Multiplanar CT-guided stereotaxis and 125I interstitial radiotherapy. Image-guided tumor volume assessment, planning, dosimetric calculations, stereotactic biopsy and implantation of removable catheters

A method using Multiplanar CT-guided stereotactic biopsy and high-dose 125I interstitial radiotherapy in patients with malignant nonresectable or recurrent brain tumors is presented. Optimal interstitial radiotherapy requires careful preoperative planning, computer-assisted dosimetry, CT-guided stereotactic biopsy and implantation of catheters that will be loaded with 125I seeds. A method is presented by which the isodose curve distribution is adjusted to the tumor size, volume and axis, allowing treatment of the imaged and histologically determined border of the tumor with 60 Gy at a dose rate of 40 rad/h.     

Modification of radiation-induced brain injury by alpha-difluoromethylornithine

The effect of alpha-difluoromethylornithine (DFMO) on 125I-induced brain injury was investigated in a dog model. Cerebrospinal putrescine levels were reduced from baseline levels 1-2 weeks after irradiation in animals treated with 125I and DFMO, while putrescine levels were elevated in 125I and saline-treated animals. In addition, the time course of changes in the volumes of edema, necrosis, and tissue showing evidence of blood-brain barrier breakdown was altered significantly by DFMO treatment. The most significant alterations occurred 2-4 weeks after irradiation, at which times the average volumes of damage in DFMO-treated animals were reduced compared to saline-treated animals. The time course of alterations in blood-to-brain transfer, brain-to-blood transfer, and vascularity following irradiation was also altered by DFMO treatment. Analysis of variance demonstrated a strong relationship of blood-to-brain transfer and vascularity to volume of edema, suggesting that the effect of DFMO on edema may be partially mediated by its effects on blood-brain barrier breakdown.     

The use of PET/CT in radiotherapy of patients with non-small cell lung cancer

The goal of this paper was to investigate the influence of FDG-PET/CT scan on the modification of staging and irradiation planning in patients suffering from non-small cell lung cancer (NSCLC). Fifteen patients suffering from NSCLC were analyzed by the authors from January, 2008 to July, 2009. The aim of the analysis was to examine the influence of FDG-PET/CT on irradiation planning and on decision-making of the complex oncologic therapy. The FDG-PET/CT scan was carried out in the position of irradiation performed later. For irradiation planning, planning target volumes (PTV) and the organs of risk were contoured on the patients' topometric CT slides as well as on the fused FDG-PET/CT slides. We evaluated how the application of PET/CT modified the stage of the illness, the complex oncologic therapeutic plan, the volume and the localization of the PTV, and the irradiation doses of the organs at risk. The mean and maximum dose of the spinal cord, the mean and V20 dose load of the lungs and the mean dose loads of the heart as well as of the left ventricle were measured. In 8 of 15 cases the stage of the disease and the treatment strategy was modified, since distant metastases were detected by the PET/CT. We evaluated the modification of the PTV and dose load of the organs at risk in 7 cases. According to the PET/CT the PTV was reduced in 5 cases (mean: 393.6 cm3) and was increased in 2 cases (mean: 250.8 cm3). Concerning the risk organs we found that the average (8.8 Gy/9.5 Gy) and maximum (33.4 Gy/36.4 Gy) dose load of the spinal cord increased, while the average (24.5 Gy/13.8 Gy) and V20 (33.7%/22.1%) dose load of the lungs decreased. We likewise found a decrease in the mean dose load of the heart (17.3 Gy/16.8 Gy) and left ventricle (12.9 Gy/9.6 Gy). In the majority of the cases the FDG-PET/CT scan modified the therapeutic decision, the size of the irradiated volume, and the dose load of the lung, the organ at risk causing the most difficulties at irradiation planning, was also reduced. The PET/CT scan plays an essential role in the complex oncologic treatment and irradiation therapy of NSCLC.     

Identifying the Association of Contrast Enhancement with Vascular Endothelia Growth Factor Expression in Anaplastic Gliomas: A Volumetric Magnetic Resonance Imaging Analysis

