Repeatability of SUV measurements in serial PET.

PURPOSE: The standardized uptake value (SUV) is a quantitative measure of FDG tumor uptake frequently used as a tool to monitor therapeutic response. This study aims to (i) assess the reproducibility and uncertainty of SUV max and SUV mean, due to purely statistical, i.e., nonbiological, effects and (ii) to establish the minimum uncertainty below which changes in SUV cannot be expected to be an indicator of physiological changes. METHODS: Three sets of measurements were made using a GE Discovery STE PET/CT Scanner in 3D mode: (1) A uniform 68Ge 20 cm diameter cylindrical phantom was imaged. Thirty serial frames were acquired for durations of 3, 6, 10, 15, and 30 min. (2) Esser flangeless phantom (Data Spectrum, approximately 6.1 L) with fillable thin-walled cylinders inserts (diameters: 8, 12, 16, and 25 mm; height: approximately 3.8 mm) was scanned for five consecutive 3 min runs. The cylinders were filled with 18FDG with a 37 kBq/cc concentration, and with a target-to-background ratio (T/BKG) of 3/1. (3) Eight cancer patients with healthy livers were scanned approximately 1.5 h post injection. Three sequential 3 min scans were performed for one bed position covering the liver, with the patient and bed remaining at the same position for the entire length of the scan. Volumes of interest were drawn on all images using the corresponding CT and then transferred to the PET images. For each study (1-3), the average percent change in SUV mean and SUV max were determined for each run pair. Moreover, the repeatability coefficient was calculated for both the SUV mean and SUV max for each pair of runs. Finally, the overall ROI repeatability coefficient was determined for each pair of runs. RESULTS: For the 68Ge phantom the average percent change in SUV max and SUV mean decrease as a function of increasing acquisition time from 4.7 +/- 3.1 to 1.1 +/- 0.6%, and from 0.14 +/- 0.09 to 0.04 +/- 0.03%, respectively. Similarly, the coefficients of repeatability also decrease between the 3 and 30 min acquisition scans, in the range of 10.9 +/- 3.9% - 2.6 +/- 0.9%, and 0.3 +/- 0.1% - 0.10 +/- 0.04%, for the SUV max and SUV mean, respectively. The overall ROI repeatability decreased from 18.9 +/- 0.2 to 6.0 +/- 0.1% between the 3 and 30 min acquisition scans. For the l8FDG phantom, the average percent change in SUV max and SUV mean decreases with target diameter from 3.6 +/- 2.0 to 1.5 +/- 0.8% and 1.5 +/- 1.3 to 0.26 +/- 0.15%, respectively, for targets from 8-25 mm in diameter and for a region in the background (BKG). The coefficients of repeatability for SUV max and SUV mean also decrease as a function of target diameter from 7.1 +/- 2.5 to 2.4 +/- 0.9 and 4.2 +/- 1.5 to 0.6 +/- 0.2, respectively, for targets from 8 mm to BKG in diameter. Finally, overall ROI repeatability decreased from 12.0 +/- 4.1 to 13.4 +/- 0.5 targets from 8 mm to BKG in diameter. Finally, for the measurements in healthy livers the average percent change in SUVmax and SUV mean were in the range of 0.5 +/- 0.2% - 6.2 +/- 3.9% and 0.4 +/- 0.1 and 1.6 +/- 1%, respectively. The coefficients of repeatability for SUV max and SUV men are in the range of 0.6 +/- 0.7% - 9.5 +/- 12% and 0.6 +/- 0.7% - 2.9 +/- 3.6%, respectively. The overall target repeatability varied between 27.9 +/- 0.5% and 41.1 +/- 1.0%. CONCLUSIONS: The statistical fluctuations of the SUV mean are half as large as those of the SUV max in the absence of biological or physiological effects. In addition, for clinically applicable scan durations (i.e., approximately 3 min) and FDG concentrations, the SUV max and SUV mean have similar amounts of statistical fluctuation for small regions. However, the statistical fluctuations of the SUVmean rapidly decrease with respect tothe SUVmax as the statistical power of the data grows either due to longer scanning times or as the target regions encompass a larger volume.

A novel respiratory tracking system for smart-gated PET acquisition.

