Application of MINERVA Monte Carlo simulations to targeted radionuclide therapy

Recent clinical results have demonstrated the promise of targeted radionuclide therapy for advanced cancer. As the success of this emerging form of radiation therapy grows, accurate treatment planning and radiation dose simulations are likely to become increasingly important. To address this need, we have initiated the development of a new, Monte Carlo transport-based treatment planning system for molecular targeted radiation therapy as part of the MINERVA system. The goal of the MINERVA dose calculation system is to provide 3-D Monte Carlo simulation-based dosimetry for radiation therapy, focusing on experimental and emerging applications. For molecular targeted radionuclide therapy applications, MINERVA calculates patient-specific radiation dose estimates using computed tomography to describe the patient anatomy, combined with a user-defined 3-D radiation source. This paper describes the validation of the 3-D Monte Carlo transport methods to be used in MINERVA for molecular targeted radionuclide dosimetry. It reports comparisons of MINERVA dose simulations with published absorbed fraction data for distributed, monoenergetic photon and electron sources, and for radioisotope photon emission. MINERVA simulations are generally within 2% of EGS4 results and 10% of MCNP results, but differ by up to 40% from the recommendations given in MIRD Pamphlets 3 and 8 for identical medium composition and density. For several representative source and target organs in the abdomen and thorax, specific absorbed fractions calculated with the MINERVA system are generally within 5% of those published in the revised MIRD Pamphlet 5 for 100 keV photons. However, results differ by up to 23% for the adrenal glands, the smallest of our target organs. Finally, we show examples of Monte Carlo simulations in a patient-like geometry for a source of uniform activity located in the kidney.     

Sensitivity of model-based calculations of red marrow dosimetry to changes in patient-specific parameters

We have investigated several of the key model parameters and assumptions involved in the calculation of red marrow absorbed dose in order to better understand the sensitivity of the predicted results to changes in these model features and the subsequent effect on correlations of the red marrow absorbed dose values with observed hematologic toxicity. Red marrow dose calculations based on measured blood activity concentrations (to determine red marrow cumulated activity) and measured total body cumulated activity have a mass-independent and mass-dependent term. Adjustments for patient mass should be made in these calculations when patients' lean body masses are more than 10% different from that in the assumed standard models. The blood-based red marrow dose methodology has the potential to provide a reasonable estimate of red marrow dose as long as there is no specific uptake in red marrow or bone due to the presence of free radionuclide, disease, or retention of activity due to metabolism by the reticuloendothelial system. If these additional sources of red marrow dose are present, the blood-based methodology will significantly underestimate red marrow dose. For radiometals, such as in (90)Y-labeled antibodies, bone or red marrow uptake of free yttrium or catabolized (90)Y products may have a significant impact on the calculated dose, assuming fairly low amounts of free (90)Y or marrow activity uptake (5-10%), even in the absence of disease in red marrow and/or bone. This is also true for (131)I-labeled antibodies, although to a lesser extent due to typically reduced activity retention in the bone marrow in the absence of disease and lack of bone uptake of free radionuclide. Radiation dose calculations for the red marrow must be made as carefully as possible, taking into account all possible sources of radiation dose, and considering all sources of uncertainties, in order to give the best possible correlations of radiation dose with observed toxicity.     

Internal microdosimetry for single cells in radioimmunotherapy of B-cell lymphoma

Patients with B-cell lymphoma may have disease manifestations ranging in size from more than a 1000 cm3 down to the volume of a single cell. If targeted radionuclide therapy is to become a curative treatment, all individual tumor cells must also be eliminated. Given the vast differences in particle energy of different electron- emitting radionuclides, one questions whether the mean absorbed dose is a relevant parameter for use in single-cell dosimetry and whether it would not be more accurate to adopt a stochastic approach to dosimetry. Monte Carlo simulations were performed of energy deposition from 1000, 300, 100, or 10 electrons uniformly distributed in a sphere with a radius of 7.7 microm. The simulated electrons were monoenergetic (18 keV, 28 keV, 141 keV, or 935 keV). The absorbed dose per emitted electron, the absorbed fraction, the fraction of the cellular volume in which energy is deposited, and the dose-volume histograms were calculated. Absorbed fractions varied between 0.60 (18 keV) and 0.001 (935 keV), and the absorbed dose to the cell per electron emitted varied by a factor of 10, from 0.898 mGy (18 keV) to 0.096 mGy (935 keV). The specific energy varied between 0 and 46 mGy for the case showing the best uniformity (1000 18-keV electrons). The nonuniformity of the absorbed dose to a cell increases with increasing electron energy and decreases with the number of decays inside the studied volume. The wide distribution of energy deposition should be taken into account when analyzing and designing trials for targeted radionuclide therapy.     