Contrast enhancement is a crucial radiologic feature of malignant brain tumors, which are associated with genetic changes of the tumor. The purpose of the current study was to investigate the potential relationship among tumor contrast enhancement with MR imaging, vascular endothelial growth factor (VEGF) expression, and survival outcome in anaplastic gliomas. MR images from 240 patients with histologically confirmed anaplastic gliomas were retrospectively analyzed. The volumes of T2 hyperintense, contrast enhanced regions and necrotic regions on postcontrast T1-weighted images were measured. The ratio of the enhanced volume to necrotic volume was compared between patients with high versus low levels of VEGF expression and was further used in the survival analysis. The volumetric ratio of enhancement to necrosis was significantly higher in patients with low VEGF expression than in those with high VEGF expression (Mann-Whitney, p = 0.009). In addition, the enhancement/necrosis ratio was identified as a significant predictor of progression-free survival (Cox regression model, p = 0.004) and overall survival (Cox regression model, p = 0.006) in the multivariate analysis. These results suggest that the volumetric ratio of enhancement to necrosis could serve as a noninvasive radiographic marker associated with VEGF expression and that this ratio is an independent predictor for progression-free survival and overall survival in patients with anaplastic gliomas.     

Generation of reactive oxygen species and radiation response in lymphocytes and tumor cells

Several types of lymphoid and myeloid tumor cells are known to be relatively resistant to radiation-induced apoptosis compared to normal lymphocytes. The intracellular generation of reactive oxygen species was measured in irradiated spleen cells from C57BL/6 and BALB/c mice and murine tumor cells (EL-4 and P388) by flow cytometry using dichlorodihydrofluoresceindiacetate and dihydrorhodamine 123 as fluorescent probes. The amount of reactive oxygen species generated per cell was low in the tumor cells compared to spleen cells exposed to 1 to 10 Gy of gamma radiation. This could be due to the higher total antioxidant levels in tumor cells compared to normal cells. Further, the changes in mitochondrial membrane potential and cytoplasmic Ca2+ content were appreciable in lymphocytes even at a dose of 1 Gy. In EL-4 cells, no such changes were observed at any of the doses used. About 65% of spleen cells underwent apoptosis 24 h after 1 Gy irradiation. However, under the same conditions, EL-4 and P388 cells failed to undergo apoptosis, but they accumulated in G2/M phase. Thus the intrinsic radioresistance of tumor cells may be due to a decreased generation of reactive oxygen species after irradiation and down-regulation of the subsequent events leading to apoptosis.     

Interstitial radiation in recurrent malignant gliomas

Twelve patients with recurrent supratentorial gliomas were treated with implanted 125I seeds. The interval from initial surgery to interstitial radiation ranged from 3 months to 9 years. The techniques for brachytherapy included volume implantation by craniotomy in one, stereotactic implantation with low-activity seeds in 7 and high-activity seeds in 4 patients. The total dose received ranged from 5,500 to 27,000 cGy. CT scans performed sequentially on all patients showed progressive attenuation in areas previously enhancing, suggestive of tumor necrosis produced by the interstitial sources. The mean and median survival of these patients was 23 and 22 weeks, with the 4 most recent patients still alive.     

Conformal stereotactic radiosurgery therapy: plan evaluation methods and results

The purpose of our study was the objective evaluation of micro-multileaf collimator (mMLC)-based stereotactic radiosurgery treatment plans. Forty-seven patients, 71 lesions received static beam conformal stereotactic radiosurgery treatment in our institute between November 2005 and June 2008. Target volume and organs at risk were outlined on a MRI-CT image fusion basis. BrainSCAN 5.31 system (BrainLAB AG, Heimstetten, Germany) was used for treatment planning, Elekta Presice TS linear accelerator (Elekta Oncology Systems Ltd, Crawley, UK) and BrainLAB m3 mMLC were used for treatment delivery. An invasive head frame, mounted to the treatment table, was used with four screws for patient head fixation. Treatment plans were analysed with objective parameters, such as conformal index (COIN), homogeneity index (HI), coverage index (CI) and healthy tissue relative overdose factor (HTOF) tools. x2 tests were performed between COIN, HI and the geometrical parameters of the target volume (lesion volume - LV, lesion-organ distance - LOD, lesion deformity index - LDI). Mean value of COIN, HI, HTOF and CI was 0.52 (SD 0.13), 1.16 (SD 0.1), 0.88 (SD 0.53), and 0.94 (SD 0.11), respectively. COIN significantly correlated with (p<0.001 in all three cases), while HI was independent of LV, LOD, LDI (p=0.94; 0.14 and 0.72). COIN is similar, HTOF is less than data from the literature. According to our results geometrical parameters of the target volume (size, location, deformation) significantly influence the COIN, but they have no effect on HI.     