PURPOSE: In this study, the authors validated a novel respiratory tracking device, the multidimensional respiratory tracking (MDRT) system, that was designed to assist in correcting for respiratory motion in PET/CT images. The authors also investigated a novel PET acquisition technique, smart gating (SG), that enables to acquire motion-free PET data prospectively, with minimum user interference and with no additional postprocessing of the PET data. METHODS: MDRT uses visual tracking techniques to track simultaneously the two-dimensional (in the vertical plane) motion of multiple fiducial markers using a standard video camera. A threshold window is set at the breathing amplitude of interest using the MDRT GUI. A trigger is generated at a rate of 250 Hz as long as the breathing signal is within the threshold window. The triggers are fed into the PET scanner to initialize one single bin of a gated acquisition every 4 ms. No triggers are delivered as the breathing signal drifts outside the threshold window. Consequently, PET data are acquired only whenever the breathing signal is confined within the amplitude threshold window, thus resulting into a motion-free image set. The accuracy of MDRT in tracking the breathing signal was assessed (1) by comparing the period of an oscillating phantom, as measured by MDRT, to that measured with a photogate timer and (2) by comparing the MDRT output to that of the real-time position management (RPM) in ten patients. The SG PET/CT acquisition was validated in phantoms and in two stereotactic body radiosurgery (SBRS) lung DIBH-PET/CT patients. RESULTS: MDRT was in agreement with the photogate timer in determining the period of motion to less than 2%. The percent errors between MDRT and RPM in the positions of the peaks and troughs of the ten patients' breathing signals were within 10%. In phantoms, SG technique enables to correct for motion-induced artifacts in the PET images and improve the accuracy of PET quantitation. For the SBRS application, in one patient, the patient's CT lesion was not detected in the corresponding clinical PET images, while it exhibited an SUV of 1.8 in the DIBH image set. In the second patient, DIBH-PET images showed an improved PET-to-CT spatial matching and a 52% increase in the lesion SUV. CONCLUSIONS: MDRT has been shown to be accurate in tracking breathing motion and assisted in implementing a smart-gating PET acquisition technique that allowed to acquire prospectively motion-free PET images.

Radiation segmentectomy of hepatic metastases with Y-90 glass microspheres.

PURPOSE: To evaluate safety and efficacy of radiation segmentectomy (RS) with 90Y glass microspheres in patients with limited metastatic liver disease not amenable to resection or percutaneous ablation. METHODS: Patients with ≤ 3 tumors treated with RS from 6/2015 to 12/2017 were included. Target tumor radiation dose was > 190 Gy based on medical internal radiation dose (MIRD) dosimetry. Tumor response, local tumor progression (LTP), LTP-free survival (LTPFS) and disease progression rate in the treated segment were defined using Choi and RECIST 1.1 criteria. Toxicities were evaluated using modified SIR criteria. RESULTS: Ten patients with 14 tumors underwent 12 RS. Median tumor size was 3 cm (range 1.4-5.6). Median follow-up was 17.8 months (range 1.6-37.3). Response rates per Choi and RECIST 1.1 criteria were 8/8 (100%) and 4/9 (44%), respectively. Overall LTP rate was 3/14 (21%) during the study period. One-, two- and three-year LTPFS was 83%, 83% and 69%, respectively. Median LTPFS was not reached. Disease progression rate in the treated segment was 6/18 (33%). Median overall survival was 41.5 months (IQR 16.7-41.5). Median delivered tumor radiation dose was 293 Gy (range 163-1303). One major complication was recorded in a patient post-Whipple procedure who suffered anaphylactic reaction to prophylactic cefotetan and liver abscess in RS region 6.5 months post-RS. All patients were alive on last follow-up. CONCLUSION: RS of ≤ 3 hepatic segments can safely provide a 2-year local tumor control rate of 83% in selected patients with limited metastatic liver disease and limited treatment options. Optimal dosimetry methodology requires further investigation.

KRAS mutation effects on the 2-[18F]FDG PET uptake of colorectal adenocarcinoma metastases in the liver.

