Inter-observer variation of hippocampus delineation in hippocampal avoidance prophylactic cranial irradiation.

BACKGROUND: Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) techniques have been developed to reduce radiation damage to the hippocampus. An inter-observer hippocampus delineation analysis was performed and the influence of the delineation variability on dose to the hippocampus was studied. MATERIALS AND METHODS: For five patients, seven observers delineated both hippocampi on brain MRI. The intra-class correlation (ICC) with absolute agreement and the generalized conformity index (CIgen) were computed. Median surfaces over all observers' delineations were created for each patient and regional outlining differences were analysed. HA-PCI dose plans were made from the median surfaces and we investigated whether dose constraints in the hippocampus could be met for all delineations. RESULTS: The ICC for the left and right hippocampus was 0.56 and 0.69, respectively, while the CIgen ranged from 0.55 to 0.70. The posterior and anterior-medial hippocampal regions had most variation with SDs ranging from approximately 1 to 2.5 mm. The mean dose (Dmean) constraint was met for all delineations, but for the dose received by 1% of the hippocampal volume (D1%) violations were observed. CONCLUSION: The relatively low ICC and CIgen indicate that delineation variability among observers for both left and right hippocampus was large. The posterior and anterior-medial border have the largest delineation inaccuracy. The hippocampus Dmean constraint was not violated.

pH, hypoxia and metastasis.

The vascular supply to tumours is often poorly formed and irregular with the result that tumours may contain regions of poor nutritional supply with hypoxia and acidic pH. Clinical studies have demonstrated substantial heterogeneity in oxygenation in human tumours. In some studies tumours with poorer oxygenation were more likely to have metastasized. In our studies of carcinoma of the cervix, nodal metastases were 1.5 times more likely at diagnosis in patients with more hypoxic tumours relative to those with less hypoxic tumours. Transplanted rodent KHT fibrosarcomas and SCC-VII squamous cell tumours also have variability in levels of oxygenation; again, the more hypoxic tumours are found to be more metastatic. Furthermore, deliberate exposure of KHT tumours to cyclic hypoxia (12 cycles of 5% oxygen breathing for 10 min interspersed with 10 min air breathing) every day during their growth, doubled the level of micrometastases that were detected in the lungs of the mice. These findings are consistent with in vitro studies demonstrating that KHT and SCC-VII cells and B-16 melanoma cells exposed to hypoxia or low pH have increased propensity to form metastases following injection into-mice. This effect is transient and is lost within about 48 h of removal of exposure to hypoxia or low pH, suggesting that the effect may be due to changes in gene expression associated with that stress. Recent studies have implicated a number of genes, such as vascular endothelial growth factor and interleukin 8, in the effect of hypoxic and acid pH on metastasis.

The effect of breathing and set-up errors on the cumulative dose to a lung tumor.

BACKGROUND AND PURPOSE: To assess the impact of both set-up errors and respiration-induced tumor motion on the cumulative dose delivered to a clinical target volume (CTV) in lung, for an irradiation based on current clinically applied field sizes. MATERIALS AND METHODS: A cork phantom, having a 50 mm spherically shaped polystyrene insertion to simulate a gross tumor volume (GTV) located centrally in a lung was irradiated with two parallel opposed beams. The planned 95% isodose surface was conformed to the planning target volume (PTV) using a multi leaf collimator. The resulting margin between the CTV and the field edge was 16 mm in beam's eye view. A dose of 70 Gy was prescribed. Dose area histograms (DAHs) of the central plane of the CTV (GTV+5 mm) were determined using radiographic film for different combinations of set-up errors and respiration-induced tumor motion. The DAHs were evaluated using the population averaged tumor control probability (TCP(pop)) and the equivalent uniform dose (EUD) model. RESULTS: Compared with dose volume histograms of the entire CTV, DAHs overestimate the impact of tumor motion on tumor control. Due to the choice of field sizes a large part of the PTV will receive a too low dose resulting in an EUD of the central plane of the CTV of 68.9 Gy for the static case. The EUD drops to 68.2, 66.1 and 51.1 Gy for systematic set-up errors of 5, 10 and 15 mm, respectively. For random set-up errors of 5, 10 and 15 mm (1 SD), the EUD decreases to 68.7, 67.4 and 64.9 Gy, respectively. For similar amplitudes of respiration-induced motion, the EUD decreases to 68.8, 68.5 and 67.7 Gy, respectively. For a clinically relevant scenario of 7.5 mm systematic set-up error, 3 mm random set-up error and 5 mm amplitude of breathing motion, the EUD is 66.7 Gy. This corresponds with a tumor control probability TCP(pop) of 41.7%, compared with 50.0% for homogeneous irradiation of the CTV to 70 Gy. CONCLUSION: Systematic set-up errors have a dominant effect on the cumulative dose to the CTV. The effect of breathing motion and random set-up errors is smaller. Therefore the gain of controlling breathing motion during irradiation is expected to be small and efforts should rather focus on minimizing systematic errors. For the current clinically applied field sizes and a clinically relevant combination of set-up errors and breathing motion, the EUD of the central plane of the CTV is reduced by 3.3 Gy, at maximum, relative to homogeneous irradiation of the CTV to 70 Gy, for our worst case scenario.

