Intensity-modulated radiation therapy for children with intraocular retinoblastoma: potential sparing of the bony orbit.

AIMS: We have evaluated the potential for intensity-modulated radiation therapy (IMRT) to reduce dose to surrounding normal tissues in children with retinoblastoma confined to the globe of the eye. MATERIALS AND METHODS: Treatment planning computed tomography (CT) scans from five children were used for comparison of four radiotherapy techniques to treat the eye. IMRT, conformal, anterior-lateral photon and en face electron plans were generated using the Corvus (NOMOS) and PLUNC treatment planning systems. Doses to surrounding critical structures were compared after normalisation of target coverage. RESULTS: The IMRT treatment technique allowed the greatest sparing of the surrounding bony orbit, with an average of 60% of the ipsilateral bony orbit treated above 20 Gy and 48% treated above 24 Gy when 45 Gy is prescribed to the globe. IMRT techniques reduced dose to the surrounding bony orbit by more than one-third compared with anterior-lateral photon and electron techniques, and by 23% compared with conformal techniques. The application of IMRT also reduced dose to other surrounding normal tissues, including the temporal lobe and contralateral orbit. CONCLUSION: IMRT shows potential for protecting normal tissues in patients requiring external beam radiation therapy for retinoblastoma.

Comparison of two immobilization techniques using portal film and digitally reconstructed radiographs for pediatric patients with brain tumors.

PURPOSE: To compare the accuracy of two immobilization techniques for pediatric brain tumor patients. METHODS AND MATERIALS: We analyzed data from 128 treatments involving 22 patients. Patients were immobilized with either a relocatable head frame (12 patients) or a vacuum bag (10 patients). Orthogonal portal films were used as verification images. Errors in patient positioning were measured by comparing verification images with digitally reconstructed radiographs generated by a three-dimensional treatment-planning system. RESULTS: With the head frame, systematic errors ranged from 1.4 mm to 2.1 mm; random errors, from 1.7 mm to 2.1 mm. With the vacuum bag, systematic errors ranged from 2.1 mm to 2.5 mm; random errors, from 2.0 mm to 2.6 mm. For the head frame, the mean length of the radial displacement was 4.4 mm; 90% of the total three-dimensional deviation was less than 6.8 mm. The corresponding values for the vacuum bag were 5.0 and 6.6 mm, respectively. CONCLUSIONS: The head frame and vacuum bag techniques limit the random and systematic errors in each of the three directions to within +/- 5 mm. We have used these results to determine the margin used to create the planning target volume for conformal radiation therapy.

Late effects of ionizing radiation on the microvascular networks in normal tissue.

Damage to the microvascular networks constitutes one of the most important components of ionizing radiation damage to normal tissue. Previously, we have reported the early (3, 7 and 30 days postirradiation) effects of ionizing radiation on the structure and function of normal tissue microvascular networks. Here we report on the late effects of ionizing radiation on the structural and functional changes in microvascular networks in locally irradiated (single 10-Gy dose) hamster cremaster muscles observed 60, 120 and 180 days postirradiation; age-matched animals were used as controls. As in the previous study, intravital microscopy was used to measure structural and functional parameters in complete microvascular networks in vivo. A factorial design was used to examine the effects of radiation status, time postirradiation, and network vessel type on the structure and function of microvascular networks. Our results indicate that the progression of radiation-induced microvascular damage continues during the late times but that there is partial recovery from radiation damage within 6 months postirradiation. Red blood cell flux, red blood cell velocity, and capillary blood flow in irradiated networks at 180 days postirradiation were significantly greater than control levels. As at the early times, all vessel types were not damaged equally by radiation at every time.

Performance and beam characteristics of the Siemens Primus linear accelerator.

