Antitumor enhancement of celecoxib, a selective Cyclooxygenase-2 inhibitor, in a Lewis lung carcinoma expressing Cyclooxygenase-2

<p>Abstract</p> <p>Background</p> <p>The goal of this study was to determine the effects of a selective Cyclooxygenase (COX)-2 inhibitor on the inhibition of tumor growth and pulmonary metastasis in a Lewis Lung Carcinoma (LLC) animal model.</p> <p>Methods</p> <p>For immunoblot analysis of COX-2 and PGE2, cells were treated with irradiation in the presence or absence of celecoxib. The right thighs of male, 6-week old C57/BL mice were subcutaneously injected with 1 × 10⁶LLC cells. The animals were randomized into one of six groups: (1) no treatment, (2) 25 mg/kg celecoxib daily, (3) 75 mg/kg celecoxib daily, (4) 10 Gy irradiation, (5) 10 Gy irradiation plus 25 mg/kg celecoxib daily, and (6) 10 Gy irradiation plus 75 mg/kg celecoxib daily. Mice were irradiated only once, and celecoxib was administered orally. Mice were irradiated with 4-MV photons once the tumor volume of the control group reached 500 mm³. All mice were sacrificed when the mean tumor volume of control animals grew to 4000 mm³. The left lobes of the lungs were extracted for the measurement of metastatic nodules.</p> <p>Results</p> <p>Irradiation resulted in a dose-dependent increase in PGE2 production. PGE2 synthesis decreased markedly after treatment with celecoxib alone or in combination with irradiation. Compared to mice treated with low dose celecoxib, mean tumor volume decreased significantly in mice treated with a high dose of celecoxib with or without irradiation. Mice treated with a high dose celecoxib alone, with irradiation alone, or with irradiation plus celecoxib had markedly fewer metastatic lung nodules than controls. The mean metastatic area was the smallest for mice treated with irradiation plus a high dose celecoxib.</p> <p>Conclusion</p> <p>Oral administration of high dose celecoxib significantly inhibited tumor growth, as compared to a low dose treatment. Radiotherapy in combination with high dose celecoxib delayed tumor growth and reduced the number of pulmonary metastases to a greater extent than celecoxib or radiotherapy alone.</p

Reduced radiation exposure to circulating blood cells in proton therapy compared with X-ray therapy in locally advanced lung cancer: Computational simulation based on circulating blood cells

BackgroundWe estimated the dose of circulating blood cells (CBCs) in patients with locally advanced non-small cell lung cancer for predicting severe radiation-induced lymphopenia (SRIL) and compared pencil-beam scanning proton therapy (PBSPT) and intensity-modulated (photon) radiotherapy (IMRT).Materials and methodsAfter reviewing 325 patients who received definitive chemoradiotherapy with PBSPT (n = 37) or IMRT (n = 164). SRIL was diagnosed when two or more events of an absolute lymphocyte count &lt; 200 µL occurred during the treatment course. Dose information for the heart and lungs was utilized for the time-dependent computational dose calculation of CBCs.ResultsThe dose distribution of CBCs was significantly lesser in the PBSPT group than that in the IMRT group. Overall, 75 (37.3%) patients experienced SRIL during the treatment course; 72 and 3 patients were treated with IMRT and PBSPT, respectively. SRIL was associated with poor progression-free and overall survival outcomes. Upon incorporating the dose information of CBCs for predicting SRIL, CBC D90% &gt; 2.6 GyE was associated with the development of SRIL with the baseline lymphocyte count and target volume. Furthermore, PBSPT significantly reduced the dose of CBC D90% (odds ratio = 0.11; p = 0.004) compared with IMRT.ConclusionThe results of this study demonstrate the significance of the dose distribution of CBCs in predicting SRIL. Furthermore, reducing the dose of CBCs after PBSPT minimized the risk of SRIL. Lymphocyte-sparing radiotherapy in PBSPT could improve outcomes, particularly in the setting of maintenance immunotherapy

TREATMENT-RELATED PNEUMONITIS AND ACUTE ESOPHAGITIS IN NON-SMALL-CELL LUNG CANCER PATIENTS TREATED WITH CHEMOTHERAPY AND HELICAL TOMOTHERAPY: IN REGARD TO SONG ET AL. REPLY

