The Impact of Dose Rate on the Accuracy of Step-and-Shoot Intensity-modulated Radiation Therapy Quality Assurance Using Varian 2300CD.

INTRODUCTION: Intensity-modulated radiation therapy (IMRT) delivery using "step-and-shoot" technique on Varian C-Series linear accelerator (linac) is influenced by the communication frequency between the multileaf collimator and linac controllers. Hence, the dose delivery accuracy is affected by the dose rate. AIM: Our aim was to quantify the impact of using two dose rates on plan quality assurance (QA). MATERIALS AND METHODS: Twenty IMRT patients were selected for this study. The plan QA was measured at two different dose rates. A gamma analysis was performed, and the degree of plan modulation on the QA pass rate was also evaluated in terms of average monitor unit per segment (MU/segment) and the total number of segments. RESULTS: The mean percentage gamma pass rate of 94.9% and 93.5% for 300 MU/min and 600 MU/min dose rate, respectively, was observed. There was a significant (P = 0.001) decrease in percentage gamma pass rate when the dose rate was increased from 300 MU/min to 600 MU/min. There was a weak, but significant association between the percentage pass rate at both dose rate and total number of segments. The total number of MU was significantly correlated to the total number of segments (r = 0.59). We found a positive correlation between the percentage pass rate and mean MU/segment, r = 0.52 and r = 0.57 for 300 MU/min and 600 MU/min, respectively. CONCLUSION: IMRT delivery using step-and-shoot technique on Varian 2300CD is impacted by the dose rate and the total amount of segments.

Vascular development in mouse lung metastases.

Dissemination of cancer cells is strongly associated with reduction in quality of life, worsening of prognosis, and remains the primary cause of therapeutic failure and high mortality in cancer. A crucial factor in the progression of metastases is the ability to establish a functioning blood vessel network. Consequently therapeutic strategies which selectively target tumor vasculature may hold promise for the treatment of metastatic disease. A complicating factor in the assessment of the efficacy of vascular targeting therapies is that the metastatic process can result in multiple neoplastic lesions at various stages of growth and vascularity in a single organ. The goal of this project was to utilize a rodent squamous cell carcinoma (SCCVII) model to characterize the development of metastatic lung lesions and their associated vasculature. Mice were injected with tumor cells via the tail vein to introduce a reproducible number of lung metastases. At various times after cell injection, lungs were removed and serial sections were taken throughout the lobes for morphometric analysis. Tumor volumes were calculated for each nodule using 2 hematoxylin and eosin (H&E) stained sections that were a known distance apart. Sections adjacent to those used for size determination were reserved for immunohistochemical staining with CD31 to identify blood vessels associated with each nodule. The results showed that although the median tumor volume increased from 0.006 to 0.51 mm(3) between 7 and 18 days post SCCVII cell injection, a range of tumor sizes existed at all-times. Irrespective of the time of assessment, nodules with volumes ≤ 0.5 mm(3) had a constant vessel density while those with volumes >0.5 mm(3) showed increasing vessel densities with increasing size. These findings indicate that the methodology outlined in this study can identify metastases in various stages of vascular development and could therefore be applied to evaluate and distinguish therapeutic interventions that seek to prevent the initiation of blood vessel networks and those targeting already established expanding tumor vasculature. Examining the efficacy of such approaches, alone or in combination, in the treatment of metastases in a preclinical model could lead to the development of more effective therapeutic strategies for metastatic disease.

Monitoring the treatment efficacy of the vascular disrupting agent CA4P.

The purpose of this study was to investigate two non-invasive methods for determining the treatment efficacy of the vascular disrupting agent (VDA) CA4P: gadolinium enhanced dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for perfusion analysis and enzyme-linked immunosorbent assay (ELISA) of blood samples. Candidate proteins were identified by multi-analyte profile analysis of plasma from KHT sarcoma-bearing C3H/HeJ mice after CA4P administration. Candidate proteins were further analysed by ELISA of plasma from treated C3H/HeJ, BALBc and C57BL6 mice. Changes in selected proteins, tumour perfusion and tumour necrotic fraction after CA4P treatment were then compared in individual animals. The cytokines KC and MCP-1 were observed to increase after CA4P treatment in all tested models. No correlation was found between KC or MCP-1 levels and tumour necrosis. However, tumour perfusion correlated (r=0.89, p<0.00001) with CA4P treatment efficacy as measured by necrotic fraction, suggesting that DCE-MRI may have utility in a clinical setting.

