated taking into account (i) different surgical resection cavity (SRC) volumes, (ii) different percentages of conjugate binding to the cavity wall, and (iii) different depths of percolation of the conjugate trough the cavity wall. BAT was divided into 1-mm-thick consecutive adjacent shells to evaluate the dose distribution around the cavity. Corresponding S values were obtained to allow dosimetric evaluation in brain LR therapy with (90)Y-conjugates. In the clinical treatments, 0.4-1.1 GBq of (90)Y-DOTATOC were injected into the SRC via an appropriate catheter. The activity in the SRC was assumed to be the difference between the total injected activity and the activity in the blood plus the activity cumulatively eliminated with the urine. RESULTS: Assuming no diffusion, with a mean residence time in SRC of 60 +/- 8 h, absorbed doses to shell II were 0.25 and 0.03 Gy/MBq for SRC volumes of 7.2 and 65.4 mL, respectively. Assuming a slight diffusion of 1 mm with a 7.2-mL SRC, absorbed dose to shells I, II, and VI were consistently different: 5.32, 2.53, and 0.12 Gy/MBq, respectively. Mean doses to normal brain, red marrow, bladder wall, and total body were 0.015, 0.03, 1.22, and 0.006 MGy/MBq. CONCLUSION: The model proved to be suitable for the dosimetry of several LR therapies with (90)Y-conjugates. According to our results, LR treatment with (90)Y-DOTATOC can safely deliver very high doses to target tissue, sparing normal organs including brain.

3D optoelectronic analysis of interfractional patient setup variability in frameless extracranial stereotactic radiotherapy.

PURPOSE: To investigate size and frequency of interfractional patient setup variability in hypofractionated stereotactic extracranial radiotherapy. METHODS AND MATERIALS: Infrared optical 3D tracking of surface markers was applied to quantify setup variability on 51 patients. Isocenter position repeatability was assessed by means of frameless anatomic calibration and was compared with portal image evaluation. Specific data analysis allowed for compensation of patients' breathing movements and for separation of the effects of operator-dependent misalignments and respiration-induced displacements. Effects of patient position (supine vs. prone) and treatment table configuration were investigated. RESULTS: Patient positioning assisted by the optical tracking device allowed reducing displacements of surface control points within the 3-mm range. Errors in isocenter localization were in the range of a few millimeters. This was in agreement with the portal image evaluation. Breathing motion introduced appreciable errors, which increased control points and isocenter 3D variability. This effect was significantly higher than those related to other investigated factors. CONCLUSIONS: The role of infrared optical tracking devices for patient positioning is assessed on a large patient population. Their use in the frame of high-precision radiotherapy is emphasized by the application of related methodologies for breathing phase detection and frameless isocenter localization.

Real-time in vivo dosimetry using micro-MOSFET detectors during intraoperative electron beam radiation therapy in early-stage breast cancer.

PURPOSE: In a previous paper we reported the results of off-line in vivo measurements using radiochromic films in IOERT. In the present study, a further step was made, aiming at the improvement of the effectiveness of in vivo dosimetry, based on a real-time check of the dose. MATERIALS AND METHODS: Entrance dose was determined using micro-MOSFET detectors placed inside a thin, sterile, transparent catheter. The epoxy side of the detector was faced towards the beam to minimize the anisotropy. Each detector was plugged into a bias supply (standard sensitivity) and calibrated at 5 Gy using 6 MeV electrons produced by a conventional linac. Detectors were characterized in terms of linearity, precision and dose per pulse dependence. No energy and temperature dependence was found. The sensitivity change of detectors was about 1% per 20 Gy accumulated dose. Correction factors to convert surface to entrance dose were determined for each combination of energy and applicator. From November 2004 to May 2005, in vivo dosimetry was performed on 45 patients affected by early-stage breast cancer, who underwent IOERT to the tumour bed. IOERT was delivered using electrons (4-10 MeV) at high dose per pulse, produced by either a Novac7 or a Liac mobile linac. RESULTS: The mean ratio between measured and expected dose was 1.006+/-0.035 (1 SD), in the range 0.92-1.1. The procedure uncertainty was 3.6%. Micro-MOSFETs appeared suitable for in vivo dosimetry in IOERT, although some unfavourable aspects, like the limited lifetime and the anisotropy with no build-up, were found. Prospectively, a real-time action level (+/-6%) on dose discrepancy was defined. CONCLUSIONS: Excellent agreement between measured and expected doses was found. Real-time in vivo dosimetry appeared feasible, reliable and more effective than the method previously published.