Dosimetry in a myeloablative setting

In clinical therapy trials using high dosages of systemically administered radioactivity to treat cancer, myeloablation may occur. This is either an effect of the circulating radioactivity labeled to antibodies exposing the bone marrow to radiation, or it may occur because malignant cells in the bone marrow are targeted. Bone marrow cells may be targeted through antigens expressed on cells in the bone marrow or because radioactivity is targeted to the skeleton. Assessment of radiation absorbed dose to the marrow may be useful for dose escalation or individualized patient treatment planning. With successful preservation of marrow function with autologous marrow or peripheral blood stem cell transplantation, other normal organs may also receive sufficient radiation to show toxicity. Accurate dose estimates to these organs is important for the design of future studies in order to minimize or avoid toxicity. This paper reviews internally administered high dose radiation therapy studies, and examines the radiation absorbed dose estimates reported from these studies.     

Options for radionuclide therapy: from fixed activity to patient-specific treatment planning

The therapeutic use of radioisotopes in medicine as unsealed sources has a long history dating back to the 1930s. The established and continuing objectives are to provide radiation dose to the target tissue at the desired cytotoxic level while avoiding or minimizing toxic effects. Selected radionuclide therapy protocols including 32P for polycythemia vera, 131I for Graves' disease, and 131I for postsurgical ablation of thyroid remnants in the management of differentiated thyroid cancer are presented for historical review with the focus on protocols for administering the radiopharmaceuticals and the role played by dosimetry. The discussion also includes consideration of complications and the assessment of outcome for these diseases. The vista for radionuclide therapy today is reviewed along with the options for determining the administered activity. Patient specific dosimetry encompasses a number of levels ranging from basic measurement of relevant biokinetic parameters and use of standard models to calculate (and extrapolate) radiation dose to sophisticated three-dimensional techniques employing fusion of physiologic and high-resolution anatomic images coupled with advanced 3-D voxel patient representation and Monte Carlo techniques for use in radiation dose calculation. The role of patient specific dosimetry in clinical trials (Phase I, II, III trials) along with its utility in treatment planning, follow-up evaluation, and elucidation of dose-response relationships is discussed. The challenge ahead for those who advocate patient specific dosimetry is to assemble the outcome data and perform the analysis to support this contention.     

Generation of dose-volume histograms using Monte Carlo simulations on a multicellular model in radionuclide therapy

An accurate calculation of the absorbed dose at the cellular level can lead to the optimization of the administered activity and the best clinical response in radionuclide therapy. This paper describes the implementation of dose-volume histograms (DVHs) for dosimetry at the cellular level in radionuclide therapy. The FOTELP code, based on Monte Carlo simulations of photon and electron transport, was used on a three-dimensional multicellular tumor model, which includes tumor morphometry and cell-labeling parameters. Differential and cumulated DVHs were generated for different radionuclides (Cu-67, I-131, Sm-153, Y-90, and Re-188) and labeled cell densities (10, 20, 40, 80, and 100%). DVHs were generated as a percentage of tumor cells in the function of a relative absorbed dose, defined as a cell-absorbed dose divided by an average tumor-absorbed dose. DVHs for high-energy beta emitters, such as Re-188 and Y- 90, were very close to the average tumor-absorbed dose. For low-energy beta emitters, such as Cu-67 and I-131, spectra showed that many cells absorbed a much lower dose than the average tumor-absorbed dose. Nonhomogeneity of the radionuclide distribution in tumor, presented by labeled cell density, had a greater influence on DVHs for low-energy beta emitters. Radionuclide therapy plans can be optimized using DVHs.     

Internal radiation therapy for malignant neoplasm]

Internal radiation therapy selectively targets beta- or alpha-emitting radionuclides to the area of the tumor tissue, and is therefore capable of treating disease regardless of the location and number of foci. The biological effect of internal radiation therapy is thought to be different from that of conventional external beam radiation. Thyroid cancer: The local recurrence and metastatic lesions from differentiated thyroid cancers can be controlled with 131I administration. Even though the patient does not have macroscopic disease, 131I is also utilized for thyroid remnant ablation in locally advanced cases. Recently, the maximum tolerable dose can be calculated based on the dosimetry of each patient, and safely administered. The therapeutic effect of this method is superior to the fixed dose method. 131I-MIBG: 131I-MIBG is taken up by sympathetic neurons as well as a group of tumors originating in the neural crest, especially phecromocytomas and neuroblastomas. The various symptoms caused by the hypersecretions of hormone-producing tumors can be improved. Pain palliation of bone metastases: Pain palliation using 89Sr is a very promising option in treating patients with painful bone metastases. The pain palliation mechanism of 89Sr is different from other drugs; therefore, complimentary usage is reasonable. The symptomatical improvement can last for several months, thus helping to maintain the quality of life of the patient.     

