[Clinical reasoning supportive to a medical service provider as a tool for complaint management: a case study for pragmatic reasoning]. / Beschwerdebearbeitung in einem medizinischen Dienstleistungsunternehmen als Clinical Reasoning Prozess: Reflexion eines Fallbeispiels an Hand des pragmatischen Reasoning.

The process of "clinical reasoning" is exemplified as supportive to the complaint management of the Statutory Medical Health Advisory Board in Lower Saxony, Germany, within the operational division for long-term care insurance. A model case from real life illustrates in detail the hypothetical-deductive approach by Beusheusen and Klemme/Siegmann. Because of the potential area of conflicts between human concern in the case of a long-term care burden and legal requirements, the process was analysed in terms of a pragmatic reasoning. Human resources of the claimant and persons in charge at customer's service were demonstrated as well as political, statutory and institutional determining factors. Concluding self-perception validates the process in the context of evidence-based practice.

Combined in vivo and in silico investigations of activation of glycolysis in contracting skeletal muscle.

The hypothesis was tested that the variation of in vivo glycolytic flux with contraction frequency in skeletal muscle can be qualitatively and quantitatively explained by calcium-calmodulin activation of phosphofructokinase (PFK-1). Ischemic rat tibialis anterior muscle was electrically stimulated at frequencies between 0 and 80 Hz to covary the ATP turnover rate and calcium concentration in the tissue. Estimates of in vivo glycolytic rates and cellular free energetic states were derived from dynamic changes in intramuscular pH and phosphocreatine content, respectively, determined by phosphorus magnetic resonance spectroscopy ((31)P-MRS). Computational modeling was applied to relate these empirical observations to understanding of the biochemistry of muscle glycolysis. Hereto, the kinetic model of PFK activity in a previously reported mathematical model of the glycolytic pathway (Vinnakota KC, Rusk J, Palmer L, Shankland E, Kushmerick MJ. J Physiol 588: 1961-1983, 2010) was adapted to contain a calcium-calmodulin binding sensitivity. The two main results were introduction of regulation of PFK-1 activity by binding of a calcium-calmodulin complex in combination with activation by increased concentrations of AMP and ADP was essential to qualitatively and quantitatively explain the experimental observations. Secondly, the model predicted that shutdown of glycolytic ATP production flux in muscle postexercise may lag behind deactivation of PFK-1 (timescales: 5-10 s vs. 100-200 ms, respectively) as a result of accumulation of glycolytic intermediates downstream of PFK during contractions.

SU-E-T-600: Utilizing Collimator Rotation to Increase Maximum Treatable Target Dimensions Using an Elekta Synergy-S with Beam Modulator Multileaf Collimator.

PURPOSE: To determine if a rotated collimator on an Elekta Synergy-S with Beam Modulator MLC (BMx) allows for dosimetrically acceptable treatment of targets exceeding the length of the maximum field size (21×16cm). The BMx is a high-resolution MLC with 4mm leaves but is of limited clinical use on patient target volumes exceeding 20cm in length. Rotation of the collimator utilizes the Pythagorean geometry to extend treatment length. This potentially increases the length of the PTV that be conformally treated. METHODS: Rods of 21-23cm length were contoured in water with the Pinnacle treatment planning system. The width of the rods varies from 1 -5cm. Four isocentric treatment plans were generated for each target: four-field conformal, 7-field IMRT, single-arc VMAT, and a modified double-arc VMAT (MDAV), with the collimator angled at 55°. The MDAV method consists of two opposing 180° arcs with the collimator turned 55° in opposite directions. A successful plan is defined as 99% of the target volume being covered by a minimum of 95% of the prescribed dose. Conformality is determined as a ratio of the volume exposed to prescribed isodose and target volume. RESULTS: Targets of length 21cm, 22cm, and 23 cm are able to be treated with widths of 4cm, 5 cm, and 4cm respectively. The MDAV method achieves these results on all trials. The VMAT method achieves these results for the 21cm and 23cm long target. The IMRT Method achieves these results for the 21cm long target. With the exception of the 1cm wide targets, the average conformality is approximately 2.5. CONCLUSIONS: Changing the collimator angle of the BMx Elekta-S machine allows for a 3cm length increase of targets up to 5cm. Further work will assess clinical suitability of these findings for treatment of head and neck tumors and spinal masses.

