[en] Purpose: We compare practical conformal treatment approaches to pancreatic cancer using 6 and 18 MV photons and contrast those approaches against standard techniques. Methods and Materials: A four-field conformal technique for treating pancreas cancer has been developed using nonopposed 18 MV photons. This approach has been extended to 6 MV photon application by the addition of one to two fields. These techniques have been optimized to increase sparing of normal liver and bowel, compared with opposed-field methods, to improve patient tolerance of high doses. In this study we compare these techniques in a simulated tumor model in a cylindrical phantom. Dose-volume analysis is used to quantify differences between the conformal, nonopposed techniques with conformal, opposed field methods. This model is also used to evaluate the effect of 1-2 cm setup errors on dose-volume coverage. Results: Dose-volume analysis demonstrates that five-to-six field conformal treatments using 6 MV photons provides similar or better dose coverage and normal tissue sparing characteristics as an optimized 18 MV, four-field approach when 1-2 cm margins are included for setup uncertainty. All approaches using nonopposed beam geometry provide significant reduction in the volume of tissue encompassed by the 30-50% isodose surfaces, as compared with four-field box techniques. Conclusions: Three-dimensional (3D) conformal treatments can be designed that significantly improve dose-volume characteristics over conventional treatment designs without costing unacceptable amounts of machine time. Further, deep intraabdominal sites can be adequately accessed and treated on intermediate energy machines with a relatively moderate increase in machine time

[en] Purpose/Objective: A large number of investigators have begun utilizing radiation modalities in order to prevent or delay neointimal hyperplasia (NIH) formation. Following our initial successful studies looking at single fraction low doses of HDR brachytherapy given immediately after injury, we extended this model to look at the long term effects on the inhibition of NIH in the rat common carotid artery. Materials and Methods: The right common carotid arteries (CCA) of 4-5 month old male Sprague Dawley rats were injured using a 2F balloon catheter. Immediately post-injury, a delivery catheter was sutured alongside the injured artery and the vessel received either 0, 5, or 10 Gy irradiation using an Iridium 192 afterloader. Six months post-treatment, the animals were sacrificed and both the right and left CCA were harvested following perfusion fixation, and processed for light and electron micrography. Specimens were stained with PAS and the intima and media areas were calculated using a computer-assisted digitizing program. Additional immunocytochemical staining was carried out, looking particularly at PDGF. Results: In contrast to our previous findings which were assessed at 3 weeks post-treatment, at the later time point of 6 months post-treatment, there was no significant reduction in intimal area of the radiation-treated balloon-injured animals compared to the balloon-injured alone and the intima: media ratios was the same in both groups (Fig. 1). The lumenal area in both treatment groups was significantly reduced from normal controls (Fig. 2). Immunocytochemical staining for PDGF at 3 weeks demonstrated that there was an immediate (24 hours) release of growth factor from the medial smooth muscle in the balloon-injured animals; there was no similar release in the radiation-treated animals at the 1 day, 1 or 3 week time points. This will now be assessed at the later time points. Higher doses of 15-25 Gy are now being studied since other investigators have shown persistent inhibition at 1 and 6 months post-treatment following >10 to 30 Gy. Conclusion: Low dose HDR brachytherapy inhibited NIH in the rat model at 3 weeks post-treatment, but this effect was not sustained at the doses studied (5-10 Gy) to the later time point of 6 months

[en] Purpose: Three-dimensional treatment planning was performed to evaluate three standard coplanar irradiation techniques (two-field parallel-opposed, three-field, and 110 deg. bilateral arcs), the 330 deg. single rotational arc, and a four noncoplanar arc technique for the treatment of pituitary adenomas. We sought to identify the optimal technique for minimizing the dose delivered to the normal tissues around the pituitary gland. Methods and Materials: Contours of the pituitary tumor and normal tissues were traced onto computed axial tomography (CT) scans and reconstructed in three dimensions using a three-dimensional planning system. A total dose of 45 Gy was delivered to the pituitary lesion with the five techniques using 6 MV and 18 MV photons, and dose-volume histograms were generated. Results: The 18 MV photons delivered a lower dose to the temporal lobe than did the 6 MV photons in the two-field technique, but this advantage was not evident for the other techniques. The three-field technique improved dose distribution throughout the temporal lobes with low doses being delivered to the frontal lobe. The bilateral arc and the 330 deg. arc techniques were superior to stationary two- and three-fields techniques for sparing the temporal lobes. The four noncoplanar arc technique delivered less doses to the temporal and frontal lobes than did the other techniques. However, the lens dose (3.6 (Gy(25)) fractions) was higher compared to the other techniques. Conclusion: Analysis of the dose-volume histograms shows the various dosimetric advantages and disadvantages of the five techniques. Based upon individual considerations, including the patient's age and medical history, one can decide the optimal technique for treatment