Siemens Primus is a small footprint, klystron driven medical linear accelerator incorporating a compact solid state modulator. A double focused multileaf collimator (MLC) replaces the lower jaw. The first Primus in the world was installed at St. Jude Children's Research Hospital in early 1997 with x-ray energies of 6 and 15 MV and electron energies of 8, 10, 12, 15, 18, and 21 MeV. The 10 cm depth dose for a 100 cm SSD 10 X 10 cm2 beam is 68% and 77% for 6 and 15 MV x rays, respectively. For both x-ray energies, beam flatness is slightly better than the manufacturers specification of 3% and beam symmetry is considerably better than 1%. The double focus design of the MLC produces a sharp penumbra (5-7 mm at 6 MV and 6-8 mm at 15 MV), increasing modestly with beam size. MLC leaf leakage is less than 1.25%. The depths of the 80% depth dose for the six electron energies of 8, 10, 12, 15, 18, and 21 MeV are 2.6, 3.2, 4.0, 4.9, 6.0, and 7.4 cm, respectively. Beam flatness is typically 2%-3% for all electron energies except 21 MeV, where it reaches 4% for a 25 X 25 cm2 cone. Electron beam symmetry is better than 1% for all energies except 21 MeV, where it is equal to 1%. The results are stored electronically and may be retrieved using anonymous ftp from the American Institute of Physics, Physics Auxiliary Publication Service.

Early effects of ionizing radiation on the microvascular networks in normal tissue.

Microvascular networks, which control the delivery of oxygen and nutrients and the removal of metabolic waste, are the most sensitive part of the vascular system to ionizing radiation. Structural and functional changes in microvascular networks were studied in locally irradiated (single 10-Gy dose) hamster cremaster muscles observed 3, 7 and 30 days post-irradiation. Networks were selected in reference to a well-defined location in the tissue to reduce heterogeneity due to spatial variations. Intravital microscopy was used to measure structural and functional parameters in vivo. A factorial design was used to examine the effects of radiation status, time postirradiation, and network vessel type on the structure and function of microvascular networks. While the diameter of microvessels in control animals increased significantly with age, vessel diameter in irradiated vessels decreased significantly with age. Red blood cell velocity in irradiated networks at 3 and 30 days postirradiation was significantly lower than in control networks. There was a significant decrease in capillary surface area and a significant increase in vessel hematocrit in irradiated animals. Blood flow in irradiated vessels was significantly lower than in control vessels. Changes in functional parameters were evident at 3 days postirradiation while changes in structural parameters occurred later. All vessel types were not damaged equally by radiation at every time examined.

Determination of differential scatter-air ratios (dSAR) for three-dimensional scatter integration.

Scatter dose may be calculated by summing the scatter contribution from individual volume elements. These contributions may be represented by differential scatter-air ratios (dSAR). Determination of dSAR from measured data is only approximately correct for second and higher orders of scatter and yields values often limited to one significant figure. Monte Carlo calculation, on the other hand, is time intensive, requires some knowledge of the beam's x-ray spectrum, and mastering the complexities of a program such as EGS4. Total scatter dose at a point may be determined by measuring depth dose or tissue-air ratios and partitioning the dose into its primary and scatter components. Scatter may be represented by scatter-air ratios, which can be characterized by the sum of first, second, and higher orders of scatter. The first scatter dose may be computed exactly by summing the first scatter contribution from individual elements, determined from the first principle. Separation of dSAR into primary attenuation and depth-independent terms allows the latter to be precomputed once for a given energy and stored in tabular form. Second scatter may be treated in a similar manner. The higher orders of scatter are computed by subtracting the sum of calculated first and second scatter doses from the total scatter dose. Elements close to and approximately 1 cm above the point of calculation contribute most heavily to the first scatter dose. Compared to the first scatter dose, the second scatter dose contribution is lower, particularly for elements close to the point of calculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Techniques of experimental animal radiotherapy.