SU-E-T-460: Isoeffective Dose Display (EQD2) for Composite Plan of Radiosurgery and Conventional 3D Radiotherapy.

PURPOSE: Direct addition of doses between plans with different fractionation fails to provide accurate dose-response information to anticipate clinical outcome. To combine different fractionation patterns, first-order biological model correction for dose-rate must be included. Moreover, 3-D isoeffect patterns of the combined doses must be displayed so that overlap area to elegant volumes can be avoided. The linear quadratic (LQ) model and biologically effective dose (BED) method were used to produce a combined plan in equivalent 2 Gy fractions (EQD2) for radiosurgery and conventional 3D radiotherapy. METHODS: For patients with multiple courses of radiotherapy, dose distributions of the prior and boost treatment plans were converted to BED. The fraction size specified by the prescription was applied globally for each BED calculation, α/ß ratio of 10 and 2.5 was used for early and late effect, respectively. Image registration with CT or MR was performed for initial and boost plans. The registration information was applied to dose distributions to obtain the composite EQD2. RESULTS: As a demonstration of this method, two patients were selected who had combined treatments from substantially different modalities. A patient with liver cancer initially received radiotherapy of 30 Gy/10 Fx and re-irradiation with CyberKnife radiosurgery (15 Gy/1 Fx). The combined plan showed that the PTV received EQD2 of 63.8 Gy. Another patient had brain metastasis treated with GammaKnife of 18 Gy (50% isodose) followed by conventional 3D whole brain radiation of 30 Gy/10 Fx. The minimal combined tumor EQD2 was 74.5 Gy. Early and late calculated responses showed that all critical organ doses were within tolerance. CONCLUSIONS: For patients receiving radiation with different fractionation schemes, combined isoeffective dose distributions were calculated and displayed. In both cases, crucial information regarding 3-D dose distributions assisted the physicians in determining whether tolerance limits of overlap areas of retreated critical structures were preserved.

Quality of coverage: conformity measures for stereotactic radiosurgery.

In radiosurgery, conformity indices are often used to compare competing plans, evaluate treatment techniques, and assess clinical complications. Several different indices have been reported to measure the conformity of the prescription isodose to the target volume. The PITV recommended in the Radiation Therapy Oncology Group (RTOG) radiosurgery guidelines, defined as the ratio of the prescription isodose volume (PI) over the target volume (TV), is probably the most frequently quoted. However, these currently used conformity indices depend on target size and shape complexity. The objectives of this study are to systematically investigate the influence of target size and shape complexity on existing conformity indices, and to propose a different conformity index-the conformity distance index (CDI). The CDI is defined as the average distance between the target and the prescription isodose line. This study examines five case groups with volumes of 0.3, 1.0, 3.0, 10.0, and 30.0 cm(3). Each case group includes four simulated shapes: a sphere, a moderate ellipsoid, an extreme ellipsoid, and a concave "C" shape. Prescription dose coverages are generated for three simplified clinical scenarios, i.e., the PI completely covers the TV with 1 and 2 mm margins, and the PI over-covers one half of the TV with a 1 mm margin and under-covers the other half with a 1 mm margin. Existing conformity indices and the CDI are calculated for these five case groups as well as seven clinical cases. When these values are compared, the RTOG PITV conformity index and other similar conformity measures have much higher values than the CDI for smaller and more complex shapes. With the same quality of prescription dose coverage, the CDI yields a consistent conformity measure. For the seven clinical cases, we also find that the same PITV values can be associated with very different conformity qualities while the CDI predicts the conformity quality accurately. In summary, the proposed CDI provides more consistent and accurate conformity measurements for all target sizes and shapes studied, and therefore will be a more useful conformity index for irregularly shaped targets.