BACKGROUND: Deriving individual tumor genomic characteristics from patient imaging analysis is desirable. We explore the predictive value of 2-[18F]FDG uptake with regard to the KRAS mutational status of colorectal adenocarcinoma liver metastases (CLM). METHODS: 2-[18F]FDG PET/CT images, surgical pathology and molecular diagnostic reports of 37 patients who underwent PET/CT-guided biopsy of CLM were reviewed under an IRB-approved retrospective research protocol. Sixty CLM in 39 interventional PET scans of the 37 patients were segmented using two different auto-segmentation tools implemented in different commercially available software packages. PET standard uptake values (SUV) were corrected for: (1) partial volume effect (PVE) using cold wall-corrected contrast recovery coefficients derived from phantom spheres with variable diameter and (2) variability of arterial tracer supply and variability of uptake time after injection until start of PET scan derived from the tumor-to-blood standard uptake ratio (SUR) approach. The correlations between the KRAS mutational status and the mean, peak and maximum SUV were investigated using Student's t test, Wilcoxon rank sum test with continuity correction, logistic regression and receiver operation characteristic (ROC) analysis. These correlation analyses were also performed for the ratios of the mean, peak and maximum tumor uptake to the mean blood activity concentration at the time of scan: SURMEAN, SURPEAK and SURMAX, respectively. RESULTS: Fifteen patients harbored KRAS missense mutations (KRAS+), while another 3 harbored KRAS gene amplification. For 31 lesions, the mutational status was derived from the PET/CT-guided biopsy. The Student's t test p values for separating KRAS mutant cases decreased after applying PVE correction to all uptake metrics of each lesion and when applying correction for uptake time variability to the SUR metrics. The observed correlations were strongest when both corrections were applied to SURMAX and when the patients harboring gene amplification were grouped with the wild type: p ≤ 0.001; ROC area under the curve = 0.77 and 0.75 for the two different segmentations, respectively, with a mean specificity of 0.69 and sensitivity of 0.85. CONCLUSION: The correlations observed after applying the described corrections show potential for assigning probabilities for the KRAS missense mutation status in CLM using 2-[18F]FDG PET images.

An iterative technique to segment PET lesions using a Monte Carlo based mathematical model.

PURPOSE: The need for an accurate lesion segmentation tool in 18FDG PET is a prerequisite for the estimation of lesion response to therapy, for radionuclide dosimetry, and for the application of 18FDG PET to radiotherapy planning. In this work, the authors have developed an iterative method based on a mathematical fit deduced from Monte Carlo simulations to estimate tumor segmentation thresholds. METHODS: The GATE software, a GEANT4 based Monte Carlo tool, was used to model the GE Advance PET scanner geometry. Spheres ranging between 1 and 6 cm in diameters were simulated in a 10 cm high and 11 cm in diameter cylinder. The spheres were filled with water-equivalent density and simulated in both water and lung equivalent background. The simulations were performed with an infinite, 8/1, and 4/1 target-to-background ratio (T/B). A mathematical fit describing the correlation between the lesion volume and the corresponding optimum threshold value was then deduced through analysis of the reconstructed images. An iterative method, based on this mathematical fit, was developed to determine the optimum threshold value. The effects of the lesion volume and T/B on the threshold value were investigated. This method was evaluated experimentally using the NEMA NU2-2001 IEC phantom, the ACNP cardiac phantom, a randomly deformed aluminum can, and a spheroidal shape phantom implemented artificially in the lung, liver, and brain of patient PET images. Clinically, the algorithm was evaluated in six lesions from five patients. Clinical results were compared to CT volumes. RESULTS: This mathematical fit predicts an existing relationship between the PET lesion size and the percent of maximum activity concentration within the target volume (or threshold). It also showed a dependence of the threshold value on the T/B, which could be eliminated by background subtraction. In the phantom studies, the volumes of the segmented PET targets in the PET images were within 10% of the nominal ones. Clinically, the PET target volumes were also within 10% of those measured from CT images. CONCLUSIONS: This iterative algorithm enabled accurately segment PET lesions, independently of their contrast value.

Phase and amplitude binning for 4D-CT imaging.

We compare the consistency and accuracy of two image binning approaches used in 4D-CT imaging. One approach, phase binning (PB), assigns each breathing cycle 2pi rad, within which the images are grouped. In amplitude binning (AB), the images are assigned bins according to the breathing signal's full amplitude. To quantitate both approaches we used a NEMA NU2-2001 IEC phantom oscillating in the axial direction and at random frequencies and amplitudes, approximately simulating a patient's breathing. 4D-CT images were obtained using a four-slice GE Lightspeed CT scanner operating in cine mode. We define consistency error as a measure of ability to correctly bin over repeated cycles in the same field of view. Average consistency error mue+/-sigmae in PB ranged from 18%+/-20% to 30%+/-35%, while in AB the error ranged from 11%+/-14% to 20%+/-24%. In PB nearly all bins contained sphere slices. AB was more accurate, revealing empty bins where no sphere slices existed. As a proof of principle, we present examples of two non-small cell lung carcinoma patients' 4D-CT lung images binned by both approaches. While AB can lead to gaps in the coronal images, depending on the patient's breathing pattern, PB exhibits no gaps but suffers visible artifacts due to misbinning, yielding images that cover a relatively large amplitude range. AB was more consistent, though often resulted in gaps when no data existed due to patients' breathing pattern. We conclude AB is more accurate than PB. This has important consequences to treatment planning and diagnosis.