[en] PURPOSE: The relationship of dose and volume to arteriovenous malformation (AVM) obliteration, complications, and hemorrhage is not well defined for large AVMs. Multivariate analysis was performed to assess the relationship of multiple factors to the outcome of a series of AVMs significantly larger than previously reported in the literature. MATERIALS and METHODS: Between 1988 and 1991, 73 patients with intracranial AVMs were treated with LINAC based radiosurgery. The median treatment volume was 8 cc (range 0.4 - 143 cc). 40% of the AVMs were larger than 15 cc. The median equivalent diameter of the treatment volumes was 2.5 cm (range 0.9 - 6.8 cm). The median Spetzler-Martin grade was III. The median number of treatment isocenters was 2 (range 1 - 7) and the median prescription isodose line (normalized to the maximum dose) was 66% (range 23 - 90%). The median minimum and maximum AVM doses were 1600 cGy (range 1000 - 2200 cGy) and 2518 cGy (range 1745 - 4652 cGy) respectively. RESULTS: Clinical follow-up was available for all patients and radiologic follow-up was available for 98% of living patients. At 5 years, 27 patients (37%) had complete AVM obliteration documented by either angiogram or MRI/MRA, 7 (10%) were retreated with radiosurgery, 2 (3%) underwent surgical resection, 5 (7%) died of intracranial hemorrhage, and 4 (5%) died of intercurrent disease. The median follow-up for the remaining 28 patients (38%) who did not reach one of these endpoints was 71 months. The 5 year actuarial radiographic obliteration rate was 46%. Angiograms were obtained when a MRI suggested obliteration or at the time of retreatment. The 5 year angiographic obliteration rate in these selected patients was 63%. Fifty-two percent of patients had AVM obliteration documented after 3 years. For AVMs <1 cc, 1-5 cc, 5-15 cc, and >15 cc, the 5 year radiographic obliteration rates were 81%, 62%, 47% and 27%. The mean doses for the groups were 1834, 1763, 1660, and 1519 cGy. In multivariate analysis, AVM obliteration was significantly associated with minimum dose and negatively associated with a history of prior embolization. Volume was statistically significant in univariate but not multivariate analysis. The 5 year actuarial rate of developing post-radiosurgical MRI T2 changes was 52% with a median time to detection of 12 months. Forty-eight percent of patients with these MRI abnormalities had clinically significant symptoms and 18% required medical intervention. There were 4 cases (5%) of radiation necrosis requiring surgical resection including 1 fatality (1%). In multivariate analysis, equivalent treatment diameter and K-index were statistically significant. Nine patients (12%) suffered clinically significant hemorrhages, 5 of which were fatal. Following radiosurgery, the annualized rate of hemorrhage was 3-5% per person-year and the annualized mortality rate from hemorrhage was 2-3% per person-year. These rates were consistent with those calculated using the Kaplan-Meier life table method. The median time to first hemorrhage following radiosurgery was 31 months (range 11 - 73 months). In multivariate analysis, post-treatment hemorrhage was significantly associated with treatment volume, number of prior hemorrhages, and venous restrictive disease. CONCLUSION: The low rate of AVM obliteration for this series compared to other series in the literature may be attributed to the inclusion of non-angiographic failures in the reported obliteration rate, the large size of AVMs, the moderate doses prescribed, and possibly the high incidence of prior embolization procedures (59%). Reports of AVM obliteration rates should include non-angiographic MRI/MRA failures. With long follow-up, a significant rate of late obliteration and a higher than expected rate of post-radiosurgical hemorrhage were observed. AVM obliteration was associated with minimum AVM dose and negatively associated with a history of prior embolization. Complications were associated with equivalent treatment diameter and K-index. Post-radiosurgery hemorrhage was associated with treatment volume, number of prior hemorrhages, and venous restrictive disease. Large AVMs are problematic as they are associated with low obliteration rates (27% for AVM > 20 cc), higher complication rates, and higher rates of post-radiosurgery hemorrhage