Radioimmunoguided imaging of prostate cancer foci with histopathological correlation.

PURPOSE: We have previously presented a technique that fuses ProstaScint and pelvic CT images for the purpose of designing brachytherapy that targets areas at high risk for treatment failure. We now correlate areas of increased intensity seen on ProstaScint-CT fusion images to biopsy results in a series of 7 patients to evaluate the accuracy of this technique in localizing intraprostatic disease. METHODS AND MATERIALS: The 7 patients included in this study were evaluated between June 1998 and March 29, 1999 at Metrohealth Medical Center and University Hospitals of Cleveland in Cleveland, Ohio. ProstaScint and CT scans of each patient were obtained before transperineal biopsy and seed implantation. Each patient's prostate gland was biopsied at 12 separate sites determined independently of Prostascint-CT scan results. RESULTS: When correlated with biopsy results, our method yielded an overall accuracy of 80%: with a sensitivity of 79%, a specificity of 80%, a positive predictive value of 68%, and a negative predictive value of 88%. CONCLUSION: The image fusion of the pelvic CT scan and ProstaScint scan helped identify foci of adenocarcinoma within the prostate that correlated well with biopsy results. These data may be useful to escalate doses in regions containing tumor by either high-dose rate or low-dose rate brachytherapy, as well as by external beam techniques such as intensity modulated radiotherapy (IMRT).

Red marrow dosimetry for radiolabeled antibodies that bind to marrow, bone, or blood components.

Hematologic toxicity limits the radioactivity that may be administered for radiolabeled antibody therapy. This work examines approaches for obtaining biodistribution data and performing dosimetry when the administered antibody is known to bind to a cellular component of blood, bone, or marrow. Marrow dosimetry in this case is more difficult because the kinetics of antibody clearance from the blood cannot be related to the marrow. Several approaches for obtaining antibody kinetics in the marrow are examined and evaluated. The absorbed fractions and S factors that should be used in performing marrow dosimetry are also examined and the effect of including greater anatomical detail is considered. The radiobiology of the red marrow is briefly reviewed. Recommendations for performing marrow dosimetry when the antibody binds to the marrow are provided.

Physical and chemical properties of radionuclide therapy.

As more radionuclide therapies move from laboratory feasibility studies into clinical reality, it becomes increasingly important for the labeling chemistry to produce consistently a stable radiopharmaceutical that remains intact under the challenge of human catabolism. Similarly, once proof of principle is established to bring a radionuclide conjugate into clinical therapy trials, dosimetric estimates should be made to select the appropriate radionuclide properties, which are based on animal-specific or patient-specific pharmacokinetics and match a set of specific clinical endpoints. These properties may include the radionuclide physical half-life, radiolabeled conjugate biological uptake and clearance, product-specific activity, range and type of emissions, and resultant effects on tumor and normal tissue cellular survival. The immunologist and labeling chemist have now produced a variety of strategies that have potential to increase the therapeutic ratio (tumor-to-normal tissue dose ratio). The advent of normal tissue clearing agents, fragmented or chimerized carriers to improve targeting, and the method of bispecific or two-step and three-step targeting agents has increased the need for realistic modeling of the carrier in vivo to guide prospectively the competitive development of these radiopharmaceuticals. In this article, examples have been taken from the literature to elucidate the benchmark of success that careful experimental design has fostered to bring these agents into clinical practice by creative and logical methodologies.

131I-Lym-1 in mice implanted with human Burkitt's lymphoma (Raji) tumors: loss of tumor specificity due to radiolysis.