Evaluation of an automated deformable image matching method for quantifying lung motion in respiration-correlated CT images.

We have evaluated an automated registration procedure for predicting tumor and lung deformation based on CT images of the thorax obtained at different respiration phases. The method uses a viscous fluid model of tissue deformation to map voxels from one CT dataset to another. To validate the deformable matching algorithm we used a respiration-correlated CT protocol to acquire images at different phases of the respiratory cycle for six patients with nonsmall cell lung carcinoma. The position and shape of the deformable gross tumor volumes (GTV) at the end-inhale (EI) phase predicted by the algorithm was compared to those drawn by four observers. To minimize interobserver differences, all observers used the contours drawn by a single observer at end-exhale (EE) phase as a guideline to outline GTV contours at EI. The differences between model-predicted and observer-drawn GTV surfaces at EI, as well as differences between structures delineated by observers at EI (interobserver variations) were evaluated using a contour comparison algorithm written for this purpose, which determined the distance between the two surfaces along different directions. The mean and 90% confidence interval for model-predicted versus observer-drawn GTV surface differences over all patients and all directions were 2.6 and 5.1 mm, respectively, whereas the mean and 90% confidence interval for interobserver differences were 2.1 and 3.7 mm. We have also evaluated the algorithm's ability to predict normal tissue deformations by examining the three-dimensional (3-D) vector displacement of 41 landmarks placed by each observer at bronchial and vascular branch points in the lung between the EE and EI image sets (mean and 90% confidence interval displacements of 11.7 and 25.1 mm, respectively). The mean and 90% confidence interval discrepancy between model-predicted and observer-determined landmark displacements over all patients were 2.9 and 7.3 mm, whereas interobserver discrepancies were 2.8 and 6.0 mm. Paired t tests indicate no significant statistical differences between model predicted and observer drawn structures. We conclude that the accuracy of the algorithm to map lung anatomy in CT images at different respiratory phases is comparable to the variability in manual delineation. This method has therefore the potential for predicting and quantifying respiration-induced tumor motion in the lung.

Distribution of radiolabeled monoclonal antibody MX35 F(ab')2 in tissue samples by storage phosphor screen image analysis: evaluation of antibody localization to micrometastatic disease in epithelial ovarian cancer.

Our objective was to quantify the targeting of the monoclonal antibody (mAb) MX35 F(ab')2 to micrometastatic epithelial ovarian cancer. This mAb detects a Mr 95,000 glycoprotein with homogeneous distribution on 80% of ovarian tumor specimens. Six patients with minimal residual disease from an imaging trial were injected with 2 or 10 mg of 131I- and 125I-labeled mAb MX35 F(ab')2. Biopsied samples were removed at second-look laparotomy 1-5 days post-i.v. or -i.p. infusion of antibody. Serial cryostat sections were stained by indirect immunoperoxidase method for antigen distribution and exposed to storage phosphor screens for quantitative autoradiography. Coregistration of tumor histology, antigen expression, and radionuclide distribution demonstrated specific localization in micrometastatic tumor foci (50 micrometer to 1 mm) found within tissue stroma. The radiolabeled antibody uptake determined by well scintillation counts ranged between 5.2 and 223.5 x 10(-4) percentage of injected dose/g of tumor tissue for 131I. Specific localization of mAb in tumor was determined by tumor:normal tissue (fat) ratios ranging from 0.9:1 to 35.9:1 for 131I. The high resolution and linear response of the storage phosphor screen imager was used to estimate the radionuclide activity localized in each micrometastatic site. Quantitation of phosphor screen response revealed microCi/g values of 0.026-0.341 for normal tissue and 0.184-6.092 for tumor biopsies, evaluated 4 or 5 days post-antibody injection. The tumor:normal tissue (adjacent to tumor) ratios were between 1 and 4 times greater using the phosphor screen method than well counter measurements, but even larger variations of ratios up to 20:1 were observed between tumor cell foci and stromal cells within the same tissue section. This study has demonstrated that mAb MX35 F(ab')2 localizes to the micrometastatic ovarian carcinoma deposits within the peritoneal cavity. The dosimetry results suggest a therapeutic potential for this antibody in patients with minimal residual disease (<5 mm).

Using positron emission tomography with [(18)F]FDG to predict tumor behavior in experimental colorectal cancer.