SONG CH, 2010, INT J RAD ONCOL 0305

Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated

Abstract Purpose Inhibitors of epidermal growth factor receptor (EGFR) have shown dramatic results in a subset of patients with non-small cell lung cancer (NSCLC), and have also been shown to enhance the effect of ionizing radiation (IR). We investigated how gefitinib, an orally given EGFR inhibitor for NSCLC patients, can radiosensitize NSCLC cells. Experimental Design and Results In clonogenic survival assays performed in three NSCLC cell lines, gefitinib radiosensitized NCI-H460 and VMRC-LCD but not A549 cells. Gefitinib pretreatment induced multinucleated cells after IR exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. Gefitinib also inhibited activation of ataxia telangiectasia mutated (ATM) after IR-exposure in NCI-H460 and VMRC-LCD, but not in A549 cells. An ATM specific inhibitor increased IR-induced multinucleated cells in both NCI-H460 and A549 cells. Gefitinib pretreatment inhibited the gradual decrease of γH2AX foci relative to time after IR exposure in NCI-H460 but not in A549 cells. Suppression of COX-2 in A549 cells induced multinucleated cells and caused radiosensitization after gefitinib+IR treatment. In contrast, COX-2 overexpression in NCI-H460 cells attenuated the induction of multinucleation and radiosensitization after the same treatment. Conclusions Our results suggest that gefitinib radiosensitizes NSCLC cells by inhibiting ATM activity and therefore inducing mitotic cell death, and that COX-2 overexpression in NSCLC cells inhibits this action of gefitinib.</p

Hypofractionated Three-Dimensional Conformal Radiation Therapy Alone for Centrally Located cT1-3N0 Non–Small-Cell Lung Cancer

PurposeWe retrospectively analyzed the treatment outcomes and toxicities by hypofractionated three-dimensional conformal radiation therapy (RT) alone in the patients with centrally located cT1-3N0 non–small-cell lung cancer (NSCLC).MethodsSixty patients with centrally located cT1-3N0 NSCLC received definitive RT alone at 3.0 Gy per fraction for either medical comorbidity or refusal of surgery, between January 2001 and December 2010. The central tumor was defined as being within 2 cm around the proximal bronchial tree. The median total dose was 60 (39–60) Gy.ResultsThe local control (LC), overall survival (OS), and cause-specific survival rates at 2 and 5 years were 57.9%, 59.6%, 61.7%, and 50.1%, 33.5%, and 40.5%, respectively. Multivariate analyses showed that high cT stage (p = 0.007) and histology with NSCLC-not otherwise specified (p = 0.008) were the significantly unfavorable prognostic factors for OS, and that high cT stage (p = 0.031) and poor performance state (p = 0.007) were for LC. The LC rate at 2 years was 100% for cT1 tumor, 56.5% for cT2 tumor, and 28.6% for cT3 tumor, respectively. No patients experienced grade 3 or higher esophagitis, and three experienced grade 3 or higher pneumonitis.ConclusionHypofractionated RT regimen for centrally located cT1-3N0 NSCLC proved safe with minimal toxicity, and, based on the excellent clinical outcomes in cT1 tumors, might serve as an alternative option for the patients who might not tolerate stereotactic body radiation therapy. As the clinical outcomes in cT2-3 tumors were still unsatisfactory, further dose intensifying regimen coupled with the use of concurrent systemic chemotherapy might be warranted

Clinical Outcomes Following Proton and Photon Stereotactic Body Radiation Therapy for Early-Stage Lung Cancer