UNLABELLED: Preliminary evaluations of 125I-labeled Lym-1, an anti-lymphoma mouse IgG2a monoclonal antibody, demonstrated favorable tumor uptake in mice bearing human Burkitt's lymphoma (Raji) tumors. In this study, the pharmacokinetics of 125I- and 131I-Lym-1, and the dosimetry, efficacy, and toxicity of 131I-Lym-1 in Raji-tumored mice were evaluated. METHODS: Lym-1 was radioiodinated by the chloramine-T method and analyzed for monomeric fraction and immunoreactivity (antigen cell binding, relative to unmodified Lym-1). Nude mice bearing Raji tumors (20-500 mm3) received 1.5 MBq (40 microCi) 125I-Lym-1, or 1.5, 7.4, 14.8, or 18.5 MBq (40, 200, 400, or 500 microCi) 131I-Lym-1. Pharmacokinetic data (total body and blood clearance and biodistribution) were used to estimate radiation dosimetry. Mini-thermoluminescent dosimetry (TLD) was also used to measure radiation dosimetry directly for 7 days after injection of 131I-Lym-1. Tumor size, survival, body weight, and blood counts were monitored for 60 days to evaluate therapeutic efficacy and toxicity of 131I-Lym-1. RESULTS: At the time of injection, the mean quality assurance (QA) values for 125I-Lym-1 were 100% monomer and 100% relative immunoreactivity; the corresponding values for 131I-Lym-1 were 73% and 66%, indicating that radiolysis had occurred during the interval between radiolabeling and injection. 125I-Lym-1 exhibited high and sustained concentration in tumors relative to normal organs, whereas 131I-Lym-1 did not. Assuming identical pharmacokinetic behavior to 125I-Lym-1, 131I-Lym-1 would deliver radiation doses of 3.45, 0.83, 1.03, 0.34, and 0.56 Gy per MBq injected (12.8, 3.1, 3.8, 1.3, and 2.1 rad/microCi), to tumor, liver, lungs, total body, and marrow, respectively. When the actual pharmacokinetic data for 131I-Lym-1 (1.5 MBq) were used to estimate dosimetry, corresponding values of 0.51, 0.72, 0.49, 0.31, and 0.41 Gy/MBq (1.9, 2.7, 1.8, 1.1, and 1.5 rad/microCi) were obtained. Similar values were obtained for mice receiving 7.4 or 14.8 MBq of 131I-Lym-1. Similarly, TLD data indicated little preferential radiation dosimetry to tumor. Response rates (cure + CR + PR) for mice receiving 0, 7.4, 14.8, and 18.5 MBq of 131I-Lym-1 were 8%, 7%, 21%, and 45%, respectively. The LD50/30 dose of 131I-Lym-1 was 12.7 MBq (343 microCi). CONCLUSIONS: 125I-Lym-1 exhibited high and sustained concentration in Raji tumors in mice, indicating excellent therapeutic potential for 131I-Lym-1. However, in vitro QA results for 131I-Lym-1 indicated that radiolysis had occurred, and 131I-Lym-1 demonstrated little accumulation in tumor, or preferential radiation dosimetry to tumor in the same model.

Validation of an analytical expression for the absorbed dose from a spherical beta source geometry and its application to micrometastatic radionuclide therapy.

The purpose of this study was to validate an analytical expression for the absorbed-dose calculation from the spherical source of beta-emitting radionuclides and to apply it to micrometastases treated with radiolabeled monoclonal antibodies. The self-absorbed fractions from I-131 and P-32 uniform spherical sources were calculated using the analytical expression introduced by P. K. Leichner (J. Nucl. Med., 35: 1721-1729, 1994). The calculated absorbed fractions were compared with previously reported values and were found to be in reasonable agreement, with a maximum difference of 15% for smaller masses and a long-range beta emitter. The expression was subsequently applied to estimate the absorbed dose within spheroid models with nonuniform penetration of radiolabeled antibody. The corresponding absorbed dose for I-131 was compared with reported micro-thermoluminescence dosimeter measurements and found to be in good agreement. This work has independently substantiated the methodology outlined by Leichner and may be reliably incorporated into new software developments for radionuclide dosimetry treatment planning.

Can current models explain the lack of liver complications in Y-90 microsphere therapy?