This study investigates the relationship between FDG uptake as determined by positron emission tomography (PET) imaging and rates of tumor growth, cellular GLUT1 transporter density, and the activities of hexokinase and glucose-6-phosphatase in a solid tumor implant model. Five different human colorectal xenografts of different growth properties were implanted in athymic rats and evaluated by dynamic (18)F-FDG-PET. The phosphorylating and dephosphorylating activities of the key glycolytic enzymes, hexokinase and glucose-6-phosphatase, were measured in these tumor types by spectrophotometric assays and the expression of GLUT1 glucose transporter protein was determined by immunohistochemistry. Correlations among FDG accumulation, hexokinase activity, and tumor doubling time are reported in these colon xenografts. The results indicate that the activity of tumor hexokinase may be a marker of tumor growth rate that can be determined by (18)F-FDG-PET imaging. PET scanning may not only be a useful tool for staging patients for extent of disease, but may provide important prognostic information concerning the proliferative rates of malignancies.

A microdosimetric model of astatine-211 labeled antibodies for radioimmunotherapy.

Astatine-211 is an alpha-emitter with a short half-life (7.2 hr). This paper discusses the potential of 211At targeted by antibodies for tumor therapy and the possible advantage of 211At over beta- and gamma-emitting radionuclides such as 131I currently employed in the field of radioimmunotherapy. Since the longest range alpha-particle from 211At is only 67 microns and the rate of energy loss is high (track averaged linear energy transfer LT approximately 120 keV/micron), a disintegration of 211At produces a large and extremely localized deposition of energy. A Monte-Carlo model has been developed for studying the stochastic fluctuation of alpha-particle hits and energy deposition in cell nuclei in an attempt to determine the efficacy of 211At-labeled antibodies for tumor cell inactivation. Calculations have been performed for 2 extreme conditions: (a) the case of 211At retained in the capillary, and (b) for a homogeneous distribution of 211At-labeled antibody in the tumor. The results of these two calculations represent the boundary conditions between which any real solution must lie. Finally, developments to the model to include antibody transport across the capillary membrane and through the tumor tissue are discussed.

A new calculational method to assess the therapeutic potential of Auger electron emission.

This paper discusses a new computer code to estimate the efficacy of Auger electron sources in cancer therapy. Auger electron emission accompanies the decay of many radionuclides already commonly used in nuclear medicine, for example; 99mTc and 201Tl. The range of these electrons is in general sub-cellular, therefore, the toxicity of the source depends on the site of decay relative to the genetic material of the cell. Electron track structure methods have been used which enable the study of energy deposition from Auger sources down to the Angstrom level. A figure for the minimum energy required per single strand break is obtained by fitting our energy deposition calculations for 125I decays in a model of the DNA to experimental data on break lengths from 125I labeled plasmid fragments. This method is used to investigate the efficiency of double strand break production by other Auger sources which have potential value for therapy. The high RBE of Auger sources depends critically on the distance between the source and target material. The application of Auger emitters for therapy may necessitate a carrier molecule that can append the source to the DNA. Many DNA localizing agents are known in the field of chemotherapy, some of which could be carrier molecules for Auger sources; the halogenated thymidine precursors are under scrutiny in this field. The activation of Auger cascades in situ by high energy, collimated X ray and neutron beams is also assessed.

Collision detection and avoidance during treatment planning.

PURPOSE: To develop computer software that assists the planner avoid potential gantry collisions with the patient or patient support assembly during the treatment planning process. METHODS AND MATERIALS: The approach uses a simulation of the therapy room with a scale model of the treatment machine. Because the dimensions of the machine and patient are known, one can calculate a priori whether any desired therapy field is possible or will result in a collision. To assist the planner, we have developed a graphical interface enabling the accurate visualization of each treatment field configuration within a "room's eye view" treatment planning window. This enables the planner to be aware of, and alleviate any potential collision hazards. To circumvent blind spots in the graphic representation, an analytical software module precomputes whether each update of the gantry or turntable position is safe. RESULTS: If a collision is detected, the module alerts the planner and suggests collision evasive actions such as either an extended distance treatment or the gantry angle of closest approach. CONCLUSIONS: The model enables the planner to experiment with unconventional noncoplanar treatment fields, and immediately test their feasibility.

Electron wedges for radiation therapy.