Animal research is a crucial component of the generation of new knowledge in human and veterinary medicine. Total body irradiation, whole brain irradiation, total lymphoid irradiation, and local field irradiation of experimental animals are powerful tools for immunology, oncology, studies of normal tissue radiation tolerance, and medical physics. Animal radiotherapy requires specialized techniques. Because of necessarily smaller field sizes, beam localization must be particularly precise. Care must be taken to obtain optimum and accurate dose distribution. This requires consultation with a medical physicist. Optimum dose distribution may be obtained, depending upon the circumstance, by use of either a single beam or two parallel opposed beams with or without bolus. To ensure a proper dose to the animal target volume, care must be paid to the selection of beam energy and the use of radiation attenuators. Beams may be shaped by custom-made lead alloy blocks. Radiation dose rate may be modified by changing the linear accelerator output or the distance from the beam source to the animal, or by attenuating the beam. Reliable targeting of animals requires, for fields other than total body irradiation, anesthesia-utilizing agents such as ether, ketamine, and pentobarbital. The objective of this report is to review the techniques of experimental animal radiotherapy.

Clinical use of a concomitant boost technique using a gypsum compensator.

PURPOSE: To develop a clinical procedure to treat field within a field (concomitant boost) portals with a single compensated field. METHODS AND MATERIALS: An ordinary manual cerrobend block former was used to produce styrofoam molds from simulator film data. A special gypsum compound was poured into the molds. The compensator block is independently mounted to the treatment machine via a custom-made compensator holder. RESULTS: Measurements confirm that the inhomogeneous dose distribution has been reliably delivered via this technique. The accuracy of placement of the high dose region is sufficient for clinical use. CONCLUSION: The procedure enables the concomitant boost effect to be easily implemented in the clinic without increasing clinical setup time.

Synaptonemal complex aberrations in the pseudoautosomal region of X, Y chromosomes in irradiated hamsters.

The effects of X-radiation, bleomycin and amsacrine (m-AMSA) on the meiotic chromosomes of male Armenian hamsters were determined by electron microscopic analysis of synaptonemal complex (SC) damage. Pachytene stage cells were analyzed 5 or 6 days following their treatment at putative preleptotene-leptotene stages of meiosis. Of the multiple types of SC aberrations observed to be significantly increased over control levels, lateral element breakage and synaptic anomalies were most prevalent. The focus of these studies was on the sex chromosomes which, in the Armenian hamster, reveal an unusually well-defined pseudoautosomal region. In the XY pair, radiation and chemical treatments caused certain forms of structural and synaptic anomalies which appeared to be preferentially localized to telomeric and/or crossover regions. The nature of these specific aberrations, involving breakage, bridge formation and asynapsis, is not well understood; however, their distributions are suggestive of possible relationships with sites and processes of crossing over.

Management of radiation oncology patients with implanted cardiac pacemakers: report of AAPM Task Group No. 34. American Association of Physicists in Medicine.

Contemporary cardiac pacemakers can fail from radiation damage at doses as low as 10 gray and can exhibit functional changes at doses as low as 2 gray. A review and discussion of this potential problem is presented and a protocol is offered that suggests that radiation therapy patients with implanted pacemakers be planned so as to limit accumulated dose to the pacemaker to 2 gray. Although certain levels and types of electromagnetic interference can cause pacemaker malfunction, there is evidence that this is not a serious problem around most contemporary radiation therapy equipment.

The utility of SPECT lung perfusion scans in minimizing and assessing the physiologic consequences of thoracic irradiation.

