Lawrence B. Marks

Background: To evaluate the effect of diabetes mellitus (DM) on clinical outcomes in patients managed surgically for non-small cell lung cancer (NSCLC). Methods: Patients who underwent surgery for pathological I-IIIA NSCLC at Duke University from 1995–2005 were analyzed. Postoperative mortality was defined as any death occurring within 30 days of resection or during the initial hospitalization after surgery. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered a local/regional recurrence (LRR). Survival and LRR rates were estimated using the Kaplan-Meier method and compared using a log rank test. A multivariate regression analysis assessed the association between candidate factors, including DM, and disease recurrence and survival. Results: Of 957 patients, DM was present in 122 (13%). DM was associated with an increased risk of postoperative mortality (7.4% vs. 3.2%, P= 0.04). However, the proportion of patients undergoing sublobar resections, mediastinal lymph node dissection, and receiving adjuvant chemotherapy, was no different among patients with or without DM. Five-year LRR rates were 27% in patients with DM, versus 21% in patients without DM (P= 0.23). Survival at five years was 43% for patients with DM, and 47% for patients without DM (P= 0.10). On multivariate analysis, DM was not independently associated with a higher risk of LRR (hazard ratio [HR] 1.33, P= 0.34), distant recurrence (HR 0.86, P= 0.58), or overall survival (HR 1.08, P= 0.63). Conclusions: Although a higher risk of postoperative mortality was noted in patients with DM, a detriment in local or distant disease control or overall survival was not observed.

Radiation therapy (RT) is an important treatment modality for multiple thoracic malignancies. Incidental irradiation of the lungs, which are particularly susceptible to injury, is unavoidable and often dose-limiting. The most radiosensitive subunit of the lung is the alveolar/capillary complex, and RT-induced lung injury is often described as diffuse alveolar damage. Reactive oxygen species generated by RT are directly toxic to parenchymal cells and initiate a cascade of molecular events that alter the cytokine milieu of the microenvironment, creating a self-sustaining cycle of inflammation and chronic oxidative stress. Replacement of normal lung parenchyma by fibrosis is the culminating event. Depending on the dose and volume of lung irradiated, acute radiation pneumonitis may develop, characterized by dry cough and dyspnea. Fibrosis of the lung, which can also cause dyspnea, is the late complication. Imaging studies and pulmonary function tests can be used to quantify the extent of lung injury. While strict dose-volume constraints to minimize the risk of injury are difficult to impose, substantial data support some general guidelines. New modalities such as intensity-modulated radiation therapy and stereotactic body radiation therapy provide new treatment options but also pose new challenges in safely delivering thoracic RT.

A dose-volume based tool for evaluating and ranking IMRT treatment plans

A novel iterative penalized likelihood algorithm with evolutionary components for the optimization of beamlet fluences for intensity modulated radiation therapy (IMRT) is presented. This algorithm is designed to be flexible in terms of the objective function and automatically escalates dose, as long as the objective function increases and all constraints are met. For this study, the objective function employed was the product of target equivalent uniform dose (EUD) and fraction of target tissue within set homogeneity constraints. The likelihood component of the algorithm iteratively attempts to minimize the mean squared error between a homogeneous dose prescription and the actual target dose distribution. The updated beamlet fluences are then adjusted via a quadratic penalty function that is based on the dose-volume histogram (DVH) constraints of the organs at risk. The evolutionary components were included to prevent the algorithm from converging to a local maximum. The algorithm was applied to a prostate cancer dataset, with especially difficult DVH constraints on bladder, rectum, and femoral heads. Dose distributions were generated for manually selected sets of three-, four-, five-, and seven-field treatment plans. Additionally, a global search was performed to find the optimal orientations for an axial three-beam plan. The results from this optimal orientation set were compared to results for manually selected orientation (gantry angle) sets of 3- (0 degrees, 90 degrees, 270 degrees), 4- (0 degrees, 90 degrees, 180 degrees, 270 degrees), 5- (0 degrees, 50 degrees, 130 degrees, 230 degrees, 310 degrees), and 7- (0 degrees, 40 degrees, 90 degrees, 140 degrees, 230 degrees, 270 degrees, 320 degrees) field axial treatment plans. For all the plans generated, all DVH constraints were met and average optimization computation time was approximately 30 seconds. For the manually selected orientations, the algorithm was successful in providing a relatively homogeneous target dose distribution, while simultaneously satisfying dose-volume limits by diverting dose away from proximal critical structures. The global search for an optimal three-beam orientation set yielded gantry angles of 70 degrees, 170 degrees, and 320 degrees. The EUD for this orientation set was 58 Gy, with 96% of the target within the set upper and lower limits. In comparison, optimized EUDs for the manually selected orientation sets of three, four, five and seven beams were 52.3, 52.6, 56.9, and 61.3 Gy, respectively. The orientation optimized three-beam plan yielded higher EUDs than the manually selected three-, four-, and five-beam plans, but lower EUDs than the seven-beam plan. In conclusion, a novel penalized likelihood algorithm with evolutionary components has successfully been implemented to optimize beamlet fluences for IMRT. Initial results are promising for dose conformity and uniformity of dose to target. When combined with optimal beam orientation selection for prostate cancer treatment planning, the results indicate that plans with a small number of optimized beam orientations achieve results comparable to those with a larger number of conventionally oriented beams.