PURPOSE: Brain tumors can be advantageously treated with electron over photon radiation, by exploiting the rapid fall-off in dose with depth. This advantage could be further enhanced by utilizing multiple electron beams. However, in some beam configurations, wedged dose profiles would be necessary for the dose uniformity. Unlike photons, shaped pieces of material placed in electron beam severely degrade the energy, give additional scattering and, therefore, are suboptimal. The purpose of this study was to create wedged electron fields, using intensity modulation. The combination of electron wedges enables a more uniform coverage of brain tumors with a reduced dose to normal tissue. METHODS AND MATERIALS: Intensity modulation was performed for 10 to 50 MeV electrons using a narrow scanning elementary beam of a racetrack Microtron accelerator, delivering radiation pulses with coordinates and intensities prescribed by a custom scan matrix. Dispensing more pulses (or longer pulses) within the field to increase the local dose, one can sharpen the penumbra at depth and generate wedged dose distributions of arbitrary angle as well as many other desired profiles. We modulated the electron beams, measured dose distributions using film in an anthropomorphic phantom, and compared the results with conventional techniques. RESULTS: Intensity modulation of electron beams decreases the 50-90% penumbra at depth by 40% and increases the flatness by 80%. Wedged profiles at depth can be created for any angle up to about 70 degrees, depending on the beam energy. Multiple modulated electron beams give smaller 20-70% but larger 70-100% isodose regions than photon beams. CONCLUSIONS: Electron beams can improve dose distributions in brain compared to the same number of photon beams, reducing the 20-70% isodoses region in normal tissue by 30%. Intensity modulation significantly improves the dose distribution from combined electron beams providing a sharper penumbra, better conformity, and reduced margin.

Cell cycle alterations, apoptosis, and response to low-dose-rate radioimmunotherapy in lymphoma cells.

PURPOSE: In an attempt to elucidate some aspects of the radiobiological basis of radioimmunotherapy, we have evaluated the in vitro cellular response patterns for malignant lymphoma cell lines exposed to high- and low-dose-rate radiation administered within the physiological context of antibody cell-surface binding. METHODS AND MATERIALS: We used two different malignant lymphoma cell lines, a Thy1.2+ murine T-lymphoma line called EL-4 and a CD20+ human B-lymphoma line called Raji. Cells were grown in suspension cultures and exposed to high-dose-rate gamma radiation from an external 137Cs source or low-dose-rate beta radiation from DTPA-solubilized 90Y in solution. In some experiments, cells were pre-incubated with an excess of nonradioactive antibody in order to assess the effects of immunoglobulin surface binding during radiation exposure. Irradiated cells were evaluated for viability, cell-cycle changes, patterns of post-radiation morphologic changes, and biochemical hallmarks of radiation-associated necrosis and programmed cell death. RESULTS: The EL-4 line was sensitive to both high-dose-rate and low-dose-rate irradiation, while the Raji showed efficient cell kill only after high-dose-rate irradiation. Studies of radiation-induced cell cycle changes demonstrated that both cell lines were efficiently blocked at the G2/M interface by high-dose-rate irradiation, with the Raji cells appearing somewhat more susceptible than the EL-4 cells to low-dose-rate radiation-induced G2/M block. Electron microscopy and DNA gel electrophoresis studies showed that a significant proportion of the EL-4 cells appeared to be dying by radiation-induced programmed cell death (apoptosis) while the Raji cells appeared to be dying primarily by classical radiation-induced cellular necrosis. CONCLUSION: We propose that the unusual clinical responsiveness of some high and low grade lymphomas to modest doses of low-dose-rate radioimmunotherapy may be explained in part by the induction of apoptosis. The unusual dose-response characteristics observed in some experimental models of radiation-induced apoptosis may require a reappraisal of standard linear quadratic and alpha/beta algorithms used to predict target tissue cytoreduction after radioimmunotherapy.

Effect of set-up error on the dose across the junction of matching cranial-spinal fields in the treatment of medulloblastoma.