Survey of computed tomography techniques and absorbed dose in Italian hospitals: a comparison between two methods to estimate the dose-length product and the effective dose and to verify fulfilment of the diagnostic reference levels.

The aim of this study was the production of the first Italian survey of radiation dose in computed tomography (CT) prior to the widespread adoption of multislice CT, in order to have a reference point to facilitate later investigation of dose exposure changes brought by this new CT modality. The collected dose data were compared with diagnostic reference levels (DRLs). The agreement between experimental dose evaluation and Monte Carlo (MC) simulations was investigated. The survey was carried out in 29 Italian hospitals, covered 48 CT scanners and 232 examinations. The dose-length product (DLP) and effective dose (E) values were estimated based on MC simulations for seven clinical protocols using the CT-Dose program. Statistical analysis showed a significant difference (p<0.01) in the DLP between the two methods, with MC values being greater than the experimental ones. For E, the MC values were greater in routine head (8.2%), cervical spine (2.7%) and lumbar spine (2.9%) studies. The weighted CT dose index, the DLP and E were always below the DRLs set by the European Community. This dose survey gives a good but incomplete picture of the Italian CT dose situation and may be useful as a reference baseline for defining clinical multislice protocols in the near future.

Angular dependence of the TL reading of thin alpha-Al2O3:C dosemeters exposed to different beta spectra.

The angular dependence of the thermoluminescent (TL) signal of thin alpha-Al2O3:C dosemeters was investigated for a series of beta-emitting radionuclides commonly employed in nuclear medicine and characterised by different mean energies (99Tc, 177Lu, 90Sr/90Y and 90Y). Irradiations were performed in a controlled geometry, using a properly designed irradiator intended to realistically reproduce the situation of exposure of hospital personnel to beta-emitting pharmaceuticals. Under the conditions of extended source and short source to detector distance, the TL signal of thin alpha-Al2O3:C layers per unit irradiation time was observed to be independent on the angle of incidence within acceptable limits, particularly for those radionuclides with maximum energy >500 keV. This property may be easily explained by using simple physical considerations, such as the limited thickness of the dosemeters. The results confirm that these detectors are suitable for beta-ray extremity dose measurements, when the photon contribution is negligible, as in the case considered.

MR and CT image fusion for postimplant analysis in permanent prostate seed implants.

PURPOSE: To compare the outcome of two different image-based postimplant dosimetry methods in permanent seed implantation. METHODS AND MATERIALS: Between October 1999 and October 2002, 150 patients with low-risk prostate carcinoma were treated with (125)I and (103)Pd in our institution. A CT-MRI image fusion protocol was used in 21 consecutive patients treated with exclusive brachytherapy. The accuracy and reproducibility of the method was calculated, and then the CT-based dosimetry was compared with the CT-MRI-based dosimetry using the dose-volume histogram (DVH) related parameters recommended by the American Brachytherapy Society and the American Association of Physicists in Medicine. RESULTS: Our method for CT-MRI image fusion was accurate and reproducible (median shift <1 mm). Differences in prostate volume were found, depending on the image modality used. Quality assurance DVH-related parameters strongly depended on the image modality (CT vs. CT-MRI): V(100) = 82% vs. 88%, p < 0.05. D(90) = 96% vs. 115%, p < 0.05. Those results depend on the institutional implant technique and reflect the importance of lowering inter- and intraobserver discrepancies when outlining prostate and organs at risk for postimplant dosimetry. CONCLUSIONS: Computed tomography-MRI fused images allow accurate determination of prostate size, significantly improving the dosimetric evaluation based on DVH analysis. This provides a consistent method to judge a prostate seed implant's quality.