Normal liver complications have not been observed in Y-90 microsphere therapy of hepatic tumors [selective internal radiation (SIR)], despite clinical studies reporting estimated absorbed doses to normal liver between 100 and 150 Gy. The purpose of the study was to see whether predictions of normal tissue complication probability (NTCP) models for liver based on clinical data from external beam therapy are consistent with clinical results of SIR. Liver NTCP was calculated using a parallel architecture model and normal liver dose-volume histograms that have been proposed for SIR. A parallel model including internal functional subunit structure is also proposed. Dose rate effects are incorporated. A criterion for comparing model calculations with clinical data is presented. For the parallel architecture model, the predicted NTCP is sensitive to the dose distribution in normal liver and to the model parameters, particularly the repair time. With reasonable assumptions about the microsphere distribution, the parallel model with parameters deduced from external beam therapy outcome analysis is consistent with the observed lack of liver complications. Inclusion of FSU structure widens the range of assumptions under which consistency is found. The parallel model can be consistent with the clinically observed lack of liver complications in SIR. More information about the activity distribution and the radiobiology of normal liver under conditions typical of microsphere therapy should be sought.

The MIRD perspective 1999. Medical Internal Radiation Dose Committee.

The MIRD schema is a general approach for medical internal radiation dosimetry. Although the schema has traditionally been used for organ dosimetry, it is also applicable to dosimetry at the suborgan, voxel, multicellular and cellular levels. The MIRD pamphlets that follow in this issue and in coming issues, as well as the recent monograph on cellular dosimetry, demonstrate the flexibility of this approach. Furthermore, these pamphlets provide new tools for radionuclide dosimetry applications, including the dynamic bladder model, S values for small structures within the brain (i.e., suborgan dosimetry), voxel S values for constructing three-dimensional dose distributions and dose-volume histograms and techniques for acquiring quantitative distribution and pharmacokinetic data.

MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions--radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee.

The availability of quantitative three-dimensional in vivo data on radionuclide distributions within the body makes it possible to calculate the corresponding nonuniform distribution of radiation absorbed dose in body organs and tissues. This pamphlet emphasizes the utility of the MIRD schema for such calculations through the use of radionuclide S values defined at the voxel level. The use of both dose point-kernels and Monte Carlo simulation methods is also discussed. PET and SPECT imaging can provide quantitative activity data in voxels of several millimeters on edge. For smaller voxel sizes, accurate data cannot be obtained using present imaging technology. For submillimeter dimensions, autoradiographic methods may be used when tissues are obtained through biopsy or autopsy. Sample S value tabulations for five radionuclides within cubical voxels of 3 mm and 6 mm on edge are given in the appendices to this pamphlet. These S values may be used to construct three-dimensional dose profiles for nonuniform distributions of radioactivity encountered in therapeutic and diagnostic nuclear medicine. Data are also tabulated for 131I in 0.1-mm voxels for use in autoradiography. Two examples illustrating the use of voxel S values are given, followed by a discussion of the use of three-dimensional dose distributions in understanding and predicting biologic response.

MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data processing, involves curve-fitting techniques to integrate the source time-activity curves (determining the area under these curves). For some applications, compartmental modeling procedures may be used. Last, appendices are included that provide a table of symbols and definitions, a checklist for study protocol design, example formats for quantitative imaging protocols, temporal sampling error analysis techniques and selected calculational examples. The utilization of the presented approach should aid in the standardization of protocol design for collecting kinetic data and in the calculation of absorbed dose estimates.

Use of the fast Hartley transform for three-dimensional dose calculation in radionuclide therapy.

Effective radioimmunotherapy may depend on a priori knowledge of the radiation absorbed dose distribution obtained by trace imaging activities administered to a patient before treatment. A new, fast, and effective treatment planning approach is developed to deal with a heterogeneous activity distribution. Calculation of the three-dimensional absorbed dose distribution requires convolution of a cumulated activity distribution matrix with a point-source kernel; both are represented by large matrices (64 x 64 x 64). To reduce the computation time required for these calculations, an implementation of convolution using three-dimensional (3-D) fast Hartley transform (FHT) is realized. Using the 3-D FHT convolution, absorbed dose calculation time was reduced over 1000 times. With this system, fast and accurate absorbed dose calculations are possible in radioimmunotherapy. This approach was validated in simple geometries and then was used to calculate the absorbed dose distribution for a patient's tumor and a bone marrow sample.