PURPOSE: The effect of systematic and stochastic setup error on the dose delivered to the gap region for the three field radiation treatment of medulloblastoma is studied. The consequences of such setup error is discussed. METHODS AND MATERIALS: The treatment of medulloblastoma is typically a 3 field technique, in which two lateral cranial fields are matched with a spine field. The x-ray dose delivered to the region between the matched fields depends upon the gap size. The choice of the gap width between the cranial and spinal fields is controversial. It is currently a compromise between minimizing the risk of dose hot spots to the spine, and the associated clinical complications, as well as the magnitude of cold spots (underdosing) across the gap, with the associated risk of disease recurrence. In this paper, we examine the effect of gap width with a moving junction, referred to as "field feathering", on the dose across the field junction for a 6MV photon beam. In addition, we have studied 129 portal films and 40 simulation films to assess the accuracy and precision of patient setup during treatment with a plan involving feathered fields. Selected landmarks observable on both portal and simulation films were identified and the variation in the distances to the field edges measured. The distribution of patient setup error was convoluted with the beam profiles for a 6MV linac. These convoluted field edges were used obtain dose profiles across the gap region as a function of gap separation. The consequences for therapy are discussed. In addition, analysis of patient setup error on an alternative treatment involving beam modifiers to broaden the beam penumbra is discussed. RESULTS: The magnitude of the spatial stochastic and systematic setup error was determined to be approximately three and two millimeters respectively. The dosimetric consequences of patient setup error lead to over and under dosing in the spinal gap region for the three field technique. The degree of under or over dose depends on the nature and magnitude of the patient setup error. CONCLUSIONS: The effect of patient setup error can lead to significant dosimetric errors in the dose to the gap region depending on the magnitude of the setup errors. The effective over and under dose can be compensated by the use beams modifiers such as a beam spoiler or vibrating jaws.

Dosimetric aspects of radiolabeled antibodies for tumor therapy.

Radioimmunotherapy (RIT) is rapidly attracting interest as a potential new weapon in the arsenal for cancer therapy. This article concentrates on some of the dosimetric aspects affecting the potential success of RIT, and examines factors which influence the choice of a radiolabel for RIT. No radionuclide is likely to give an optimum tumor/nontumor insult for all tumor types; therefore, the concept of matching the source to tumor morphology is introduced. Lists of candidate radionuclides are given, classified according to the type of decay, range, and energy of the emission. The article examines how the choice of radionuclide for radiolabeling the antibody affects the local energy deposition in the tumor. Both the effect of tumor size on the energy absorbed fraction and the problem of antibody binding heterogeneity are discussed. The approach to RIT is to relate the choice of radionuclide to the physical properties of the tumor.

Nonuniformity of tumor dose in radioimmunotherapy.

The conventional approach to calculating tumor radiation dose from internally administered radioisotopes is by the MIRD schema. The raw input data for such dose calculations is obtained by immunoscintigraphic methods, PLANAR or SPECT imaging. Limitations in the spatial resolution of these techniques can lead to a considerable underestimate of the gross variation in tumor dose. The use of radiolabeled monoclonal antibodies for therapy can result in large nonuniformities in tumor dose. This paper discusses how antibody distribution can influence the energy deposition in the nuclei of target cells. Heterogeneity of antibody binding will lead to an expected decrease in the effectiveness of the radiation delivered. However, enhanced cell killing is possible if the radiolabeled Ab binds to the cell surface membrane and may be further enhanced if the Ab is internalized. Calculations are presented for two cases: (a) a three-dimensional random packing arrangement of cells as a model of the astructural nondifferentiated form seen in some tumors, and (b) differentiated carcinoma of the colon with the cells in tubules. Results for the magnitude of the mean energy deposition to individual cell nuclei from: (a) cell membrane bound 211At, 199Au, 131I, and 90Y-labeled Abs, and (b) a uniform distribution of these sources, as a function of internuclear distance for the two histologies are presented. Energy deposition in tumor cell nuclei from membrane bound radiolabeled antibody may be several times greater than estimated with the assumption of a uniform source distribution.

Hypoxia-Induced increase in FDG uptake in MCF7 cells.

UNLABELLED: Recent clinical data indicate that tumor hypoxia negatively affects the treatment outcome of both radiotherapy and surgery in various cancers, emphasizing the need for noninvasive detection of tumor hypoxia. Several studies have shown an increased uptake of FDG in hypoxic regions of xenografts, suggesting the use of PET with FDG as a potential technique. In this study, we examine the mechanism underlying the hypoxia-induced increase of FDG uptake in the human breast carcinoma cell line MCF7. METHODS: The uptake of 3H-FDG into MCF7 cells was determined after incubation under hypoxic (0% oxygen) or normoxic conditions, with or without redox agents, for varying time periods. In addition, the effects of the redox agents on the glucose transporter activity and the hexokinase activity were determined independently, and the effects of hypoxia on glucose transporter protein and hexokinase levels were assessed. RESULTS: A more than twofold increase (2.53 +/- 0.79; P < 0.005) in 3H-FDG uptake was observed under hypoxic conditions, but no changes in the cellular levels of glucose transporter proteins or hexokinase were observed. A reducing agent, dithiothreitol (DTT), also caused an increase in 3H-FDG uptake but failed to affect uptake under hypoxic conditions. This indicates that the mechanisms by which hypoxia and DTT affect 3H-FDG uptake might be the same. The oxidizing agent p-chloromercuribenzenesulfonic acid (pCMBS) had no effect on 3H-FDG uptake under normoxic conditions but counteracted the effect of hypoxia. DTT caused an increase in glucose transporter activity, whereas it had no effect on hexokinase activity. pCMBS had no effect on either glucose transporter activity or hexokinase activity. CONCLUSION: The hypoxia-induced increase in 3H-FDG uptake in MCF7 cells is the result, in part, of an increase in glucose transporter activity resulting from the modification (reduction) of thiol group(s) in the glucose transport protein(s). Modulation of hexokinase activity is probably not involved in the hypoxia-induced increase in 3H-FDG uptake in these cells.