We aimed to report the clinical outcomes following stereotactic body radiation therapy (SBRT) using photon or proton equipment in early-stage lung cancer. We retrospectively reviewed 202 cT1-2N0M0 lung cancer patients who underwent SBRT with 60 Gy in four consecutive fractions between 2010 and 2019 at our institution: 168 photon SBRT and 34 proton SBRT. Patients who underwent proton SBRT had relatively poor baseline lung condition compared to those who underwent photon SBRT. Clinical outcomes were comparable between treatment modalities: 5-year local control (90.8% vs. 83.6%, p = 0.602); progression-free survival (61.6% vs. 57.8%, p = 0.370); overall survival (51.7% vs. 51.9%, p = 0.475); and cause-specific survival (70.3% vs. 62.6%, p = 0.618). There was no statistically significant difference in grade &ge; 2 toxicities: radiation pneumonitis (19.6% vs. 26.4%, p = 0.371); musculoskeletal (13.7% vs. 5.9%, p = 0.264); and skin (3.6% vs. 0.0%, p = 0.604). In the binary logistic regression analysis of grade &ge;3 radiation pneumonitis, poor performance status and poor baseline diffusion capacity of lung for carbon monoxide were significant. To summarize, though patients with high risk of developing lung toxicity underwent proton SBRT more frequently, the SBRT techniques resulted in comparable oncologic outcomes with similar toxicity profiles. Proton SBRT could be considered for patients at high risk of radiation pneumonitis

Prospective Study of Proton Therapy for Lung Cancer Patients with Poor Lung Function or Pulmonary Fibrosis

PBT has a unique depth–dose curve with a Bragg peak that enables one to reduce the dose to normal lung tissue. We prospectively enrolled 54 patients with non-small cell lung cancer treated with definitive PBT. The inclusion criteria were forced expiratory volume in 1 s (FEV1) ≤ 1.0 L or FEV1 ≤ 50% of predicted or diffusing capacity of the lungs for carbon monoxide (DLco) ≤ 50%, or pulmonary fibrosis. The primary endpoint was grade ≥ 3 pulmonary toxicity, and secondary endpoints were changes in pulmonary function and quality of life. The median age was 71.5 years (range, 57–87). Fifteen (27.8%) and fourteen (25.9%) patients had IPF and combined pulmonary fibrosis and emphysema, respectively. The median predicted forced vital capacity (FVC), FEV1, and DLco were 77% (range, 42–104%), 66% (range, 31–117%), and 46% (range, 23–94%), respectively. During the follow-up (median, 14.7 months), seven (13.0%) patients experienced grade ≥ 3 pulmonary toxicity. Seven months after the completion of PBT, patients with IPF or non-IPF interstitial lung disease (ILD) experienced a decrease in the FVC but the decrease in DLco was not significant. Under careful monitoring by pulmonologists, PBT could be a useful treatment modality for lung cancer patients with poor lung function or pulmonary fibrosis

Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X-ray and proton therapy

Abstract Background Idiopathic pulmonary fibrosis (IPF) is associated with fatal complications after radiotherapy (RT) for lung cancer patients; however, the role of proton therapy to reduce the incidence of life-threatening complications is unclear. Herein, we present the preliminary results of early-stage lung cancer patients having IPF and treated with RT, with a focus on the comparison between X-ray and proton therapy. Methods From January 2010 to October 2017, we retrospectively reviewed the medical records of 264 patients with stage I-II non-small cell lung cancer (NSCLC) treated with definitive RT alone. Ultimately, 30 patients (11.4%) who had underlying IPF were analyzed. Among these, X-ray and proton RT were delivered to 22 and 8 patients, respectively. Treatment-related complications and survival outcomes were compared between X-ray and proton therapy. Results The median follow-up duration was 11 months (range, 2 to 51 months). All living patients were followed-up at least 9 months. Treatment-related death occurred in four patients (18.2%) treated with X-ray but none with proton therapy. Most patients died within one month after the onset of pulmonary symptoms in spite of aggressive treatment. In addition, the 1-year overall survival (OS) rate in patients treated with X-ray and proton was 46.4 and 66.7%, respectively, and patients treated with proton therapy showed a tendency of better survival compared to X-ray (p = 0.081). Especially, in GAP stage II and III subgroups, patients treated with proton therapy showed significantly increased survival outcomes compared to X-ray (1-year OS rate; 50.0% versus 26.4%, p = 0.036) in univariate analysis. Conclusions RT is associated with serious treatment-related complications in patients with IPF. Proton therapy may be helpful to reduce these acute and fatal complications. Trial registration retrospectively registered