Clinical trial design and scoring of radionuclide therapy endpoints: normal organ toxicity and tumor response

Like other cancer therapy agents under development, radionuclide therapies are usually evaluated in a progressive series of clinical trials after basic science, human cell culture and animal model studies. Toxicities during these trials are graded using common scoring systems that are in widespread use such as the Common Toxicity Criteria from the National Cancer Institute. Information on normal tissue toxicity from radionuclides is more limited than that from external beam radiation and is more variable. Variability is likely due to many biologic factors as well as less precise dose quantitation than those used in external beam radiation practice. As expected based on known radiobiologic effects, tolerance to radionuclide therapy appears to exceed that from high dose rate external beam radiation in most organs. Although the correlation between reported dose estimates and toxicity has progressively and substantially improved over the past two decades, further progress is needed to establish optimal toxicity predictive relationships. Continued refinement of dosimetry techniques and standardization is expected to increase the accuracy and comparability of radiation dose reports between institutions as well as improve dose/response correlation.     

A Monte Carlo Program Converting Activity Distributions to Absorbed Dose Distributions in a Radionuclide Treatment Planning System

In systemic radiation therapy, the absorbed dose distribution must be calculated from the individual activity distribution. A computer code has been developed for the conversion of an arbitrary activity distribution to a 3-D absorbed dose distribution. The activity distribution can be described either analytically or as a voxel based distribution, which comes from a SPECT acquisition. Decay points are sampled according to the activity map, and particles (photons and electrons) from the decay are followed through the tissue until they either escape the patient or drop below a cut off energy. To verify the calculated results, the mathematically defined MIRD phantom and unity density spheres have been included in the code. Also other published dosimetry data were used for verification. Absorbed fractions and S-values were calculated. A comparison with simulated data from the code with MIRD data shows good agreement. The S values are within 10-20% of published MIRD S values for most organs. Absorbed fractions for photons and electrons in spheres (masses between 1 g and 200 kg) are within 10-15% of those published. Radial absorbed dose distributions in a necrotic tumor show good agreement with published data. The application of the code in a radionuclide therapy dose planning system, based on quantitative SPECT, is discussed     

Internal radionuclide dosimetry: diagnostic and therapeutic nuclear medicine,occupational and environmental exposures. Differences and similarities

In diagnostic nuclear medicine, model-derived effective dose estimates have been considered adequate for risk estimates for various patient groups. Average anthropomorphic models (normally MIRD models) and representative biokinetic models are used, with the main uncertainty being due to limited information on the biokinetics of the substance in representative groups of patients. In nuclear medicine therapy it is necessary to make patient-specific absorbed dose estimates, especially to dose-limiting risk organs and to the tumor tissue. Together with information on the time-activity curve (which may differ for the low test activity and the high therapeutic activity) in different organs and tissues, there is a need for detailed anatomical information, normally collected through CT- and/or MR-imaging through the body volumes of interest. The wish to get the radionuclide localized in the tumor cells and preferentially in the cell nuclei makes it essential to consider the increased biological effect resulting from the nonuniform distribution of the absorbed energy in tumors as well as in dose-limiting organs such as bone marrow, liver, and kidneys. The situation in occupational and environmental internal dosimetry resembles that of diagnostic nuclear medicine. However, biokinetic models derived for the former purposes are often constructed for relatively long-lived isotopes, and cannot be used for the short-lived isotopes of the same element, which are used in diagnostic nuclear medicine. Similarities and differences in objectives and methods for dosimetry in the different areas are discussed.     