Marrow toxicity and radiation absorbed dose estimates from rhenium-186-labeled monoclonal antibody.

UNLABELLED: Estimates of radiation absorbed dose to the red marrow (RM) would be valuable in treatment planning for radioimmunotherapy if they could show a correlation with clinical toxicity. In this study, a correlation analysis was performed to determine whether estimates of radiation absorbed dose to the bone marrow could accurately predict marrow toxicity in patients who had received 186Re-labeled monoclonal antibody. METHODS: White blood cell and platelet count data from 25 patients who received 186Re-NR-LU-10 during Phase I radioimmunotherapy trials were analyzed, and the toxicity grade, the fraction of the baseline counts at the nadir (percentage baseline) and the actual nadir were used as the indicators of marrow toxicity. Toxicity was correlated with various predictors of toxicity. These predictors included the absorbed dose to RM, the absorbed dose to whole body (WB) and the total radioactivity administered. RESULTS: Percentage baseline and grade of white blood cells and platelets all showed a moderate correlation with absorbed dose and radioactivity administered (normalized for body size). The percentage baseline platelet count was the indicator of toxicity that achieved the highest correlation with the various predictors of toxicity (r = 0.73-0.79). The estimated RM absorbed dose was not a better predictor of toxicity than either the WB dose or the total radioactivity administered. There was substantial variation in the blood count response of the patients who were administered similar radioactivity doses and who had similar absorbed dose estimates. CONCLUSION: Although there was a moderately good correlation of toxicity with dose, the value of the dose estimates in predicting toxicity is limited by the patient-to-patient variability in response to internally administered radioactivity. In this analysis of patients receiving 186Re-labeled monoclonal antibody, a moderate correlation of toxicity with dose was observed but marrow dose was of limited use in predicting toxicity for individual patients.

Dosimetry overview: keeping score on the scorekeepers.

BACKGROUND: As a direct result of the use of the absorbed dose unit the 'Gray' as the gold standard for predicting response in external beam radiotherapy, the physicist role has been essential to clinical practice for many decades. However, although the dosimetry for internal emitters has proven useful in managing health physics concerns and diagnostic nuclear medicine, the relative success of correlating absorbed dose with response from radionuclide therapy has been limited. METHODS: This overview presents the relative success and/or failure of model-based dosimetry for radionuclide therapy in comparison to results quoted for external beam therapy dosimetry. RESULTS: Using the standard MIRD formalism for macroscopic dosimetry, the marked non-uniform distribution of radionuclide in both tumor and normal tissue has resulted in limited correlation between computed absorbed dose and biological response in clinical trials. Several efforts are underway aimed at improving this dose-response correlation which include individualized patient specific dosimetry and selected biological parameters. CONCLUSIONS: The physicist role in helping the clinician determining which patients will succeed on given radionuclide therapy has been improved with simplified methods such as the assessment of tracer whole body absorbed dose on a per patient basis. The dose-response correlations are now in the moderate range of significance when individualized patient dosimetry is included. These correlations are expected to improve as unified treatment planning programs are instituted and standard methods of clinically based dosimetry are widely accepted and practiced universally.

Radiobiologic studies of radioimmunotherapy and external beam radiotherapy in vitro and in vivo in human renal cell carcinoma xenografts.

