Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features.

PURPOSE: One major uncertainty in radiotherapy planning of non-small-cell lung cancer concerns the definition of the clinical target volume (CTV), meant to cover potential microscopic disease extension (MDE) around the macroscopically visible tumor. The primary aim of this study was to establish pretreatment risk factors for the presence of MDE. The secondary aim was to establish the impact of these factors on the accuracy of positron emission tomography (PET) and computed tomography (CT) to assess the total tumor-bearing region at pathologic examination (CTV(path)). METHODS AND MATERIALS: 34 patients with non-small-cell lung cancer who underwent CT and PET before lobectomy were included. Specimens were examined microscopically for MDE. The gross tumor volume (GTV) on CT and PET (GTV(CT) and GTV(PET), respectively) was compared with the GTV and the CTV at pathologic examination, tissue deformations being taken into account. Using multivariate logistic regression, image-based risk factors for the presence of MDE were identified, and a prediction model was developed based on these factors. RESULTS: MDE was found in 17 of 34 patients (50%). The MDE did not exceed 26 mm in 90% of patients. In multivariate analysis, two parameters (mean CT tumor density and GTV(CT)) were significantly associated with MDE. The area under the curve of the two-parameter prediction model was 0.86. Thirteen tumors (38%, 95% CI: 24-55%) were identified as low risk for MDE, being potential candidates for reduced-intensity therapy around the GTV. In the low-risk group, the effective diameter of the GTV(CT/PET) accurately represented the CTV(path). In the high-risk group, GTV(CT/PET) underestimated the CTV(path) with, on average, 19.2 and 26.7 mm, respectively. CONCLUSIONS: CT features have potential to predict the presence of MDE. Tumors identified as low risk of MDE show lower rates of disease around the GTV than do high-risk tumors. Both CT and PET accurately visualize the CTV(path) in low-risk tumors but underestimate it in high-risk tumors.

The impact of microscopic disease on the tumor control probability in non-small-cell lung cancer.

PURPOSE: To indicate which clinical target volume (CTV) margin (if any) is needed for an adequate treatment of non-small-cell lung cancer (NSCLC) using either 3D conformal or stereotactic radiotherapy, taking the distribution of the microscopic disease extension (MDE) into account. METHODS AND MATERIALS: On the basis of the linear-quadratic biological model, a Monte-Carlo simulation was used to study the impact of MDE and setup deviations on the tumor control probability (TCP) after typical 3D conformal and stereotactic irradiation techniques. Setup deviations were properly accounted for in the planning target volume (PTV) margin. Previously measured distributions of MDE outside the macroscopic tumor in NSCLC patients were used. The dependence of the TCP on the CTV margins was quantified. RESULTS: The presence of MDE had a demonstratable influence on the TCP in both the 3D conformal and the stereotactic technique when no CTV margins were employed. The impact of MDE on the TCP values was greater in the 3D conformal scenario (67% TCP with MDE; 84% TCP without MDE) than for stereotactic radiotherapy (91% TCP with MDE; 100% TCP without MDE). Accordingly, an increase of the CTV margin had the greatest impact for the 3D conformal technique. Larger setup errors, with appropriate PTV margins, lead to an increase in TCP for both techniques, showing the interdependence of CTV and PTV margins. CONCLUSIONS: MDE may not always be eradicated by the beam penumbra or existing PTV margins using either 3D conformal or stereotactic radiotherapy. Nonetheless, TCP modeling indicates an overall local control rate above 90% for the stereotactic technique, while a non-zero CTV margin is recommended for better local control of MDE when using the 3D conformal technique.

Feasibility of pathology-correlated lung imaging for accurate target definition of lung tumors.

PURPOSE: To accurately define the gross tumor volume (GTV) and clinical target volume (GTV plus microscopic disease spread) for radiotherapy, the pretreatment imaging findings should be correlated with the histopathologic findings. In this pilot study, we investigated the feasibility of pathology-correlated imaging for lung tumors, taking into account lung deformations after surgery. METHODS AND MATERIALS: High-resolution multislice computed tomography (CT) and positron emission tomography (PET) scans were obtained for 5 patients who had non-small-cell lung cancer (NSCLC) before lobectomy. At the pathologic examination, the involved lung lobes were inflated with formalin, sectioned in parallel slices, and photographed, and microscopic sections were obtained. The GTVs were delineated for CT and autocontoured at the 42% PET level, and both were compared with the histopathologic volumes. The CT data were subsequently reformatted in the direction of the macroscopic sections, and the corresponding fiducial points in both images were compared. Hence, the lung deformations were determined to correct the distances of microscopic spread. RESULTS: In 4 of 5 patients, the GTV(CT) was, on average, 4 cm(3) ( approximately 53%) too large. In contrast, for 1 patient (with lymphangitis carcinomatosa), the GTV(CT) was 16 cm(3) ( approximately 40%) too small. The GTV(PET) was too small for the same patient. Regarding deformations, the volume of the well-inflated lung lobes on pathologic examination was still, on average, only 50% of the lobe volume on CT. Consequently, the observed average maximal distance of microscopic spread (5 mm) might, in vivo, be as large as 9 mm. CONCLUSIONS: Our results have shown that pathology-correlated lung imaging is feasible and can be used to improve target definition. Ignoring deformations of the lung might result in underestimation of the microscopic spread.

Small rare-gas clusters in soft x-ray pulses.

We develop a microscopic model for the interaction of small rare-gas clusters with soft x-ray radiation from a free electron laser. It is shown that, while the overall charging of the clusters is rather low, unexpectedly high atomic charge states can arise due to charge imbalances inside the cluster. These findings are explained by an increased absorption via inverse bremsstrahlung due to high intermediate charge states and by a nonhomogenous charge distribution inside the cluster.

Electron release of fare-gas atomic clusters under an intense laser pulse.

Calculating the energy absorption of atomic clusters as a function of the laser pulse length T we find a maximum for a critical T(*). We show that T(*) can be linked to an optimal cluster radius R(*). The existence of this radius can be attributed to the enhanced ionization mechanism originally discovered for diatomic molecules. Our findings indicate that enhanced ionization should be operative for a wide class of rare-gas clusters. From a simple Coulomb-explosion ansatz, we derive an analytical expression relating the maximum energy release to a suitably scaled expansion time which can be expressed with the pulse length T(*).