Imaging in targeted delivery of therapy to cancer

We review the current status of imaging as applied to targeted therapy with particular focus on antibody-based therapeutics. Antibodies have high tumor specificity and can be engineered to optimize delivery to, and retention within, the tumor. Whole antibodies can activate natural immune effector mechanisms and can be conjugated to β- and α-emitting radionuclides, toxins, enzymes, and nanoparticles for enhanced therapeutic effect. Imaging is central to the development of these agents and is used for patient selection, performing dosimetry and assessment of response. γ- and positron-emitting radionuclides may be used to image the distribution of antibody-targeted therapeutics While some radionuclides such as iodine-131 emit both β and γ radiation and are therefore suitable for both imaging and therapy, others are more suited to imaging or therapy alone. Hence for radionuclide therapy of neuroendocrine tumors, patients can be selected for therapy on the basis of γ-emitting indium-111-octreotide imaging and treated with β-emitting yttrium-90-octreotate. Positron-emitting radionuclides can give greater sensitivity that γ-emitters but only a single radionuclide can be imaged at one time and the range of radionuclides is more limited. The multiple options for antibody-based therapeutic molecules, imaging technologies and therapeutic scenarios mean that very large amounts of diverse data are being acquired. This can be most effectively shared and progress accelerated by use of common data standards for imaging, biological, and clinical data.     

Evaluation of methods for red marrow dosimetry based on patients undergoing radioimmunotherapy

Red marrow dosimetry is essential during radioimmunotherapy and a reliable method is essential in order to find a measure correlated to the toxic effect observed. The aim of this study was to calculate the absorbed dose to red marrow with different methods for the same patients and to compare the results. Patients diagnosed with B-cell lymphoma were treated with ¹³¹I-labelled monoclonal antibodies (LL2, anti-CD22). Blood samples were collected, scintillation camera images were taken and single probe measurements were carried out at different points in time after administration of the radiopharmaceutical. The absorbed dose to red marrow per unit activity administered was calculated using four varieties of the blood method and from activity quantification in the sacrum in the scintillation camera images. The absorbed dose to the total body per unit activity, sometimes used as a measure for determining the toxic effect in red marrow, was calculated from both the scintillation camera images and the single probe measurements. The results from the different methods of calculating the absorbed dose for the same patient and treatment were compared. The ratio of the maximum and the minimum absorbed dose to red marrow calculated using the four variations of the blood method and the sacrum imaging method for one and the same patient varied between 1.8 and 2.8. The correlation coefficients for all the possible combinations of the dosimetry methods, including total body measurements, varied from 0.51 to 0.99. The results show that the variability of the absorbed dose to the bone marrow is dependent on both method and patient.     

Tumour therapy with radionuclides: assessment of progress and problems.

Radionuclide therapy is a promising modality for treatment of tumours of haematopoietic origin while the success for treatment of solid tumours so far has been limited. The authors consider radionuclide therapy mainly as a method to eradicate disseminated tumour cells and small metastases while bulky tumours and large metastases have to be treated surgically or by external radiation therapy. The promising therapeutic results for haematological tumours give hope that radionuclide therapy will have a breakthrough also for treatment of disseminated cells from solid tumours. New knowledge related to this is continuously emerging since new molecular target structures are being characterised and the knowledge on pharmacokinetics and cellular processing of different types of targeting agents increases. There is also improved understanding of the factors of importance for the choice of appropriate radionuclides with respect to their decay properties and the therapeutic applications. Furthermore, new methods to modify the uptake of radionuclides in tumour cells and normal tissues are emerging. However, we still need improvements regarding dosimetry and treatment planning as well as an increased knowledge about the tolerance doses for normal tissues and the radiobiological effects on tumour cells. This is especially important in targeted radionuclide therapy where the dose rates often are lower than 1Gy/h.     

A new look at radionuclides therapy in metastatic disease of bone (review and prospects)

Bone-seeking radionuclides have been used to treat bone pain due to metastatic bone disease for over 40 years. More than 10 clinical studies using radiostrontium (Sr-89) have shown benefit in about 70-80% of patients having refractory bone pain from prostate, breast and other metastatic bone cancers, with minimal hematological toxicity. Other radionuclides, such as, radiophosphate (P-32), Yttrium-90, lodine-131, Rhenium-186, have also been used. Tumor necrosis has been found within the range of beta irradiation from the surrounding shell of bone incorporating the radionuclide. New strategies using radionuclides may be able to provide more effective methods of treatment, perhaps, beyond palliation. For example, the effect of low dose continuous radiation can be potentiated by hypoxic cell sensitizers. In addition, the kinetics of radionuclide uptake and retention can be modulated to increase the dose of radiation delivered to osteoblastic metastatic lesions, such as osteosarcoma.     

The influence of lung and bone dosimetry on the choice of radiation energy for total body irradiation.