Finding dose-volume constraints to reduce late rectal toxicity following 3D-conformal radiotherapy (3D-CRT) of prostate cancer.

BACKGROUND AND PURPOSE: The rectum is known to display a dose-volume effect following high-dose 3D-conformal radiotherapy (3D-CRT). The aim of the study is to search for significant dose-volume combinations with the specific treatment technique and patient set-up currently used in our institution. PATIENTS AND METHODS: We retrospectively analyzed the dose-volume histograms (DVH) of 135 patients with stage T1b-T3b prostate cancer treated consecutively with 3D-CRT between 1996 and 2000 to a total dose of 76 Gy. The median follow-up was 28 months (range 12-62). All late rectal complications were scored using RTOG criteria. Time to late toxicity was assessed using the Kaplan-Meyer method. The association between variables at baseline and > or=2 rectal toxicity was tested using chi(2) test or Fisher's exact test. A multivariate analysis using logistic regression was performed. RESULTS: Late rectal toxicity grade > or=2 was observed in 24 of the 135 patients (17.8%). A 'grey area' of increased risk has been identified. Average DVHs of the bleeding and non-bleeding patients were generated. The area under the percent volume DVH for the rectum of the bleeding patients was significantly higher than that of patients without late rectal toxicity. On multivariate analysis the correlation between the high risk DVHs and late rectal bleeding was confirmed. CONCLUSIONS: The present analysis confirms the role of the rectal DVH as a tool to discriminate patients undergoing high-dose 3D-CRT into a low and a high risk of developing late rectal bleeding. Based on our own results and taking into account the data published in the literature, we have been able to establish new dose-volume constraints for treatment planning: if possible, the percentage of rectal volume exposed to 40, 50, 60, 72 and 76 Gy should be limited to 60, 50, 25, 15 and 5%, respectively.

In vivo dosimetry using radiochromic films during intraoperative electron beam radiation therapy in early-stage breast cancer.

BACKGROUND AND PURPOSE: To check the dose delivered to patients during intraoperative electron beam radiation therapy (IOERT) for early breast cancer and also to define appropriate action levels. PATIENTS AND METHODS: Between December 2000 and June 2001, 54 patients affected by early-stage breast cancer underwent exclusive IOERT to the tumour bed using a Novac7 mobile linac, after quadrantectomy. Electron beams (5, 7, 9 MeV) at high dose per pulse values (0.02-0.09 Gy/pulse) were used. The prescribed single dose was 21 Gy at the depth of 90% isodose (14-22 mm). In 35 cases, in vivo dosimetry was performed. The entrance dose was derived from the surface dose measured with thin and calibrated MD-55-2 radiochromic films, wrapped in sterile envelopes. Films were analysed 24-72 h after the irradiation using a charge-coupled-device imaging system. Field disturbance caused by the film envelope was negligible. RESULTS: The mean deviation between measured and expected doses was 1.8%, with one SD equal to 4.7%. Deviations larger than 7% were found in 23% of cases, never consecutively, not correlated with beam energy or field size and with no evidence of linac daily output variation or serious malfunctioning or human mistake. The estimated overall uncertainty of dose measurement was about 4%. In vivo dosimetry appeared both reliable and feasible. Two action levels, for unexplained observed deviations larger than 7 and 10%, were preliminary defined. CONCLUSIONS: Satisfactory agreement between measured and expected doses was found. The implementation of in vivo dosimetry in IOERT is suggested, particularly for patients enrolled in a clinical trial.