Magnetic Hyperthermia and Radiation Therapy: Radiobiological Principles and Current Practice †.

Hyperthermia, though by itself generally non-curative for cancer, can significantly increase the efficacy of radiation therapy, as demonstrated by in vitro, in vivo, and clinical results. Its limited use in the clinic is mainly due to various practical implementation difficulties, the most important being how to adequately heat the tumor, especially deep-seated ones. In this work, we first review the effects of hyperthermia on tissue, the limitations of radiation therapy and the radiobiological rationale for combining the two treatment modalities. Subsequently, we review the theory and evidence for magnetic hyperthermia that is based on magnetic nanoparticles, its advantages compared with other methods of hyperthermia, and how it can be used to overcome the problems associated with traditional techniques of hyperthermia.

Recommendations for In Vitro and In Vivo Testing of Magnetic Nanoparticle Hyperthermia Combined with Radiation Therapy.

Magnetic nanoparticle (MNP)-mediated hyperthermia (MH) coupled with radiation therapy (RT) is a novel approach that has the potential to overcome various practical difficulties encountered in cancer treatment. In this work, we present recommendations for the in vitro and in vivo testing and application of the two treatment techniques. These recommendations were developed by the members of Working Group 3 of COST Action TD 1402: Multifunctional Nanoparticles for Magnetic Hyperthermia and Indirect Radiation Therapy ("Radiomag"). The purpose of the recommendations is not to provide definitive answers and directions but, rather, to outline those tests and considerations that a researcher must address in order to perform in vitro and in vivo studies. The recommendations are divided into 5 parts: (a) in vitro evaluation of MNPs; (b) in vitro evaluation of MNP-cell interactions; (c) in vivo evaluation of the MNPs; (d) MH combined with RT; and (e) pharmacokinetic studies of MNPs. Synthesis and characterization of the MNPs, as well as RT protocols, are beyond the scope of this work.

Does the setup of Monte Carlo simulations influence the calculated properties and effect of gold nanoparticles in radiation therapy?

PURPOSE: To investigate whether the dose-scoring process of Monte Carlo (MC) simulations of Gold nanoparticles (GNPs) in radiation therapy affects the results. METHODS: The GATE MC toolkit was used to simulate the irradiation of a water phantom containing a single solid or hollow GNP with 250 kVp and 6 MV photons. The dose was scored in 20 nm × 20 nm × 50 µm, 100 nm × 100 nm × 50 µm and 200 nm × 200 nm × 50 µm volumes using dose-scoring voxels of size 1 nm × 1 nm × 50 µm, 10 nm × 10 nm × 50 µm, 50 nm × 50 nm × 50 µm and 100 nm × 100 nm × 50 µm Εxcess dose depth-dose (EDDD) curves and lateral beam profiles were used to compare the dose-scoring voxels. RESULTS: In a given volume, neither the EDDD curves nor the lateral beam profiles are affected by the size of the dose-scoring voxels, subject to noise and uncertainty. Certain features of the EDDD curves are clearly seen in larger volumes, but hidden within the uncertainty and noise levels in smaller volumes. For the lateral beam profiles, it is the larger volumes that result in misleading results and the smaller ones that give the expected results. However, the limited statistics result in asymmetries and skewness in the profiles. CONCLUSION: For a given volume, the dose curves are not affected by the size of the dose-scoring voxels. However, the voxel size may hide or reveal the finer structure of the dose curves and/or may result in misleading curves.

Investigation of attenuation correction in SPECT using textural features, Monte Carlo simulations, and computational anthropomorphic models.