[en] Purpose: To directly compare clinical efficacy of electronic to film portal images. Methods and Materials: An observer study was designed to compare clinical efficacy of electronic to film portal images acquired using a liquid matrix ion-chamber electronic portal imaging device and a conventional metal screen/film system. Both images were acquired simultaneously for each treatment port and the electronic portal images were printed on gray-level thermal paper. Four radiation oncologists served as observers and evaluated a total of 44 sets of images for four different treatment sites: lung, pelvis, brain, and head/neck. Each set of images included a simulation image, a double-exposure portal film, and video paper prints of electronic portal images. Eight to nine anatomical landmarks were selected from each treatment site. Each observer was asked to rate each landmark in terms of its clinical visibility and to rate the ease of making the pertinent verification decision in the corresponding electronic and film portal images with the aid of the simulation image. Results: Ratings for the visibility of landmarks and for the verification decision of treatment ports were similar for electronic and film images for most landmarks. However, vertebral bodies and several landmarks in the pelvis such as the acetabulum and pubic symphysis were more visible in the portal film images than in the electronic portal images. Conclusion: The visibility of landmarks in electronic portal images is comparable to that in film portal images. Verification of treatment ports based only on electronic portal images acquired using an electronic portal imaging device is generally achievable

[en] Purpose: The major radiobiological issue in determining the rationale for the use of radiation to inhibit vascular restenosis is the identification of the target cell(s) and/or cytokine(s) responsible for neointimal hyperplasia and vascular remodeling. The central hypothesis of this report is that the macrophage/monocyte and PDGF are key elements in the process of neointimal hyperplasia seen following angioplasty, similar to their role in lesion formation and progression found in atherosclerotic thickening. Specific immunohistochemical and cytochemical stains were applied to a rat carotid model in a temporal series after balloon angioplasty to determine macrophage activity vs. smooth muscle cell proliferation, the latter being classically thought to be the cell responsible for restenosis. Methods and Materials: Neointimal hyperplasia was created in an established rat carotid artery model by a balloon catheter technique. Immediately following injury, treatment groups received irradiation via high dose rate (HDR) brachytherapy, the ¹⁹²Ir source being placed externally to the vessel. Radiation was delivered to a length of 2 cm of the injured vessel at doses of 5, 10, and 15 Gy, and the animals were sacrificed at various time points following treatment (24 h to 6 months). Serial sections of tissue were stained immunohistochemically with the primary antibodies CD11b, mac-1, anti-PDGF, and α-smooth muscle actin. Results: Immediately (24 h) postinjury, there is an apparent migration of macrophages seen in the adventitia; after 1 week, proliferation and migration of macrophages could be seen clearly within all the vessel layers, especially in the intima; by 3 weeks, when there was evidence of neointimal hyperplasia, macrophages could still be seen, mainly in the intima scattered among the smooth muscle cells and myofibroblasts, and to a lesser degree at 6 months. There was corresponding expression of PDGF, whenever and wherever there were zones of activation/neointimal hyperplasia. α-Smooth muscle actin staining identified the smooth muscle cells distinct from the macrophages, and these SMCs exhibited activation in the neointimal hyperplasia zones at all later time points. Furthermore, we showed that radiation significantly reduced the macrophage population, while the onset of neointimal hyperplasia was accompanied by a return of the macrophage population. Conclusion: Our results suggest that the activated adventitial macrophage/monocyte are the key cells responsible for initiating the arterial neointimal hyperplasia and vascular remodeling developing postangioplasty as they are in the initiation and perpetuation of atheromatous thickening. Irradiation delivered immediately postinjury is, therefore, highly effective, because the macrophage population is exquisitely radiosensitive