BACKGROUND: Previous studies suggest that the radiobiologic characteristics of in vitro survival curves are important determinants of the response of tumors to both conventional radiotherapy and radioimmunotherapy (RIT). The purpose of this study was to elucidate the relationship between in vitro radiation survival curve parameters and the relative sensitivity of tumor to RIT, exponentially decreasing low dose rate (ED LDR) irradiation and conventional high dose rate (HDR) fractionated external beam radiotherapy. METHODS: Two human renal cell carcinoma cell lines, Caki-1 and A498, were used in vitro and nude mouse xenograft studies. HDR external beam gamma irradiation (dose rate, 430 centigray [cGy]/minute) and ED LDR irradiation (initial dose rate, 22-25 cGy/hour) were performed with a cesium-137 (137Cs) gamma irradiator. RIT was carried out with yttrium-90 (90Y-labeled monoclonal antibody NR-LU-10, and the absorbed radiation doses were calculated by medical internal radiation dose methodology. A clonogenic assay was used to generate radiation survival curves, and a computer FIT program was used to calculate the radiobiologic parameters. The antitumor efficacy of the different treatments was compared in vivo using a tumor regrowth delay assay in these two tumor xenograft models. RESULTS: The radiation survival curves showed that the Caki-1 cell line was more sensitive to both HDR and ED LDR irradiation than A498 in vitro. The Caki-1 cell line, compared with A498, had a larger alpha (0.39 vs. 0.15 Gy following HDR and 0.32 vs. 0.21 Gy following ED LDR) and alpha-to-beta ratio (6.92 vs. 2.60 Gy for HDR and 40.0 vs. 19.2 Gy for ED LDR), a smaller n number (5.13 vs. 23 for HDR and 1.16 vs. 3.53 for ED LDR), a lower quasi-threshold dose (Dq) (1.60 vs. 3.15 Gy for HDR and 0.35 vs. 1.76 Gy for ED LDR), and a lower surviving fraction at 2 Gy (SF2) (0.37 vs. 0.60 for HDR and 0.51 vs. 0.61 for ED LDR), suggesting that Caki-1, compared with A498, had a steep initial slope and a small shoulder. The final slope represented by the beta value and D0 dose (the dose (Gy) required to reduce the fraction of surviving cells of 37% of its previous value in the exponential region of the survival curves) did not vary significantly between these two cell lines at either HDR or ED LDR irradiation. Tumor volume doubling times were 4.0 +/- 1.5 days for Caki-1 and 4.2 +/- 1.8 days for A498 tumor xenografts. One hundred microCi/50 microg of 90Y-labeled, isotype-matched irrelevant monoclonal antibody CCOO16-3 produced a tumor growth delay time (TGD) of 2.1 days in Caki-1 tumors but had no effect on A498 tumors (P < 0.05). RIT with 100 microCi of 90Y-NR-LU-10 resulted in a TGD of 4.8 days for Caki-1 tumors, whereas 100 microCi and 150 microCi of 90Y-NR-LU-10 produced a TGD of 1.9 and 2.7 days for A498 tumors, respectively. Estimated absorbed doses were 21.9 Gy in Caki-1 tumors treated with 100 microCi of 90Y-NR-LU-10 and 14.5 Gy and 21.8 Gy in A498 tumors treated with 100 microCi and 150 microCi of 90Y-NR-LU-10, respectively. The weighted normal tissue absorbed doses were 7.4 Gy for Caki-1 tumor-bearing mice and 9.0 Gy for A498 tumor-bearing mice (P > 0.05). To compare the responses of Caki-1 and A498 xenografts to RIT with external beam ED LDR and HDR irradiation, tumor-bearing mice were treated with equivalent doses (20-22 Gy) of 1) RIT with 90Y-NR-LU-10 (100 microCi for Caki-1 and 150 microCi for A498), 2) continuous ED LDR 137Cs irradiation with a initial dose rate of 22 cGy/hour, or 3) HDR X-irradiation (2 Gy x 10 fractions in 2 weeks). The TGDs produced by RIT, ED LDR, and HDR were 5.3, 9.7, and 8.3 days for Caki-1 and 2.7, 5.1, and 5.8 days for A498. The relative efficacy of RIT in these xenograft models correlated well with the radiobiologic parameters (i.e., the size of the initial slope and shoulder) of in vitro survival curves following HDR and ED LDR irradiation in these cell lines. (ABSTRACT TRUNCATED)

Treatment planning for radio-immunotherapy.