PURPOSE: Three-dimensional single photon emission computed tomography lung perfusion scans (SPECT) provide a unique quantitative 3-dimensional map of the distribution of functioning pulmonary vascular/alveolar subunits, information not provided by other imaging modalities. This report describes our initial experience utilizing these scans to assist in the design of radiation treatment beams and to assess changes in regional lung function following irradiation. METHODS AND MATERIALS: Patients were immobilized and scanned in the treatment position with appropriate fiducial markers. Four millicuries of technetium 99M microaggregated albumin were injected and SPECT images of the lung were generated. Pre-treatment SPECT images were used to help design radiation beams to minimize irradiation of functioning lung. Pre- and post-treatment scans were compared to assess changes in regional function. These changes in function were then correlated with the regional radiation dose. RESULTS: Pre-radiotherapy SPECT scans were obtained in 18 patients (11 with lung cancer). Marked variations in regional function were frequently noted. In patients with primary lung tumors, these variations were not necessarily immediately adjacent to the tumor volume. In general, patients with poor pulmonary function pre-treatment, in whom one would like to spare as much normal lung as possible, had the most non-uniform distribution throughout the lung of functioning vascular/alveolar subunits. In these cases, pre-treatment scans were most useful in designing radiation portals to minimize irradiation of functioning lung. SPECT scans were also used to detect changes in regional lung function secondary to radiotherapy in four patients. With doses in excess of 40 Gy, reductions in regional function were noted 1-6 months following completion of radiotherapy. These reductions were not necessarily accompanied by reductions in conventional pulmonary function tests, which are assessments of whole lung function and may not reflect regional lung injury if the volume affected is small. CONCLUSIONS: SPECT lung scans provide an excellent means of assessing regional lung function, superior to that obtainable with planar images. The functional data provided by the SPECT images is useful in designing "optimal" radiation treatment beams and in assessing the effect of radiotherapy on regional lung functions. Efforts are continuing in our laboratory to develop a dose response curve for regional lung damage using the tools of SPECT scanning and 3-dimensional dose calculations.

The radiation dose-response relationship in a human glioma xenograft and an evaluation of the influence of glutathione depletion by buthionine sulfoximine.

We have used an extensively characterized human glioma cell line in an athymic mouse model to evaluate new therapeutic approaches for human supratentorial high grade gliomas. The tumor, D-54MG, is a subline of a human anaplastic glioma. Eight days after homozygous nu/nu BALB/c athymic mice received intracranial (IC) injections of a tumor homogenate, the whole brain was irradiated with either single fractions of 4, 8, 9, and 12 Gy or twice daily fractions, separated by least 6 hr, of 2.28 Gy x 2 or 7.53 Gy x 2. To evaluate whether or not glutathione depletion influenced animal survival, animals at each dose level received either intraperitoneal (IP) buthionine sulfoximine (BSO) alone or I.P. BSO plus BSO in the drinking water. There was a stepwise prolongation of animal survival with increasing doses of external beam radiation. Mean survival in 9 of the 10 control groups (8-12 animals per group) ranged from 14.1 to 18.8 days. Mean survival ranged from 15.3 to 22.5 days at 4 Gy, 25 to 30 days at 8 Gy, 22.3 to 29.7 days at 9 Gy, and 32.9 to 33.6 days at 12 Gy single dose irradiation. At 2.28 Gy x 2 split dose irradiation mean survival was 29.3 days, for 7.53 Gy x 2 mean survival was over 47 days. The data for single fraction irradiation fit a linear regression line (r = 0.908) of mean animal survival = (1.22 [dose in Gy] + 16.7) days. Tumor GSH levels were decreased with all BSO dosing regimens tested. The most aggressive regimen (I.P. BSO+oral BSO for 5 days), reduced tumor GSH to 6.2% of control. Increased survival in irradiated glutathione depleted mice versus mice receiving radiation alone was not seen.

Interspecies cytogenetic comparisons: studies with X-radiation and bleomycin sulfate.