Dose-response curves and tolerance doses for late functional changes in the normal rat brain after stereotactic radiosurgery evaluated by magnetic resonance imaging: influence of end points and follow-up time

Late reaction of normal tissue is still a limiting factor in radiotherapy and radiosurgery of patients with brain tumors. Few quantitative data in terms of dose-response curves are available. In the present study, 99 animals were irradiated stereotactically at the right frontal lobe using a linear accelerator and single doses between 26 and 50 Gy. The diameter of the spherical dose distribution was 4.7 mm (80% isodose). Dose-response curves for late changes in the normal brain at 20 months were measured using T1- and T2-weighted magnetic resonance imaging (MRI). The dependence of the dose-response curves on the follow-up time and the definition of the biological end point were determined. Tolerance doses were calculated at several effect probability levels and times after irradiation. The MRI changes were found to be dependent on dose and progressive in time. At 20 months, the tolerance doses at a 50% effect probability level were 39.6 +/- 1.0 Gy and 42.4 +/- 1.4 Gy for changes in T1- and T2-weighted images, respectively. These dose-response curves can be used for further quantitative investigations on the influence of various treatment parameters, such as the application of charged particles, radiopharmaceuticals or the variation of tissue oxygenation.     

Evaluation of the relative biological effectiveness of a clinical epithermal neutron beam using dog brain

This investigation was designed to determine the relative biological effectiveness (RBE) of an epithermal neutron beam (FiR 1 beam) using the brains of dogs. The FiR 1 beam was developed for the treatment of patients with glioma using boron neutron capture therapy. Comparisons were made between the effects of whole-brain irradiation with epithermal neutrons and 6 MV photons. For irradiations with epithermal neutrons, three dose groups were used, 9.4 +/- 0.1, 10.2 +/- 0.1 and 11.5 +/- 0.2 Gy. These physical doses were given as a single exposure and are quoted at the 90% isodose. Four groups of five dogs were irradiated with single doses of 10, 12, 14 or 16 Gy of 6 MV photons to the 100% isodose. Different reference isodoses were used to obtain the most comparable dose distribution in the brain for the two different irradiation modalities. Sequential magnetic resonance images (MRI) were taken for 77-115 weeks after irradiation to detect changes in the brain. Dose-effect relationships were established for changes in the brain as detected either by MRI or by subsequent gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED(50)) were calculated from these dose-effect curves for each end point, and these values were used to calculate the RBE values for the different end points. The RBE values for the FiR 1 beam, based on changes observed on MRI, were in the range 1.2-1.3. For microscopic and gross pathological lesions, the values were in the range 1.2-1.4. The corresponding RBE values for the MRI and pathological end points for the high-LET components (protons from nitrogen capture and recoil protons from fast neutrons) were in the ranges 3.5-4.0 and 3.4-4.4, respectively. This assumed a dose-rate reduction factor of 0.6 for the low-dose-rate gamma-ray component of this beam. Finally, a comparison was made between experimentally derived photon doses, for a specified end point, with calculated photon equivalent doses, which were obtained using the weighting factors for clinical studies on the epithermal neutron beam on the Brookhaven Medical Research Reactor (BNL) in New York. This indicated that the radiation-induced lesions seen in the present study were, on average, detected at a 12% lower photon dose than predicted by the use of the BNL clinical weighting factors. This indicates the need for caution in the extrapolation of results from one reactor-based epithermal neutron beam to another.     

Isolation and characterization of highly radioresistant malignant hamster fibroblasts that survive acute gamma irradiation with 20 Gy

To study the acquired radioresistance of tumor cells, a model system of two cell lines, Djungarian hamster fibroblasts (DH-TK-) and their radioresistant progeny, was established. The progeny of irradiated cells were isolated by treating the parental cell monolayer with a single dose of 20 Gy (PIC-20). The genetic and morphological features, clonogenic ability, radiosensitivity, cell growth kinetics, ability to grow in methylcellulose, and tumorigenicity of these cell lines were compared. The plating efficiency of PIC-20 cells exceeded that of DH-TK- cells. The progeny of irradiated cells were more radioresistant than parental cells. The average D0 for PIC-20 cells was 7.4 +/- 0.2 Gy, which is three times higher than that for parental cells (2.5 +/- 0.1 Gy). Progeny cell survival in methylcellulose after irradiation with a dose of 10 Gy was 15 times higher than that of DH-TK- cells. In contrast to parental cells, the progeny of irradiated cells showed fast and effective repopulation after irradiation with doses of 12.5 and 15 Gy. The tumor formation ability of irradiated progeny cells was higher than that of parental cells; after 15 Gy irradiation, PIC-20 cells produced tumors as large as unirradiated progeny of irradiated cells, whereas the tumor development of DH-TK- cells diminished by 70%. High radioresistance of progeny of irradiated cells was reproduced during the long period of cultivation (more than 80 passages). The stability of the radioresistant phenotype of PIC-20 cells allows us to investigate the possible mechanisms of acquired tumor radioresistance.     