PURPOSE: To present and evaluate a new methodology to investigate the effect of attenuation correction (AC) in single-photon emission computed tomography (SPECT) using textural features analysis, Monte Carlo techniques, and a computational anthropomorphic model. MATERIALS AND METHODS: The GATE Monte Carlo toolkit was used to simulate SPECT experiments using the XCAT computational anthropomorphic model, filled with a realistic biodistribution of (99m)Tc-N-DBODC. The simulated gamma camera was the Siemens ECAM Dual-Head, equipped with a parallel hole lead collimator, with an image resolution of 3.54 × 3.54 mm(2). Thirty-six equispaced camera positions, spanning a full 360° arc, were simulated. Projections were calculated after applying a ± 20% energy window or after eliminating all scattered photons. The activity of the radioisotope was reconstructed using the MLEM algorithm. Photon attenuation was accounted for by calculating the radiological pathlength in a perpendicular line from the center of each voxel to the gamma camera. Twenty-two textural features were calculated on each slice, with and without AC, using 16 and 64 gray levels. A mask was used to identify only those pixels that belonged to each organ. RESULTS: Twelve of the 22 features showed almost no dependence on AC, irrespective of the organ involved. In both the heart and the liver, the mean and SD were the features most affected by AC. In the liver, six features were affected by AC only on some slices. Depending on the slice, skewness decreased by 22-34% with AC, kurtosis by 35-50%, long-run emphasis mean by 71-91%, and long-run emphasis range by 62-95%. In contrast, gray-level non-uniformity mean increased by 78-218% compared with the value without AC and run percentage mean by 51-159%. These results were not affected by the number of gray levels (16 vs. 64) or the data used for reconstruction: with the energy window or without scattered photons. CONCLUSION: The mean and SD were the main features affected by AC. In the heart, no other feature was affected. In the liver, other features were affected, but the effect was slice dependent. The number of gray levels did not affect the results.

First performance tests of a digital photon counter (DPC) array coupled to a CsI(Tl) crystal matrix for potential use in SPECT.

The digital photon counter (DPC) is a recently developed type of digital silicon photomultiplier that combines low dark count rates, low readout noise, and fully digital, integrated readout circuitry with neighbor logic capability, system scalability, and MR compatibility. These are desirable properties for application in scintillation detectors for single photon emission computed tomography (SPECT). In this work, the feasibility of using a DPC array in combination with a CsI(Tl) crystal matrix as a potential detector for SPECT is investigated for the first time. Given the relatively long decay time of CsI(Tl), an important consideration is the influence on the detector performance of the DPC dark count rate as a function of temperature. We present a preliminary characterization of a detector assembled with an array of 2 × 2 × 3 mm(3) CsI(Tl) crystals. Preparatory measurements were acquired with a (57)Co source in order to optimize the light-guide thickness and the sensor settings. The spatial resolution of the detector was tested by acquiring flood maps with (57)Co as well as (99m)Tc sources. Three crystal identification algorithms were compared for the reconstruction of the flood maps. All crystal elements could be visualized clearly and high values of peak-to-valley ratios were achieved. Energy resolutions of ∼18.5% FWHM and ∼15% FWHM were measured at 122 keV and 140 keV, respectively. Temperature-dependent measurements indicate that the detector can work satisfactorily up to about 15 °C.

A new method of incorporating systematic uncertainties in intensity-modulated radiotherapy optimization.

Uncertainties in tumor position during intensity-modulated radiotherapy (IMRT) plan optimization are usually accounted for by adding margins to a clinical target volume (CTV), or additionally, to organs at risk (OAR). The former approach usually favors target coverage over OAR protection, whereas the latter does not account for correlation in target and OAR movement. We investigate a new approach to incorporate systematic errors in tumor and organ position. The method models a distribution of systematic errors due to setup error and organ motion with displaced replicas of volumes of interest, each representing the patient geometry for a possible systematic error, and maximizes a score function that counts the number of replicas meeting dose or biological constraints for both CTV and OAR. Dose constraints are implemented by logistic functions of Niemierko's generalized model of equivalent uniform dose (EUD). The method is applied to prostate and nasopharynx IMRT plans, in which CTV and OAR each consists of five replicas, one representing no error (the position in the planning CT) and the other four discrete systematic setup displacements in one dimension with equal probability. The resulting IMRT plans are compared with those from two other EUD-based optimizations: a standard planning target volume (PTV) approach consisting of a single replica of each OAR in the planned position and a single PTV encompassing all CTV replicas, and a PTV-PRV approach consisting of a single PTV and a single planning risk volume (PRV) for each OAR encompassing all replicas. When systematic error is present, multiple-replica optimization provides better critical organ protection while maintaining similar target coverage compared with the PTV approach, and provides better CTV-to-OAR therapeutic ratio compared with the PTV-PRV instances where there is substantial PTV-PRV overlap. The method can be used for other systematic errors due to organ motion and deformation.