[en] Purpose: To investigate a method for the generation of digitally reconstructed radiographs directly from MR images (DRR-MRI) to guide a computerized portal verification procedure. Methods and Materials: Several major steps were developed to perform an MR image-guided portal verification procedure. Initially, a wavelet-based multiresolution adaptive thresholding method was used to segment the skin slice-by-slice in MR brain axial images. Some selected anatomical structures, such as target volume and critical organs, were then manually identified and were reassigned to relatively higher intensities. Interslice information was interpolated with a directional method to achieve comparable display resolution in three dimensions. Next, a ray-tracing method was used to generate a DRR-MRI image at the planned treatment position, and the ray tracing was simply performed on summation of voxels along the ray. The skin and its relative positions were also projected to the DRR-MRI and were used to guide the search of similar features in the portal image. A Canny edge detector was used to enhance the brain contour in both portal and simulation images. The skin in the brain portal image was then extracted using a knowledge-based searching technique. Finally, a Chamfer matching technique was used to correlate features between DRR-MRI and portal image. Results: The MR image-guided portal verification method was evaluated using a brain phantom case and a clinical patient case. Both DRR-CT and DRR-MRI were generated using CT and MR phantom images with the same beam orientation and then compared. The matching result indicated that the maximum deviation of internal structures was less than 1 mm. The segmented results for brain MR slice images indicated that a wavelet-based image segmentation technique provided a reasonable estimation for the brain skin. For the clinical patient case with a given portal field, the MR image-guided verification method provided an excellent match between features in both DRR-MRI and portal image. Moreover, target volume could be accurately visualized in the DRR-MRI and mapped over to the corresponding portal image for treatment verification. The accuracy of DRR-MRI was also examined by comparing it to the corresponding simulation image. The matching results indicated that the maximum deviation of anatomical features was less than 2.5 mm. Conclusion: A method for MR image-guided portal verification of brain treatment field was developed. Although the radiographic appearance in the DRR-MRI is different from that in the portal image, DRR-MRI provides essential anatomical features (landmarks and target volume) as well as their relative locations to be used as references for computerized portal verification

[en] Purpose: To evaluate the acute toxicity of a group of 37 pancreatic cancer patients treated with noncoplanar, nonopposed, conformal radiation therapy with concurrent chemotherapy (5-FU). Materials and Methods: We retrospectively evaluated a group of initially nonadvanced 37 pancreatic cancer patients treated with combined concurrent chemotherapy and 3D radiation therapy treated between 1992 until 1995. During this period we began treating the initially unresectable patients with preoperative chemo-RT (50.4 Gy) after treating an initial group of unresectable patients to a higher dose of 66.6 Gy. We also include a group of patients who received postop chemo-RT after Whipple resection (59.4 Gy). All radiation was delivered at a 1.8 Gy per fraction dose rate. The total group was made up of 37 patients of whom 21 were male (57%) and 16 female (43%). There were 22 (59%) head of pancreas lesions, 10 (27%) body of pancreas lesions, and 5 (14%) head and body of pancreas cancers. Of these 37 patients 7 (19%) were treated with chemo-RT as their only treatment, 10 patients (29%) were treated post Whipple resection, and 20 patients (54%) were treated with preoperative intent. Results: Three patients (8%) required a treatment break, one with a body and 2 with head lesions. Two of these patients stopped RT short of planned dose (32.56 and 46.8 Gy) both suffering from nausea, vomiting, and anorexia with the third, who finished a planned 66.6 Gy dose, after a 4 day rest for leukopenia. One of 20 patients (5%) preop patients underwent the planned post chemo-RT Whipple resection, while 4 of the 20 patients (20%), remained unresectable, but without disease progression and had Iodine 125 interstitial implants at exploration delivering a minimal tumor dose of 120 Gy on top or the 50.4 Gy delivered preoperatively. Four patients (11%) maintained a minimal Karnofsky score of 100, 23 patients (62%) maintained a minimal KPS of 90, 6 patients (16%) maintained a minimal KPS of 80, and 4 patients (11%) had a minimal KPS =/< 70. Seven of the 37 patients (19%) either lost no weight or gained weight during the chemo-RT, while the mean weight lost was 6.9 lb. with a median weight loss of 6.0 lb. for the entire group. Eighteen patients (49%) required narcotic analgesics during chemo-RT, 9 patients (24%) had ECOG grade 1 or 2 thrombocytopenia. Of those 16 patients receiving a 3 day bolus of 5-FU, 6 of 16 (38%) had thrombocytopenia while of the 96 hr infusion group 4 of 19 (21%) patients had thrombocytopenia. Eight patients had leukopenia of whom 3 had ECOG grade 3 and 4 (both on 3 day bolus 5-FU). Of 6 of 37 (16%) patients developing anemia during chemo-RT 5 were treated with 3 day bolus and one with the 96 hr infusion 5-FU. Nine of 37 (24%) patients suffered grade 0 or 1 diarrhea. Of the two patients treated with prolonged venous infusion 5-FU (225 mg/m2/d) during RT, neither developed any hematologic toxicity. Conclusions: Noncoplanar, nonopposed, conformal radiation therapy can be used with acceptable acute toxicity in the treatment of pancreatic cancer, whether the chemo-radiation is delivered preoperatively, postoperatively, or as the only treatment. The relatively acceptable acute toxicity with the 3D RT approach may allow for more effective and maybe even more potentially toxic treatment strategies to be used in combination with 3D RT