Utilization of cone-beam CT for offline evaluation of target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment

AimTo assess target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment and to assess possibility of safety margin reduction.BackgroundImplementation of IGRT should influence safety margins. Utilization of cone-beam CT provides current 3D anatomic information directly in irradiation position. Such information enables reconstruction of the actual dose distribution.Materials and methodsSeventeen prostate patients were treated with daily bony anatomy image-guidance. Cone-beam CT (CBCT) scans were acquired once a week immediately after bony anatomy alignment. After the prostate, seminal vesicles, rectum and bladder were contoured, the delivered dose distribution was reconstructed. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed a 1 cm safety margin. Alternative plans assuming a smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with the initial ones. Rectal and bladder volumes irradiated with doses higher than 75 Gy, 70 Gy, 60 Gy, 50 Gy and 40 Gy were analyzed.ResultsIn 12% of reconstructed plans the prostate coverage was not sufficient. The prostate underdosage was observed in 5 patients. Coverage of seminal vesicles was not satisfactory in 3% of plans. Most of the target underdosage corresponded to excessive rectal or bladder filling. Evaluation of alternative plans assuming a smaller 7 mm margin revealed 22% and 11% of plans where prostate and seminal vesicles coverage, respectively, was compromised. These were distributed over 8 and 7 patients, respectively.ConclusionSufficient dose coverage of target volumes was not achieved for all patients. Reducing of safety margin is not acceptable. Initial rectal and bladder volumes cannot be considered representative for subsequent treatment.     

Modification of radiation damage in the canine kidney by hyperthermia: a histologic and functional study

The purpose of this study was to evaluate the effect of hyperthermia on the histologic and functional response of the canine kidney, a late-responding normal tissue, to irradiation. Both kidneys were irradiated. Radiation was delivered in single doses of 0, 10, or 15 Gy. Whole-body hyperthermia was used to produce renal kidney temperatures approximating 42.0 degrees C for 60 min. Thirty-six beagles were placed randomly in the following six treatment groups: control, whole-body hyperthermia alone, 10 Gy alone, 10 Gy + whole-body hyperthermia, 15 Gy alone, and 15 Gy + whole-body hyperthermia. Renal histologic and functional changes were assessed at 1 to 9 months after therapy. No changes were seen in glomerular filtration rate or renal tissue volumes in control or hyperthermia alone groups. Renal vascular and glomerular volumes were not affected significantly by any combination of hyperthermia and/or radiation. In all groups receiving radiation, glomerular filtration rate decreased, percentage renal tubular volume decreased, and interstitial volume increased significantly after therapy. The magnitude of these changes in the functional and histologic response of the kidney and the latent period before expression of this damage were dependent on radiation dose. However, hyperthermia did not modify expression of radiation damage in the kidney based on glomerular filtration rate and histologic quantification of renal tissue components.     

Comparative dosimetrical analysis of intensity-modulated arc therapy,CyberKnife therapy and image-guided interstitial HDR and LDR brachytherapy of low risk prostate cancer

BackgroundThe objective of the study was to dosimetrically compare the intensity-modulated-arc-therapy (IMAT), Cyber-Knife therapy (CK), single fraction interstitial high-dose-rate (HDR) and low-dose-rate (LDR) brachytherapy (BT) in low-risk prostate cancer.Materials and methodsTreatment plans of ten patients treated with CK were selected and additional plans using IMAT, HDR and LDR BT were created on the same CT images. The prescribed dose was 2.5/70 Gy in IMAT, 8/40 Gy in CK, 21 Gy in HDR and 145 Gy in LDR BT to the prostate gland. EQD2 dose-volume parameters were calculated for each technique and compared.ResultsEQD2 total dose of the prostate was significantly lower with IMAT and CK than with HDR and LDR BT, D90 was 79.5 Gy, 116.4 Gy, 169.2 Gy and 157.9 Gy (p < 0.001). However, teletherapy plans were more conformal than BT, COIN was 0.84, 0.82, 0.76 and 0.76 (p < 0.001), respectively. The D₂ to the rectum and bladder were lower with HDR BT than with IMAT, CK and LDR BT, it was 66.7 Gy, 68.1 Gy, 36.0 Gy and 68.0 Gy (p = 0.0427), and 68.4 Gy, 78.9 Gy, 51.4 Gy and 70.3 Gy (p = 0.0091) in IMAT, CK, HDR and LDR BT plans, while D_0.1 to the urethra was lower with both IMAT and CK than with BTs: 79.9 Gy, 88.0 Gy, 132.7 Gy and 170.6 Gy (p < 0.001). D₂ to the hips was higher with IMAT and CK, than with BTs: 13.4 Gy, 20.7 Gy, 0.4 Gy and 1.5 Gy (p < 0.001), while D₂ to the sigmoid, bowel bag, testicles and penile bulb was higher with CK than with the other techniques.ConclusionsHDR monotherapy yields the most advantageous dosimetrical plans, except for the dose to the urethra, where IMAT seems to be the optimal modality in the radiotherapy of low-risk prostate cancer.     