CT image-guided intensity-modulated therapy for paraspinal tumors using stereotactic immobilization.

PURPOSE: To design and implement a noninvasive stereotactic immobilization technique with daily CT image-guided positioning to treat patients with paraspinal lesions accurately and to quantify the systematic and random patient setup errors occurring with this method. METHODS AND MATERIALS: A stereotactic body frame (SBF) was developed for "rigid" immobilization of paraspinal patients. The inherent accuracy of this system for stereotactic CT-guided treatment was evaluated with phantom studies. Seven patients with thoracic and lumbar spine lesions were immobilized with the SBF and positioned for 33 treatment fractions using daily CT scans. For all 7 patients, the daily setup errors, as assessed from the daily CT scans, were corrected at each treatment fraction. A retrospective analysis was also performed to assess what the impact on patient treatment would have been without the CT-based corrections (i.e., if patient setup had been performed only with the SBF). RESULTS: The average magnitude of systematic and random errors from uncorrected patient setups using the SBF was approximately 2 mm and 1.5 mm (1 SD), respectively. For fixed phantom targets, the system accuracy for the SBF localization and treatment was shown to be within 1 mm (1 SD) in any direction. Dose-volume histograms incorporating these uncertainties for an intensity-modulated radiotherapy plan for lumbar spine lesions were generated, and the effects on the dose-volume histograms were studied. CONCLUSION: We demonstrated a very accurate and precise method of patient immobilization and treatment delivery based on a noninvasive SBF and daily image guidance for paraspinal lesions. The SBF provides excellent immobilization for paraspinal targets, with setup accuracy better than 2 mm (1 SD). However, for highly conformal paraspinal treatments, uncorrected systematic and random errors of 2 mm in magnitude can result in a significantly greater (>100%) dose to the spinal cord than planned, even though the planned target coverage may not change substantially. With daily CT guidance using the SBF, we showed that the maximal spinal cord dose is ensured to be within 10-15% of the planned value.

Intensity-modulated radiotherapy.

Intensity-modulated radiotherapy represents a recent advancement in conformal radiotherapy. It employs specialized computer-driven technology to generate dose distributions that conform to tumor targets with extremely high precision. Treatment planning is based on inverse planning algorithms and iterative computer-driven optimization to generate treatment fields with varying intensities across the beam section. Combinations of intensity-modulated fields produce custom-tailored conformal dose distributions around the tumor, with steep dose gradients at the transition to adjacent normal tissues. Thus far, data have demonstrated improved precision of tumor targeting in carcinomas of the prostate, head and neck, thyroid, breast, and lung, as well as in gynecologic, brain, and paraspinal tumors and soft tissue sarcomas. In prostate cancer, intensity-modulated radiotherapy has resulted in reduced rectal toxicity and has permitted tumor dose escalation to previously unattainable levels. This experience indicates that intensity-modulated radiotherapy represents a significant advancement in the ability to deliver the high radiation doses that appear to be required to improve the local cure of several types of tumors. The integration of new methods of biologically based imaging into treatment planning is being explored to identify tumor foci with phenotypic expressions of radiation resistance, which would likely require high-dose treatments. Intensity-modulated radiotherapy provides an approach for differential dose painting to selectively increase the dose to specific tumor-bearing regions. The implementation of biologic evaluation of tumor sensitivity, in addition to methods that improve target delineation and dose delivery, represents a new dimension in intensity-modulated radiotherapy research.