Venkat Narra

The question of relative biological effectiveness and quality factor for auger emitters incorporated into proliferating mammalian cells.

The problem of determining RBE values for Auger emitters incorporated into proliferating mammalian cells is examined. In general, the reference radiation plays a key role in obtaining experimental RBE values. Using survival of cultured Chinese hamster V79 cells as the experimental model, new data are provided regarding selection of a reference radiation for internal Auger emitters. These data show that gamma rays delivered acutely (137Cs) are more than twice as lethal as gamma rays delivered chronically with an exponentially decreasing dose rate (99mTc). The results confirm that the reference radiation should be delivered chronically in a manner consistent with the extended exposure received by the cells in the case of incorporated radionuclides. Through a direct comparison of the radiotoxicity of Auger emitters and alpha emitters, the high RBE values reported for DNA-bound Auger emitters are confirmed. These studies reveal that the DNA binding compound [125I]iododeoxyuridine (125IdU) is about 1.6 times more effective in killing V79 cells than 5.3 MeV alpha particles from intracellularly localized 210Po-citrate. In addition, toxicity studies with the radiochemicals 125IdU and [125]-iododeoxycytidine (125IdC) establish the equivalence of the radiosensitivity of thymine and cytosine base sites in the DNA. In view of these results, and information already available, the question of establishing quality factors for Auger emitters is considered. Finally, a method for calculation of the dose equivalent for internal Auger emitters is advanced.

On the Equivalent Dose for Auger Electron Emitters

Radionuclides that emit Auger electrons are widely used in nuclear medicine (e.g., 99mTc, 123I, 201Tl) and biomedical research (e.g., 51Cr, 125I), and they are present in the environment (e.g., 40K, 55Fe). Depending on the subcellular distribution of the radionuclide, the biological effects caused by tissue-incorporated Auger emitters can be as severe as those from high-LET alpha particles. However, the recently adopted recommendations of the International Commission on Radiological Protection (ICRP) provide no guidance with regard to calculating the equivalent dose for these radionuclides. The present work, using spermatogenesis in mouse testis as the experimental model, shows that the lethality of the prolific Auger emitter 125I is linearly dependent on the fraction of the radioactivity in the organ that is bound to DNA. This suggests that the equivalent dose for Auger emitters may have a similar linear dependence. Accordingly, a formalism for calculating the equivalent dose for Auger emitters is advanced within the ICRP framework.

Radiotoxicity of Gadolinium-148 and Radium-223 in Mouse Testes: Relative Biological Effectiveness of Alpha-Particle Emitters In Vivo

The biological effects of radionuclides that emit alpha particles are of considerable interest in view of their potential for therapy and their presence in the environment. The present work is a continuation of our ongoing effort to study the radiotoxicity of alpha-particle emitters in vivo using the survival of murine testicular sperm heads as the biological end point. Specifically, the relative biological effectiveness (RBE) of very low-energy alpha particles (3.2 MeV) emitted by 148Gd is investigated and determined to be 7.4 +/- 2.4 when compared to the effects of acute external 120 kVp X rays. This datum, in conjunction with our earlier results for 210Po and 212Pb in equilibrium with its daughters, is used to revise and extend the range of validity of our previous RBE-energy relationship for alpha particles emitted by tissue-incorporated radionuclides. The new empirical relationship is given by RBE alpha = 9.14 - 0.510 E alpha where 3 < E alpha < 9 MeV. The validity of this empirical relationship is tested by determining the RBE of the prolific alpha-particle emitter 223Ra (in equilibrium with its daughters) experimentally in the same biological model and comparing the value obtained experimentally with the predicted value. The resulting RBE values are 5.4 +/- 0.9 and 5.6, respectively. This close agreement strongly supports the adequacy of the empirical RBE-E alpha relationship to predict the biological effects of alpha-particle emitters in vivo.

Vitamins as radioprotectors in vivo II. Protection by vitamin A and soybean oil against radiation damage caused by internal radionuclides