Relationship of hypoxia to metastatic ability in rodent tumours.

The relationship between tumour oxygenation in vivo and metastatic potential was investigated in 2 rodent tumour models, KHT-C fibrosarcoma and SCC-VII squamous cell carcinoma. The oxygen status in these rodent tumours transplanted intramuscularly in syngeneic mice was measured using the Eppendorf pO(2)Histograph. The results indicate a considerable heterogeneity in oxygenation between individual tumours within each tumour cell line. At different tumour sizes, animals were killed and lung lobes were examined for macroscopic and microscopic lung metastases. In the KHT-C tumours, a significant increase in early pulmonary metastasis formation was observed in mice with hypoxic primary tumours. Hypoxic SCC-VII tumours did not give rise to enhanced lung metastasis formation despite oxygenation in a range similar to the KHT-C tumours. However, the overall metastasis incidence in the SCC-VII model was very low. The results obtained in the KHT-C model, which show that hypoxic tumours are more likely to metastasize, are in agreement with recent clinical data suggesting that a hypoxic environment might be implicated in metastatic ability of human tumours.

Heterogeneity of tumor oxygenation: relationship to tumor necrosis, tumor size, and metastasis.

PURPOSE: Measurements of oxygenation in the transplanted rodent KHT-C and SCC-VII tumors demonstrate significant heterogeneity from tumor to tumor as is observed in human tumors. This finding suggests that heterogeneity in oxygenation between tumors is likely related to factors associated with tumor growth rather than to intrinsic genetic differences. In this study we examined whether measurements of the oxygenation of individual KHT-C tumors were related to necrosis in the tumors or to tumor size and whether the more hypoxic tumors gave rise to more metastases. METHODS: Tumors were grown in the gastrocnemius muscle of C3H mice and tumor oxygenation was measured at defined sizes (approx. 0.35 g, 1.0 g, and 2.0 g) using an Eppendorf polarographic oxygen probe. Necrosis was assessed by examining histological sections cut from tumors used for the oxygen measurements. Metastasis was assessed by counting macroscopic lung nodules in mice sacrificed when their tumors reached a size of approximately 2 g. RESULTS: Tumor oxygenation in individual KHT-C tumors became poorer and necrosis became more extensive as the tumors grew larger but, at a size of 0.3-0.4 g, there was no relationship between oxygenation and extent of necrosis. In general, measurements of tumor pO2 at a size of 0.3-0.4 g were predictive of tumor PO2 in the same tumor at a size of about 1 g, but by the time the tumors reached a size of about 2 g they were all very hypoxic. There was a trend suggesting a relationship between macroscopic metastases in the lung and degree of hypoxia in the KHT-C tumors but this was not statistically significant. CONCLUSION: The results indicate that the heterogeneity of oxygenation seen in KHT-C tumors is not explained by different degrees of necrosis in the individual tumors. The lack of a correlation between increased metastasis formation and increased levels of hypoxia in the KHT-C tumors is not consistent with results reported for human tumors.

Planning and delivering high doses to targets surrounding the spinal cord at the lower neck and upper mediastinal levels: static beam-segmentation technique executed with a multileaf collimator.

BACKGROUND AND PURPOSE: It remains a technical challenge to limit the dose to the spinal cord below tolerance if, in head and neck or thyroid cancer, the planning target volume reaches to a level below the shoulders. In order to avoid these dose limitations, we developed a standard plan involving Beam Intensity Modulation (BIM) executed by a static technique of beam segmentation. In this standard plan, many machine parameters (gantry angles, couch position, relative beam and segment weights) as well as the beam segmentation rules were identical for all patients. MATERIALS AND METHODS: The standard plan involved: the use of static beams with a single isocenter; BIM by field segmentation executable with a standard Philips multileaf collimator; virtual simulation and dose computation on a general 3D-planning system (Sherouse's GRATIS); heuristic computation of segment intensities and optimization (improving the dose distribution and reducing the execution time) by human intelligence. The standard plan used 20 segments spread over 8 gantry angles plus 2 non-segmented wedged beams (2 gantry angles). RESULTS: The dose that could be achieved at the lowest target voxel, without exceeding tolerance of the spinal cord (50 Gy at highest voxel) was 70-80 Gy. The in-target 3D dose-inhomogeneity was approximately 25%. The shortest time of execution of a treatment (22 segments) on a patient (unpublished) was 25 min. CONCLUSIONS: A heuristic model has been developed and investigated to obtain a 3D concave dose distribution applicable to irradiate targets in the lower neck and upper mediastinal regions. The technique spares efficiently the spinal cord and allows the delivery of higher target doses than with conventional techniques. It can be planned as a standard plan using conventional 3D-planning technology. The routine clinical implementation is performed with commercially available equipment, however, at the expense of extended execution times.