To foster the success of clinical trials in radio-immunotherapy (RIT), one needs to determine (i) the quantity and spatial distribution of the administered radionuclide carrier in the patient over time, (ii) the absorbed dose in the tumour sites and critical organs based on this distribution and (iii) the volume of tumour mass(es) and normal organs from computerized tomography or magnetic resonance imaging and appropriately correlated with nuclear medicine imaging techniques (such as planar, single-photon emission computerized tomography or positron-emission tomography). Treatment planning for RIT has become an important tool in predicting the relative benefit of therapy based on individualized dosimetry as derived from diagnostic, pre-therapy administration of the radiolabelled antibody. This allows the investigator to pre-select those patients who have 'favorable' dosimetry characteristics (high time-averaged target: non-target ratios) so that the chances for treatment success may be more accurately quantified before placing the patient at risk for treatment-related organ toxicities. The future prospects for RIT treatment planning may yield a more accurate correlation of response and critical organ toxicity with computed absorbed dose, and the compilation of dose-volume histogram information for tumour(s) and normal organ(s) such that computing tumour control probabilities and normal tissue complication probabilities becomes possible for heterogeneous distributions of the radiolabelled antibody. Additionally, radiobiological consequences of depositing absorbed doses from exponentially decaying sources must be factored into the interpretation when trying to compute the effects of standard external beam isodose display patterns combined with those associated with RIT.

Application of the linear-quadratic model to myelotoxicity associated with radioimmunotherapy.

The purposes of this study were: (1) to use the linear-quadratic model to determine time-dependent biologically effective doses (BEDs) that were delivered to the bone marrow by multiple infusions of radiolabeled antibodies, and (2) to determine whether granulocyte and platelet counts correlate better with BED than administered radioactivity, which does not take stem cell repopulation, i.e., time, into consideration. Twenty patients with B-cell malignancies that had progressed despite intensive chemotherapy and who had a significant number of malignant cells in their bone marrow were treated with multiple 0.7-3.7 GBq/m2 (18-100 mCi/m2) intravenous infusions of Lym-1, a murine monoclonal antibody that binds to a tumour-associated antigen, labeled with iodine-131. Granulocyte and platelet counts were measured in order to assess bone marrow toxicity. BEDs were calculated according to the formula: BED=D(1+gD/(alpha/beta))-0.693(Tn-Tk)/alphaTp, where D represents the absorbed dose of radiation delivered to the red marrow by penetrating emissions of 131I throughout the whole body and nonpenetrating emissions of 131I in the blood and bone marrow, g is a factor that depends on the duration of irradiation relative to the repair half-life of human bone marrow, alpha is the coefficient of nonrepairable damage per Gy, beta is the coefficient of repairable damage per Gy2, Tn is the time required to reach the granulocyte or platelet count nadir after an 131I-Lym-1 infusion, Tk is the time at which bone marrow proliferation begins after the start of treatment and Tp is the doubling time of the bone marrow after the granulocyte or platelet count nadir has been reached. The cumulative 131I-Lym-1 radioactivity administered to each patient was calculated. Biologically effective doses from multiple 131I-Lym-1 infusions were summated in order to arrive at a total BED for each patient. There was a weak association between granulocyte and platelet counts and radioactivity (the correlation coefficients were -0.23 and -0.60, respectively). Likewise, there was a weak association between granulocyte and platelet counts and BED (the correlation coefficients were -0.27 and -0.40, respectively). The attempt to take bone marrow absorbed doses and overall treatment time into consideration with the linear-quadratic model did not produce a stronger association than was observed between peripheral blood counts and administered radioactivity. The association between granulocyte and platelet counts and BED may have been weakened by several factors, including variable bone marrow reserve at the start of 131I-Lym-1 therapy and the delivery of heterogeneous absorbed doses of radiation to the bone marrow.