The radiation absorbed dose to lung and bone is of importance for total body irradiation performed prior to bone marrow transplantation for hematologic malignancies. The measurement and calculation of radiation absorbed dose to low density materials such as lung has been discussed in several publications and most total body irradiation procedures account for the increased radiation dose to the lung. However, radiation absorbed dose to bone and soft tissues within bone is not calculated and is assumed to be the same as the dose to soft tissues. Because the bone is different in both density and atomic number from soft tissues, radiation dose calculations are more complex for bone than for lung. As the energy of the radiation beam changes, the dose to heterogeneous tissue varies. This variation of the radiation dose is investigated for radiation beams ranging in energy from 60Cobalt to x-ray beams produced at 18 MV. The radiation absorbed dose to soft tissues within bone is found to increase relative to the dose to soft tissue for higher megavoltage radiations, while at the same time there is a decrease in lung dose. Therefore, since for total body irradiation procedures the target tissues are the soft tissues within bone, a higher dose to those tissues would be an advantage.     

What can be expected from nuclear medicine tomorrow?

Imaging can take advantage of developments in "omics" approaches and go from routine individual biomarkers to multiple-scale biomarker profiles. Imaging structural, functional, metabolic, cellular, and molecular changes will be made possible by multimodality hybrid techniques, such as positron emission tomography-magnetic resonance imaging. Imaging should predict treatment response, look at stratification for specific treatment modalities, and look at the "omic" characterization of an individual patient or a specific tumor. This should lead to the development of "personalized" medicine. In cancer radiotherapy, patient responses should be accurately predicted. In specific cases, proton and hadrontherapy will be further enhanced by the irradiation dose delivered to the tumors. For disseminated or metastatic disease, targeted radionuclide therapy is an effective addition to the arsenal against cancer. The clinical efficacy of radiolabeled antibodies has been clearly demonstrated in lymphoma as well as that of radiolabeled peptides derived from somatostatin in the treatment of neuroendocrine tumors. Preliminary studies now show interesting results in solid tumors, too. Even if the number of objective clinical responses based on tumor shrinkage is small, targeted radionuclide therapy increases progression-free survival or overall survival in some specific cases where tumor burden is small. Avenues for further improvement are multiple and include combination with other therapeutic modalities, development of new approaches (e.g., small molecules, pretargeting, and antibody alternatives). Using alpha-emitting radionuclides is another possibility for specific diseases, such as leukemias, multiple myeloma, or brain tumor remnants.     

Chemotherapy and bone marrow reserve: lessons learned from autologous stem cell transplantation

Cytotoxic chemotherapy is often complicated by hematopoietic toxicity. The degree of aplasia and the rapidity of count recovery following chemotherapy are indicative of bone marrow reserve. Patients who generally have a normal bone marrow function will recover from chemotherapy-induced cytopenia relatively rapidly. In contrast, patients that have poor bone marrow reserve will have significantly prolonged period of aplasia. Predicting the hematopoietic toxicity of radioimmunotherapy is an important dosimetry consideration. Unfortunately, there are no good models for predicting toxicity from chemotherapy that could be applied to radioimmunotherapy. However, models used to predict the ability to harvest autologous stem cells for use after high dose chemotherapy may be useful in predicting bone marrow reserve and potential toxicity from radioimmunotherapy. These models indicate that the successful mobilization of stem cells into the peripheral blood is inversely proportional to exposure to stem cell toxic drugs. Establishing criteria that will help predict the amount of myelotoxicity sustained from radioimmunotherapy could lead to improved dosimetry and ultimately to better therapy for patients.     

Optimization of equipment and methodology for whole body activity retention measurements in children undergoing targeted radionuclide therapy

Accurate measurements of whole-body activity retention of patients during radionuclide therapy are essential for two reasons: First, they enable the correct radiation protection advice to be given and second, they permit the accurate determination of the absorbed whole-body dose delivered during therapy. This, in turn, allows treatment planning to be carried out for future radionuclide therapy on an individual patient basis, and also enables the investigation of the potential correlation of absorbed dose with treatment outcome in groups of patients. There are significant difficulties associated with taking whole-body retention measurements of children, especially when they are very young and/or unwell. It is essential to carry these out in a way that minimises disturbance to the child while still providing good quality data. To accomplish this, we have aimed to optimize the following aspects of the procedure: (i) the environment in which the measurements are performed; (ii) the equipment--which includes the recent installation of a specially designed whole-body activity monitoring system for these patients; and (iii) the methodology for calculating the absorbed dose. These improvements have allowed large numbers of accurate and reproducible whole-body measurements to be collected following patient administrations. This has enabled the identification of more phases of radionuclide excretion during therapy than had previously been observed. These data have been used for radiation protection advice and treatment planning. Two (2) patients were given multiple radionuclide treatments and we were able to compare the whole-body doses delivered.