Study On Defining The Clinical Target Volume On The Basis Of Microscopic Extracapsular Extension Of Regional Metastatic Nodes In Patients With Non-small Cell Lung Cancer

Background Non-small cell lung cancer (NSCLC) is an especially challenging cancer to treat. Local control cannot be achieved in the majority of patients with unresectable NSCLC, even after aggressive chemotherapy and radiotherapy. In a large randomized study, the 1-year local control rate was only 15% for patients with unresectable NSCLC treated at a dose of 65 Gy, and another study suggested that a dose of 84–100 Gy may be needed to sterilize large tumors. Further, higher doses of radiation have been linked to improved local control according to recent studies.Recent technologic advances in radiotherapy, such as the routine clinical use of three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT), have made high-dose radiation feasible in routine clinical practice. The potential dosimetric superiority of 3D-CRT and IMRT offers the advantage of better tumor target coverage and critical normal tissue sparing. However, even with 3D-CRT or IMRT, the dose that can be delivered to the lung is limited by the sensitivity of lung tissue to ionizing radiation.Both the dose and the volume irradiated influence the risk of radiation damage; it has been clearly established that irradiation of a large pulmonary field causes toxic effects. In particular, the treatment outcome of 3D-CRT or IMRT for NSCLC depends, among other things, on knowing the precise mediastinal nodal volumes to be treated. Unfortunately, there is no precise definition of the optimal nodal clinical target volume (CTV) margins and thus no clearly optimal treatment plan. One of the keys to successfully treating nodal disease in patients with NSCLC is to properly delineate the target during computed tomography (CT) imaging. Accurately contouring the gross tumor volume (GTV) and CTV for NSCLC is especially difficult for physicians and has been addressed by several groups of investigators. Currently, no consensus exists regarding the microscopic extent of disease or the CTV margins that should surround gross nodal disease. How far to extend the nodal CTV beyond the nodal GTV is largely empiric and mainly left to the discretion of the physician. The nodal CTV margins around gross disease in patients with NSCLC typically ranges from 0 to 25 mm at various institutions, and whether these arbitrary margins are excessive or inadequate remains uncertain.The delineation of nodal CTV margins in NSCLC must take into account the potential for extracapsular spread (ECS) in mediastinal lymph nodes with metastatic disease because several independent studies have shown that ECS predicts recurrence and poor survival. Therefore, it is important to determine the optimal CTV margins for metastatic lymph nodes at a high risk for ECS. In this histopathologic study, we examined the extent of microscopic ECS to provide insight into the appropriate nodal CTV margins.Objective: To determine the optimal clinical target volume margins around the gross nodal tumor volume in patients with non-small cell lung cancer (NSCLC) by assessing microscopic tumor extension beyond regional lymph node capsules.Methods: The NSCLC database at Shandong Cancer Hospital was searched with institutional review board approval for all NSCLC patients who underwent mediastinal lymphadenectomy between January 2003 and December 2004. The 101 eligible patients whose specimens could be evaluated ranged in age from 31 to 78 years (median, 64 years). A median of two ECS-positive lymph node specimens (range, 1-6 specimens) was examined for each patient. To avoid interobserver variations, the same pathologist (D.M.) assessed the specimens and identified microscopic evidence of ECS. ECS was defined as extension of the tumor through the lymph node capsule (indicated by the finding of actual tumor cells); an associated desmoplastic stromal response; or a giant cell reaction to extracellular keratin extending outside the capsule. A micrometer was used to measure the maximum linear distance from the external capsule border to the farthest extent of the tumor or the tumoral reaction. If relevant points of the capsule were obliterated by tumor, the outer limit of the capsule was extrapolated from the nearest intact portion of the capsule, and the ECS was measured from that reference point. In such cases, it is possible that measurement of the ECS was underestimated. If the entire lymph node or nodal capsule was obliterated by tumor, the specimen was deemed unmeasurable and excluded from the analysis because such cases could represent extralymphatic soft tissue tumor deposits. The largest axial diameter of each lymph node was also measured. Logarithmic regression analysis was used to determine the trend between ECS frequency and distance from the capsule. Spearman's rank correlation was performed to evaluate the relationship between the extent of ECS and lymph node size. One-way analysis of variance was used to compare the extent of ECS between different groups of lymph node size, histological type, and differentiation. P values < 0.05 were considered statistically significant.Results: Among patients identified in the initial screening, 41.6% of patients (101/243) had evidence of ECE seen and measured by the study pathologist (D.M.). In the total 640 metastatic lymph nodes, 214 lymph nodes (33.4%) had evidence of ECE. The mean and median extents of ECE were 2.0 mm and 1.8 mm, respectively (range, 0.05–12.0 mm). There was no statistical significance among different pathological types (F=0.875, P>0.05). However, the difference in the mean extent of ECS between groups divided by nodal differentiation was statistically significant (χ~2=18.010, P<0.05). Taking into account 95% of local microscopic extension, a margin of 5.92mm and 5.00mm must be allowed for squmous cell carcinoma and adenocarcinoma, respectively. Overall, a significant positive correlation was found between extent of ECS and lymph node size (r = 0.645, p < 0.01). The mean extent of ECS in patients with N1 disease was significantly less than that in patients with N2 disease (χ~2=8.524, P<0.05).Conclusion: The extent of ECS appears to be related to lymph node size, regional nodal disease extent, and degree of differentiation. On the basis of the pathologic results of ECS investigation, in the target volume defining for 3DCRT and IMRT, CTV-N needs to consider carefully in the regional metastatic lymph nodes of NSCLC.