PD-1 and PD-L1 as immunotherapy targets and biomarkers in non-small cell lung cancer.

The integration of immunotherapeutic agents in the treatment of non-small cell lung cancer (NSCLC) has revolutionized the approach of the prevalent type of lung cancer. Although PD-1 and its ligands (PD-L1 and PD-L2) are stimulating molecules of the immune-checkpoint pathway, with primary function to limit inflammatory response and autoimmunity, tumor cells have found a way to exploit these molecules by obtaining the opportunity to respond with PD-L1 expression in cytokine signals and thus to evade immune surveillance. Several immunotherapeutic agents targeting these molecules have already been tested and show quick and remarkable responses and survival prolongation in about 14-20% of chemo-resistant patients in NSCLC, resulting to FDA approval of some PD-1 inhibitors (pebrolizumab, nivolumab), even for first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (pebrolizumab). Regarding to the prognostic value of PD-L1 and PD-1 expression as biomarkers in NSCLC, the results still remain contradictory. However, the elevated expression of PD-L1 has been correlated with higher efficacy of the various immunotherapeutic agents, implying a high predictive value of this biomarker, even if the truth about specificity and sensitivity of the aforementioned molecules is generally more complicated.

On the use of published radiobiological parameters and the evaluation of NTCP models regarding lung pneumonitis in clinical breast radiotherapy.

In this study we sought to evaluate and accent the importance of radiobiological parameter selection and implementation to the normal tissue complication probability (NTCP) models. The relative seriality (RS) and the Lyman-Kutcher-Burman (LKB) models were studied. For each model, a minimum and maximum set of radiobiological parameter sets was selected from the overall published sets applied in literature and a theoretical mean parameter set was computed. In order to investigate the potential model weaknesses in NTCP estimation and to point out the correct use of model parameters, these sets were used as input to the RS and the LKB model, estimating radiation induced complications for a group of 36 breast cancer patients treated with radiotherapy. The clinical endpoint examined was Radiation Pneumonitis. Each model was represented by a certain dose-response range when the selected parameter sets were applied. Comparing the models with their ranges, a large area of coincidence was revealed. If the parameter uncertainties (standard deviation) are included in the models, their area of coincidence might be enlarged, constraining even greater their predictive ability. The selection of the proper radiobiological parameter set for a given clinical endpoint is crucial. Published parameter values are not definite but should be accompanied by uncertainties, and one should be very careful when applying them to the NTCP models. Correct selection and proper implementation of published parameters provides a quite accurate fit of the NTCP models to the considered endpoint.

Hypofractionated radiotherapy for breast cancer patients treated by breast-conserving surgery: short-term morbidity and preliminary results.

BACKGROUND: Hypofractionated adjuvant radiotherapy (RT) in breast cancer patients treated by conservative surgery has been increasingly used in recent years. We present our experience regarding tolerance/acute toxicity of a hypofractionated RT schedule. METHODS AND MATERIALS: We report on 339 patients treated for 4 years (March 2003-2007) by 42.5 Gy/16 fractions at the RT Department of Larissa University Hospital. Electron boost of 9-10 Gy/3-4 fractions was given to 104/339 (31%). Axillary/supraclavicular RT was given to the node-positive patients with the same fractionation schedule. Median follow-up time was 24 months. RESULTS: RTOG grades 0, 1, 2, 3, and 4 for acute skin toxicity were 9.7, 68.7, 17.5, 4, and 0.3%, respectively. Radiation pneumonitis (resolved promptly by steroids) was suspected/diagnosed in 11/339 (3.2%). A total of 8/11 had been treated by regional lymphatics RT. In the univariate analysis, the following variables were examined as predictive of skin (grade >1) and lung (any grade) reactions: age, chemotherapy, endocrine treatment, RT of regional lymphatics, and boost RT. The only significant correlation was that of radiation pneumonitis and RT of regional lymphatics (Fisher's exact test, P = 0.000). CONCLUSION: Our current results are similar to those from other centers, although they need to be evaluated for a longer time. This fractionation seems to be effective with acceptable side effects, while it facilitates the treatment for both patients and RT centers.