Tissue-incorporated radionuclides impart radiation energy over extended periods of time depending on their effective half-lives. The capacity of vitamin A dissolved in soybean oil to protect against the biological effects caused by internal radionuclides is investigated. The radiochemicals examined are DNA-binding 125IdU, cytoplasmically localized H125IPDM and the alpha-particle emitter 210Po citrate. As in our previous studies, spermatogenesis in mice is used as the experimental model and spermatogonial cell survival is the biological end point. Surprisingly, soybean oil itself provides substantial and equal protection against the Auger effect of 125IdU, which is comparable to a high-LET radiation effect, as well as the low-LET effects of H125IPDM, the dose modification factors (DMFs) being 3.6 +/- 0.9 (SEM) and 3.4 +/- 0.9, respectively. The protection afforded by the oil against the effects of 5.3 MeV alpha particles emitted by 210Po is also significant (DMF = 2.2 +/- 0.4). The presence of vitamin A in the oil further enhanced the radioprotection against the effect of 125IdU (DMF = 4.8 +/- 1.3) and H125IPDM (DMF = 5.1 +/- 0.6); however, no enhancement is provided against the effects of alpha particles. These interesting results with soybean oil and vitamin A, together with data on the subcellular distribution of the protectors, provide clues regarding the mechanistic aspects of the protection. In addition, the data for vitamin A reaffirm our earlier conclusion that the mechanism by which DNA-bound Auger emitters impart biological damage is primarily indirect in nature.

Relative Biological Effectiveness of Alpha-Particle Emitters In Vivo at Low Doses

The therapeutic potential of radionuclides that emit alpha particles, as well as their associated health hazards, have attracted considerable attention. The 224Ra daughters 212Pb and 212Bi, by virtue of their radiation properties which involve emission of alpha and beta particles in their decay to stable 208Pb, have been proposed as candidates for radioimmunotherapy. Using mouse testes as the experimental model and testicular spermhead survival as the biological end point, the present work examines the radiotoxicity of 212Pb and its daughters. When 212Pb, in equilibrium with its daughters 212Bi, 212Po and 208Tl, was administered directly into the testis, the dose required to achieve 37% survival (D37) was 0.143 +/- 0.014 Gy and the corresponding RBE of the mixed radiation field was 4.7 when compared to the D37 for acute external 120 kVp X rays. This datum, in conjunction with our earlier results for 210Po, was used to obtain an RBE-LET relationship for alpha particles emitted by tissue-incorporated radionuclides: RBE alpha = 4.8 - 6.1 x 10(-2) LET + 1.0 x 10(-3) LET2. Similarly, the dependence of RBE on alpha-particle energy E alpha was given by RBE alpha = 22 E(-0.73) alpha. These relationships, based on in vivo experimental data, may be valuable in predicting biological effects of alpha-particle emitters.

Intensity-modulated radiation therapy for orbital lymphoma

PurposeOrbital manifestations of non-Hodgkin’s lymphoma (NHL) are rare and accounts for only 1% of all cases of NHL. There have been no reports of treating orbital lymphoma using intensity-modulated radiotherapy (IMRT).Materials and methodsFour patients were treated at our institution for orbital lymphoma using IMRT. Radiotherapy (RT) plans using wedged pair fields were developed for comparison. Clinical results using IMRT are presented and a dosimetric analysis between IMRT and RT was performed.ResultsAll patients had a complete response based on their physical examinations and post-IMRT imaging. Symptoms that had been present at initial presentation resolved in all patients during the course of the treatment. All four patients experienced only grade 1 dry eye syndrome and keratitis. The average dose to the contralateral orbit, lacrimal gland, and lens were all significantly reduced (P < 0.01) in IMRT patients as compared to the RT patients. IMRT reduced the V5 and V10 for the contralateral lens, orbit, and lacrimal gland and the optic chiasm (P < 0.05).ConclusionIMRT is feasible when treating orbital lymphoma and reduces dose to critical structures while providing excellent dose coverage of target volumes. IMRT offers patients with orbital lymphoma excellent clinical outcomes, similar to conventional RT, with no increased toxicity.

Potential of 3D printing technologies for fabrication of electron bolus and proton compensators

In electron and proton radiotherapy, applications of patient‐specific electron bolus or proton compensators during radiation treatments are often necessary to accommodate patient body surface irregularities, tissue inhomogeneity, and variations in PTV depths to achieve desired dose distributions. Emerging 3D printing technologies provide alternative fabrication methods for these bolus and compensators. This study investigated the potential of utilizing 3D printing technologies for the fabrication of the electron bolus and proton compensators. Two printing technologies, fused deposition modeling (FDM) and selective laser sintering (SLS), and two printing materials, PLA and polyamide, were investigated. Samples were printed and characterized with CT scan and under electron and proton beams. In addition, a software package was developed to convert electron bolus and proton compensator designs to printable Standard Tessellation Language file format. A phantom scalp electron bolus was printed with FDM technology with PLA material. The HU of the printed electron bolus was 106.5±15.2. A prostate patient proton compensator was printed with SLS technology and polyamide material with −70.1±8.1 HU. The profiles of the electron bolus and proton compensator were compared with the original designs. The average over all the CT slices of the largest Euclidean distance between the design and the fabricated bolus on each CT slice was found to be 0.84±0.45 mm and for the compensator to be 0.40±0.42 mm. It is recommended that the properties of specific 3D printed objects are understood before being applied to radiotherapy treatments. PACS number: 81.40