Threshold-like dose of local beta irradiation repeated throughout the life span of mice for induction of skin and bone tumors

The backs of female ICR mice were irradiated with beta rays from 90Sr-90Y three times a week throughout life. Previously we observed 100% tumor incidence at five different dose levels ranging from 1.5 to 11.8 Gy per exposure, but no tumor on repeated irradiation with 1.35 Gy for 300 days (Radiat. Res. 115, 488, 1988). In the present study, delay of tumor development was again seen at a dose of 1.5 Gy per exposure, with further delay at 1.0 Gy. The final tumor incidence was 100% with these two doses. At 0.75 Gy per exposure, no tumor appeared within 790 days after the start of irradiation, but one osteosarcoma and one squamous cell carcinoma did finally appear. These findings indicate a threshold-like response of tumor induction in this repeated irradiation system and further suggest that the apparent threshold may be somewhat less than 0.75 Gy per exposure.     

Bone in the breast? Long term toxicity 21 years after interstitial brachytherapy as a boost

An 81-year-old patient developed an exulcerous tumor in her left breast 21 years after breast cancer treatment with lumpectomy and adjuvant radiotherapy. At the time of the initial treatment 21 years ago, whole breast irradiation was performed with a prescribed dose of 48?Gy and a maximal dose of 69?Gy. In addition, the patient received a 14.7?Gy boost with multicatheter brachytherapy as partial breast irradiation.In general, fat necrosis after radiotherapy, surgery or trauma is a minor problem for patients, but can lead to diagnostic difficulties. The incidence varies: the literature indicates that it occurs in up to 34% of cases. The direct pathogenesis is not clear; it can be due to high radiation dose to the breast, dosimetric inhomogeneities or surgical complications (seromas and inflammation).The tumor in the case described here, occurring more than two decades after the primary treatment, is a rarity in this extent and is an unusual clinical, radiological, and histological finding. It provides a good example of the need for an individualized approach to treatment.     

Cerebrovascular response after interstitial irradiation.

To characterize the role of the cerebrovascular response in the development of brain injury after focal irradiation, 125I sources were implanted in frontal white matter of the brain of normal dogs; dose was 20 Gy, 7.5 mm from the source. Cerebral blood flow, vascular volume and mean transit time of blood were quantified in irradiated tissues relative to tissues in the contralateral hemisphere and analyzed with respect to previously determined volumetric measurements of damage and the blood-to-brain transfer constant. Blood flow and vascular volume within the radiation-induced focal lesion were maximally reduced 3 weeks after implant, when necrosis volume was maximal. By 6 weeks, vascular volume and mean transit time were increased, suggesting a strong neovascular response. In tissues surrounding the lesion, blood flow and vascular volume were reduced 1-4 weeks after irradiation and approached normal at 6 weeks; average mean transit time was not altered significantly. Alterations in blood flow and mean transit time were significantly related to edema volume and transfer constant, but alterations in vascular volume were not, suggesting that edema-induced vascular compression was not responsible for changes in blood flow. Reductions of radiation-induced permeability of the blood-brain barrier and/or edema might limit radiation-induced changes in blood flow and the extent of tissue injury.     

基于B超图像评价HIFU治疗剂量对组织损伤程度的影响

基于B超图像分析HIFU治疗中辐照剂量、组织凝固性坏死区域和图像参数之间的关系。通过对高强度聚焦超声辐照新鲜离体组织前后获得的B超图像做数字减影处理,计算图像灰度平均值,同时切片观察并记录生物组织的凝固性坏死区域大小,在此基础上得到大批量数据的统计特性。结果表明：辐照剂量、组织凝固性坏死区域与B超图像灰度平均值在一定范围内成正相关性;当凝固性坏死区域增大到一定程度时,B超图像灰度平均值不再增大,而是呈无规律分布。B超图像灰度可反映组织损伤程度,为实时监控HIFU治疗效果提供依据。