A series of in vitro experiments were conducted to determine if there are innate differences in the sensitivity of peripheral blood lymphocytes (PBLs) from different mammalian species to clastogens. Mouse, rat, and human whole blood samples were exposed to either 0, 0.38, 0.75, 1.5, or 3.0 Gy x-radiation or 0, 5, 10, 20, 40, or 80 micrograms/ml bleomycin for 4 hr. Bromodeoxyuridine-containing cultures were initiated and the PBLs stimulated to divide with phytohemagglutinin. All cultures were harvested following a 3-hr colcemid treatment. Slides were made and differentially stained, and first-division metaphases were scored for chromosome aberrations. In the x-radiation studies human PBLs were significantly more sensitive than mouse PBLs which were in turn more sensitive than rat PBLs as measured by either the total percent aberrant cells or the number of dicentrics. Data from all three species could be fitted to a linear-quadratic model. Results with bleomycin suggest that the mouse and human PBLs are equally sensitive to the clastogenic effects of bleomycin. Both appeared to be more sensitive than the rat PBLs, but the variation between experiments was such that the results among species were not significantly different. These results indicate that there may be inherent differences in sensitivity among PBLs of mammalian species; however, more studies are needed to determine if the differences presented here hold for other agents.

Induction of micronuclei by X-radiation in human, mouse and rat peripheral blood lymphocytes.

We compared the radiosensitivity of human, rat and mouse peripheral blood lymphocytes (PBLs) by analyzing micronuclei (MN) in cytochalasin B-induced binucleated (BN) cells. For each species and dose 4-ml aliquots of whole blood were X-irradiated to obtain doses of 38, 75, 150 or 300 cGy. Controls were sham-irradiated. After exposure to X-rays, mononuclear leukocytes were isolated using density gradients and cultured in RPMI 1640 medium containing phytohemagglutinin to stimulate mitogenesis. At 21 h cytochalasin B was added to produce BN PBLs, and all cultures were harvested at 52 h post-initiation using a cytocentrifuge. Significant dose-dependent increases in the percentage of micronucleated cells and the number of MN per BN cell were observed in all three species. The linear-quadratic regression curves for the total percentage of micronucleated cells for the three species were similar; however, the curve for the mouse PBLs had a larger quadratic component than either of the curves for the rat or human PBLs. Although the correlation between the percentage of cells with MN and those with chromosome aberrations was high (r2 greater than 0.95), the mouse and rat PBLs were over twice as efficient as human PBLs in forming MN from presumed acentric fragments. These data indicate that the induction of MN in BN cells following ionizing radiation is similar in human, rat and mouse PBLs, but care must be taken in using the MN results to predict frequencies of cells with chromosomal aberrations.

Three-dimensional photon treatment planning of the intact breast.

Three-dimensional treatment planning for the intact breast was performed on two patients who had undergone CT scanning. A total of 38 treatment plans were evaluated. Multiple plans were evaluated for each patient including plans with and without inhomogeneity corrections, plans using varying photon energies of 60Co, 4 MV, 6 MV, 10 MV, and 15 MV, and three-dimensionally unconstrained plans. Increased hot spots were appreciated in the central axis plane when lung inhomogeneity corrections were used. Additional hot spots were appreciated in off-axis planes towards the cephalad and caudad aspects of the target volume because of lung inhomogeneity corrections and changes in the breast contour. The use of 60Co was associated with an increase in the magnitude and volume of hot spots, whereas the use of higher energy photons such as 10 MV and 15 MV was associated with an unacceptable target coverage at shallow depths. Therefore, for the two patients studied, the use of a medium energy photon beam (such as from a 6 MV linear accelerator) appeared to be the energy of choice for treatment of the intact breast. The three-dimensionally unconstrained plans were able to improve slightly upon the standard plans, particularly with relationship of dose to normal tissue structures. Areas for future research were identified, including the use of tissue compensators.

Interinstitutional experience in verification of external photon dose calculations.

Under the auspices of NCI contracts, four institutions have collaborated to assess the accuracy of the pixel-based dose calculation methods they employ for external photon treatment planning. The approach relied on comparing calculations using each group's algorithm with measurements in phantoms of increasing complexity. The first set of measurements consisted of ionization chamber measurements in water phantoms in normally incident square fields, an elongated field, a wedged field, a blocked field, and an obliquely incident beam. The second group of measurements was carried out using thermoluminescent dosimeters in phantoms designed to investigate the effects of surface curvature, high density heterogeneities, and low density heterogeneities. The final study tested the entire treatment planning system, including CT data conversion, in an anthropomorphic phantom. Overall, good agreement between calculation and measurements was found for all algorithms. Regions in which discrepancies were observed are pointed out, areas for algorithm improvement are identified and the clinical import of algorithm accuracy is discussed.