[en] Purpose: For radiosurgery of large arteriovenous malformations (AVMs), the optimal relationship of dose and volume to obliteration, complications, and hemorrhage is not well defined. Multivariate analysis was performed to assess the relationship of multiple AVM and treatment factors to the outcome of AVMs significantly larger than previously reported in the literature. Methods and Materials: 73 patients with intracranial AVMs underwent LINAC radiosurgery. Over 50% of the AVMs were larger than 3 cm in diameter and the median and mean treatment volumes were 8.4 cc and 15.3 cc, respectively (range 0.4-143.4 cc). Minimum AVM treatment doses varied between 1000-2200 cGy (median: 1600 cGy). Results: The obliteration rates for treatment volumes < 4 cc, 4-13.9 cc, and ≥ 14 cc were 67%, 58%, and 23%, respectively. AVM obliteration was significantly associated with higher minimum treatment dose and negatively associated with a history of prior embolization with particulate materials. No AVM receiving < 1400 cGy was obliterated. The incidence of post-radiosurgical imaging abnormalities and clinical complications rose with increasing treatment volume. For treatment volumes > 14 cc receiving ≥ 1600 cGy, the incidence of post-radiosurgical MRI T2 abnormalities was 72% and the incidence of radiation necrosis requiring resection was 22%. The rate of post-radiosurgical hemorrhage was 2.7% per person-year for AVMs with treatment volumes < 14 cc and 7.5% per person-year for AVMs ≥ 14 cc. Conclusion: As AVM size increases, the dose-volume range for the optimal balance between successful obliteration and the risk of complications and post-radiosurgical hemorrhage narrows

[en] Purpose: To perform a Phase I study to determine the safety and feasibility of using external beam radiotherapy to prevent neointimal hyperplasia in patients after surgical bypass of occluded infrainguinal arteries. Methods and Materials: All patients undergoing operative infrainguinal bypass for chronic ischemia were eligible for enrollment, although those requiring a prosthetic graft were preferentially considered. Immediately after bypass, the distal anastomosis was marked with clips, and the baseline anatomy of the anastomosis was documented with an intraoperative angiogram. The distal anastomotic site and 2 cm of surrounding tissues were irradiated to a total dose of 30 Gy, delivered in 10 fractions. The first dose was given within 48 h of surgery. Results: Twenty-one patients were enrolled in this study. No anastomotic or wound problems or any other short-term complications of the treatment developed. However, at a mean follow-up of 10 months (range 3-18), 12 (57%) of the 21 grafts had occluded. Angiography was performed in 2 patients after successful thrombolysis and demonstrated normal anastomoses without residual stenosis. Evidence of stenosis at the irradiated anastomosis was seen in only 1 of the 21 patients by ongoing ultrasound surveillance. Conclusion: Fractionated external irradiation to a total dose of 30 Gy delivered to the distal surgical anastomosis immediately after operative bypass has no short-term complications and was associated with an apparently low rate of intimal hyperplasia. However, any possible gains made by reducing the neointimal hyperplasia at the site of anastomosis were significantly diminished by the high frequency of thrombotic events