Evaluations of vascular disrupting agents CA4P and OXi4503 in renal cell carcinoma (Caki-1) using a silicon based microvascular casting technique.

The present study evaluated the treatment efficacy of the vascular disrupting agents CA4P and OXi4503 in an orthotopically transplanted human renal cell carcinoma xenograft model (Caki-1). Experiments used vascular casting, vessel density assessments as well as tumour necrosis measurements to evaluate the efficacy of these agents. After treatment with either agent, assessment of the vascular casts showed an almost total eradication of tumour blood vessels. Histological evidence further supported this observation, showing extensive central tumour necrosis with only a small viable rim of tumour cells remaining at the periphery. These results suggest that vascular disrupting agents CA4P and OXi4503 may have utility in the treatment of renal cell carcinoma, an encouraging result given that current conventional therapies have been currently largely unsuccessful in managing this disease.

Effect of the second-generation vascular disrupting agent OXi4503 on tumor vascularity.

PURPOSE: As first-generation small-molecule vascular disrupting agents (VDA) have begun to enter clinical trials, second-generation agents are under active development. One such agent is the combretastatin A4 disodium phosphate (CA4P) analogue OXi4503 (CA1P). EXPERIMENTAL DESIGN: C3H/HeJ mice bearing KHT sarcomas were treated with CA4P and OXi4503 and the effect on tumor vasculature was determined by evaluating the extent of vascular shutdown (Hoechst-33342 vessel staining) and tumor perfusion inhibition (dynamic contrast-enhanced magnetic resonance imaging). Dynamic contrast-enhanced magnetic resonance imaging and tumor necrosis end points also were used to examine the pathophysiologic tumor effects following repeated exposures to these agents. RESULTS: Single doses of either agent (CA4P, 100 mg/kg; OXi4503, 25 mg/kg) resulted in an 80% to 90% reduction in tumor perfusion 4 hours after treatment. Whereas recovery in tumor perfusion was observed 48 hours posttreatment, this recovery was significantly slower in mice treated with OXi4503. Tumors re-treated with either VDA 72 hours after the first drug exposure showed a similar reduction and recovery in tumor perfusion. Histologic evidence showed the presence of a smaller viable rim after exposure to OXi4503 than that observed after CA4P treatment. Furthermore, the extent of recovery of tumor necrosis 72 hours after drug treatment was less for OXi4053. CONCLUSIONS: The present studies show that the second-generation VDA OXi4503 possesses significant antivascular effects in solid tumors. Importantly, the vasculature of tumors of mice that had received an initial dose this agent was as responsive to a subsequent treatment.

Utility of 19F MRS detection of the hypoxic cell marker EF5 to assess cellular hypoxia in solid tumors.

BACKGROUND AND PURPOSE: The present studies were undertaken to determine whether 19F MRS could be used to quantify the binding of the pentafluorinated derivative of etanidazole (EF5) in hypoxic cells of solid tumors. MATERIALS AND METHODS: A 4.7 T imaging magnet was used for the in situ and in vitro evaluation of EF5 signals. In order to develop a better understanding of these NMR measurements the characteristics of parent, reduced unbound, and reduced bound EF5 signals were examined in vitro using a 12 T spectrometer. RESULTS: In situ data acquired using a 4.7 T imaging magnet, showed retention of EF5 signals in KHT sarcomas that was absent in muscles for 6 h after EF5 injection. In vitro studies showed no difference in the NMR detectable signal of parent and reduced unbound EF5. T2 values determined using parent EF5 samples revealed a T2 time of 675 ms. In contrast, EF5 bound to KHT tumor cells gave rise to signals of low intensity, broad line widths, and T2 relaxation times of less than 30 ms. When the same samples were analyzed using the 4.7 T imaging magnet, the CF3 and CF2 fluorine peaks were readily identifiable in the parent EF5 sample but no fluorine signal could be detected from EF5 bound to KHT tumor cells. CONCLUSION: The inability to resolve bound EF5 metabolites even at high field strengths (12 T), coupled with the short T2 relaxation times of the bound EF5, and the limits of detection of the in situ applied imaging magnet (4.7 T), meant that hypoxic cells could not be quantified in tumors using the 19F MRS technique. In situ 19F MRS measurements of EF5 signals (parent/reduced unbound) may reflect conditions of tumor physiology and thus indicate the extent of tumor hypoxia but they are not capable of resolving the cellular oxygenation status of the tumor cells.