Radioiodine uptake in thyroid remnants during therapy after tracer dosimetry.

UNLABELLED: Our objective was to evaluate the effect of a diagnostic tracer dose of 131I on the uptake of the therapeutic dose of 1311 in the ablation of a thyroid remnant or residual tumor in patients with differentiated thyroid cancer. METHODS: Twelve consecutive patients referred for a dosimetric study and subsequent radioiodine treatment of focal neck uptake of 131I were studied. The 24-h (in 1 case, 48-h) neck activity was calculated by the region-of-interest method, after both dosimetric and therapeutic administrations. The focal activity in the neck was corrected for decay and compared with the total activity administered to obtain the percentage uptake at 24 h. This procedure was performed for both the scanning dose (range, 19.8-196.1 MBq; mean, 85.1 MBq; median, 40 MBq) and the therapeutic dose (range, 1.073-5.713 GBq; mean, 2.991 GBq). The uptake of the therapeutic dose was then expressed as a percentage of the uptake of the diagnostic dose (%T/D). Counting rate linearity was established up to 350 MBq in the field of view of the gamma camera used in the study. RESULTS: Thirteen of a total of 16 lesions exhibited reduced uptake from the therapeutic dose, 2 remained the same, and in 1 the uptake actually increased from 0.26% to 1.01%. The %T/D ranged from 7.0% to 388.5%, with a mean of 71%. If the lesion with increased uptake is excluded, the range becomes 7.0%-102.1%, with a mean of 50%. Linear regression between the percentage uptake of the diagnostic dose to that of the therapeutic dose results in a slope of 0.42, with a correlation coefficient of only 0.75. We were unable to accurately calculate the radiation dose to the lesion from the diagnostic activity of 131I, because of uncertainty about the tumor mass. CONCLUSION: The percentage uptake of the therapeutic dose is on average only one half of that predicted from the dosimetric uptake in thyroid remnants after surgery, even though the median dosimetric dose was only 40 MBq. This reduced uptake should be accounted for in the therapeutic prescription for thyroid ablation or treatment of residual thyroid cancer. We postulate that this effect is caused by radiation damage from the tracer dose during dosimetry.

Thyroid cancer dosimetry using clearance fitting.

UNLABELLED: Since 1962, Memorial Sloan Kettering Cancer Center has used an individually optimized dosimetry method for patients with thyroid carcinoma undergoing radioiodine therapy. This traditional dosimetry method involves a determination of the maximum tolerated activity or the activity that will deliver 2 Gy to the blood (A(max)), and the corresponding ablative lesion dose (D(lesion)). However, the traditional calculations of A(max) and D(lesion) were based on empirical assumptions. The objective of this work was to develop a dosimetry method that eliminates these assumptions by incorporating patient kinetics and that is not restricted to 131I as a tracer and therapeutic agent. METHODS: Patient kinetics were incorporated into the dosimetry algorithm by fitting parameters to patient clearance measurements. The radioiodines 123I, 124I, 125I and 131I were accommodated as tracers and therapeutic agents by incorporating their physical half lives and by precalculating photon-absorbed fractions for these radionuclides for several thousand patient geometries using Monte Carlo simulations. RESULTS: A(max) and D(lesion) have been calculated using the traditional and new method for a group of patients, and errors associated with each of the above assumptions were examined. Assuming that the initial blood activity is distributed instantaneously in 5 L was found to introduce an error in A(max) of up to 30%, whereas assuming physical decay beyond the last data point introduced an error of up to 50%. CONCLUSION: Individualized fitting of clearance data is a practical method to accurately account for inter-patient kinetics variations. The substitution of standard kinetics beyond measured data might lead to substantial errors in estimating A(max) and D(lesion). In addition, gamma camera images, rather than neck probe readings, should be used to determine lesion uptakes for thyroid cancer patients.