A Comparison of Helical Intensity-Modulated Radiotherapy, Intensity-Modulated Radiotherapy, and 3D-Conformal Radiation Therapy for Pancreatic Cancer

We assessed dosimetric differences in pancreatic cancer radiotherapy via helical intensity-modulated radiotherapy (HIMRT), linac-based IMRT, and 3D-conformal radiation therapy (3D-CRT) with regard to successful plan acceptance and dose to critical organs. Dosimetric analysis was performed in 16 pancreatic cases that were planned to 54 Gy; both post-pancreaticoduodenectomy (n = 8) and unresected (n = 8) cases were compared. Without volume modification, plans met constraints 75% of the time with HIMRT and IMRT and 13% with 3D-CRT. There was no statistically significantly improvement with HIMRT over conventional IMRT in reducing liver V35, stomach V45, or bowel V45. HIMRT offers improved planning target volume (PTV) dose homogeneity compared with IMRT, averaging a lower maximum dose and higher volume receiving the prescription dose (D100). HIMRT showed an increased mean dose over IMRT to bowel and liver. Both HIMRT and IMRT offer a statistically significant improvement over 3D-CRT in lowering dose to liver, stomach, and bowel. The results were similar for both unresected and resected patients. In pancreatic cancer, HIMRT offers improved dose homogeneity over conventional IMRT and several significant benefits to 3D-CRT. Factors to consider before incorporating IMRT into pancreatic cancer therapy are respiratory motion, dose inhomogeneity, and mean dose.

Optimization of couch translational corrections to compensate for rotational and deformable target deviations in image guided radiotherapy

The utilization of image-guided radiotherapy (IGRT) technologies helps correct temporal and spatial deviations of the target volume relative to planned radiation beams. With the aid of these IGRT technologies, it becomes possible to better identify the target volume before and even during radiation treatment. However, since components of the detected deviations may be translational, rotational, and deformable, the question remains whether simple treatment-couch translational movement can be optimized to compensate for these complicated deviations. Deviation of the target volume and changes in patient body shape from that acquired for treatment planning may further add to the variations from planned dose distribution. In this study, an optimization strategy is developed to investigate these issues. The optimization process involved the use of the hill climbing algorithm, the detected target volume and patient body shape, and the dose distribution based on acquired images at treatment. During the process, the planned dose distribution was iteratively adjusted to reflect the changes of depth and distance as the translational treatment couch movement was being optimized. The optimal treatment couch movement was considered achieved when the highest fraction of the detected target volume was covered by prescription dose. This optimization strategy was evaluated on clinical prostate cancer cases. For each of the cases, cone beam computed tomography (CBCT) images were acquired right after fiducial marker-based kilovolt orthogonal imaging verification and setup adjustment. Based on the CBCT images, the clinical target volume at the treatment was delineated and the translational treatment-couch movements were optimized with the developed strategy. The resultant dose coverage was compared to that without the optimization. The results showed that with the present strategy, rotational and deformable target deviations can be further compensated with translational couch correction.

Functional Magnetic Resonance Imaging and Radiosurgical Dose Planning

Objective: To assess the effect of functional magnetic resonance imaging (fMRI) on stereotactic radiosurgical (SRS) dose planning. Methods: Patients included those undergoing SRS whose lesions were in or near areas that could be identified with fMRI. After processing, an fMR scan was registered to the anatomic scan, and this dataset was registered to a stereotactic CT scan. The imaged functional areas were contoured along with standard anatomical targets. Dose planning was done at first with the functional volumes rendered invisible; the plans were then adjusted as needed using the functional targets. Doses were measured using a dose-volume histogram tool. Results: SRS was performed in 12 patients, 1 of whom also underwent SRT. Functional volumes studied included motor cortex in 8 patients, visual in 6 and language in 3; a total of 33 functional targets were imaged. Prescription doses ranged from 12 to 22.5 Gy (mean 19.5 Gy), and the maximum dose to functional volumes from 8 cGy to 18.5 Gy (mean 2.9 Gy). In 6 patients, arc adjustment using functional targets yielded a >50% reduction in dose to at least one functional volume; in all patients, the dose reduction to 50 and 75% of functional volumes averaged 4% (12 cGy) and 13% (30 cGy), respectively, while the reduction of maximal dose averaged 24% (50 cGy). Conclusions: fMRI can be used in SRS to reduce irradiation of eloquent brain using standard prescription doses. Appropriate arc adjustment may allow for escalation of the dose to the targeted lesion.