3-D dose-volume compensation using nonlinear least-squares regression technique.

A method for external beam dose-volume optimization is presented. The Gauss-Marquardt nonlinear least-squares regression technique is applied to compensator design and determination. The dose distribution (uniform or otherwise) desired throughout a volume is specified. Compensators optimized to produce the necessary variation of beam intensity across the surface of each beam are simultaneously determined for all the beams. Solutions for homogeneous dose, homogeneous target dose, and restricted dose to exterior target volume structures, and inhomogeneous target dose cases are presented. Dependence of the results on the number of parameters as well as the role of degree of desirability weighting is explained and illustrated via examples. Discussion of the significance and limitations of this optimization method is also presented.

Stage-specific damage to synaptonemal complexes and metaphase chromosomes induced by X rays in male mouse germ cells.

Synaptonemal complexes reveal mutagen-induced effects in germ cell meiotic chromosomes. This study was aimed at characterizing relationships between damage to synaptonemal complexes and metaphase I chromosomes following radiation exposure at various stages of spermatogenesis. Male mice were irradiated with doses of 0, 2, or 4 Gy, and spermatocytes were harvested at times consistent with earlier exposures as spermatogonial stem cells, preleptotene cells (premeiotic DNA synthesis), or meiotic prophase cells. After stem-cell exposure, twice as many rearrangements were observed in synaptonemal complexes as in metaphase I chromosomes. Irradiation during premeiotic DNA synthesis resulted in dose-related increases in synaptonemal complex breakage and rearrangements (including novel forms) and in metaphase chromosomal aberrations. Following prophase exposure, various types and levels of damage to synaptonemal complexes and metaphase chromosomes were observed. Irradiation of zygotene cells led to high frequencies of chromosome multivalents in metaphase I without a correspondingly high level of damage in preceding prophase synaptonemal complexes. Thus irradiation of premeiotic and meiotic cells results in variable relationships between damage to synaptonemal complexes and metaphase chromosomes. Interpretations of these relationships are based upon what is known about both radiation clastogenesis and the structural/temporal relationships between synaptonemal complexes at prophase and chromosomes at metaphase I of meiosis.

An algorithm for three-dimensional visualization of radiation therapy beams.

A computer algorithm to display radiation beams superimposed on three-dimensional (3-D) views of patient anatomy has been developed. It may be implemented as a postprocessing step to existing software for 3-D presentation and display. The algorithm takes as input a shaded 3-D view (reconstructed, for example, from computed tomography scans), together with the associated depth map, and generates as output an enhanced 3-D view highlighting in color the visible points which lie within the projected beam outlines. The algorithm is independent of the method used to generate the 3-D view (surface or volume rendering techniques may be used) and is independent of beam shape (beams may be modified with shielding blocks). It is not restricted to external surfaces and will correctly show radiation beams projected onto cut-away views of internal organs. The method is illustrated by application to a tangential pair for breast malignancy, using 3-D views generated with volume rendering software.

Rapid three-dimensional treatment planning: I. Ray-tracing approach to primary component dose calculations.

Algorithms for fully three-dimensional divergent-beam radiotherapy treatment planning have been developed to achieve very high sampling of dose in heterogeneous (inhomogeneous density) tissue throughout an arbitrarily oriented patient volume, in clinically acceptable times of calculation. Dose is calculated at points along numerous rays which sample each beam. To display the dose distribution, the calculated dose values for each beam are interpolated onto rectilinear grids of (arbitrary) parallel planes, scaled for beam weight and finally merged with the weighted dose contributions of other beams. In this paper we describe and demonstrate the algorithm for the primary component of the three-dimensional photon dose distribution delivered to a patient.