Whole Brain Radiation Therapy Plus Stereotactic Radiosurgery in the Treatment of Brain Metastases Leading to Improved Survival in Patients With Favorable Prognostic Factors

Background: Significantly better local control is achieved with combination of whole brain radiotherapy and stereotactic radiosurgery in the treatment of multiple brain metastases. However, no survival benefit was reported from this advantage in local control.Objective: The objective of this study was to review the available evidence whether better local control achieved with whole brain radiotherapy plus stereotactic radiosurgery leads to any benefit in survival in patients with favorable prognostic factors.Methods and Materials: Electronic databases (PubMed, MEDLINE, and Cochrane Library) were searched until Oct 2018 to identify studies published in English that compared efficacy of whole brain radiotherapy plus stereotactic radiosurgery vs. whole brain radiotherapy alone or stereotactic radiosurgery alone in patients with brain metastases stratified on prognostic indices (Recursive Partitioning Analysis and Diagnosis-Specific Graded Prognostic Assessment). Primary outcome was survival.Results: Five studies (n = 2728) were identified, 3 secondary analyses of the previously published RCTs and 2 retrospective studies, meeting the inclusion criteria. whole brain radiotherapy plus stereotactic radiosurgery showed improved survival in brain metastatic cancer patients with better prognostic factors particularly when compared to whole brain radiotherapy only. Its survival advantage over stereotactic radiosurgery only was limited to non-small cell lung cancer primary tumor histology.Conclusions: Whole brain radiotherapy in combination with stereotactic radiosurgery may improve survival and could be recommended selectively in patients with favorable prognostic factors particularly in comparison to whole brain radiotherapy only

Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

BACKGROUND: Hepatocellular carcinoma (HCC) has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. METHODS: Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2(4-sulfophenyl)-2 H-terazolium (MTT) assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM) added 30 min prior to radiation (pre-irradiation sorafenib) of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib) on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. RESULTS: The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9%) than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P < 0.001). Similarly, BEL-7402 cells receiving sorafenib prior to irradiation had significantly fewer cells with γ-H2AX foci (46.4 ± 3.8%) than those receiving radiation alone (25.0 ± 3.0%; P < 0.001). In addition, irradiation (6 Gy) caused a significant increase in the percentage of both SMMC-7721 and BEL-7402 cells in G2/M at 12 to 16 h post irradiation, which was markedly delayed by pre-irradiation sorafenib. CONCLUSIONS: Sorafenib combined with irradiation exerted a schedule-dependent effect in HCC cells in vitro, which has significant implications for the combined use of sorafenib and radiotherapy for HCC patients

ALK Inhibitors in the Treatment of ALK Positive NSCLC

Background: ALK inhibitors have shown positive advance in the treatment of ALK+ NSCLC. They have achieved better results in prolonging the progression free survival and improving quality of life in comparison to chemotherapy. We have assembled the evidence related to the efficacy and safety of these agents in the treatment of ALK positive NSCLC.Materials and Methods: A comprehensive search was conducted using electronic databases of PubMed, Medline and Cochrane Library to identify the studies involving comparison of ALK inhibitors to chemotherapy and Next generation ALK inhibitors to crizotinib. PFS was the primary outcome while other outcomes like ORR, adverse events, quality of life and OS were also analyzed and compared. Hazard ratios and odds ratios obtained were analyzed using fixed effect or random effects model in Review Manager Software.Results: A total of 12 studies (n = 3,297) met the criteria for inclusion in this review and meta-analysis. ALK inhibitors including crizotinib, ceritinib and alectinib revealed significantly better PFS (HR 0.42 [0.35, 0.50; p &lt; 0.00001]), ORR (Overall OR 6.59 [4.86, 8.94; p &lt; 0.00001] as compared to chemotherapy in the first line as well as second line treatment settings. Intracranial response rate was better with ALK inhibitors (ceritinib and alectinib) as compared to chemotherapy OR 6.51 [2.86, 14.83; p &lt; 0.00001]. No significant increase in grade 3 or 4 adverse events was observed with crizotinib (OR 1.21 [0.82, 1.77; p = 0.34]) or ceritinib (OR 1.49 [0.86, 2.57; p = 0.17]) when compared to chemotherapy individually. Quality of life indicators assessed were significantly improved with ALK inhibitors. Next generation agents (ceritinib, alectinib and brigatinib) revealed significant improvement in PFS (HR 0.50 [0.43, 0.57; p &lt; 0.00001]), ORR (OR 1.57 [1.21, 2.04; p = 0.0006]) in comparison to crizotinib. Next generation agents (Alectinib and brigatinib) yielded better response intra-cranially than crizotinib in terms of objective response rate (OR 5.87 [3.49, 9.87; p &lt; 0.00001]) and time to CNS progression (HR 0.25 [0.13, 0.46; p &lt; 0.0001]). Alectinib by far resulted in fewer adverse events than chemotherapy or crizotinib.Conclusions: Overall ALK inhibitors are safe and effective treatment option in ALK+ non-small cell lung cancer. Of the ALK inhibitors, Next generation agents in particular alectinib and brigatinib are safer and more effective intra-cranially and can be preferred as first option

Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells <it>in vitro</it> in a schedule-dependent manner

Abstract Background Hepatocellular carcinoma (HCC) has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. Methods Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2(4-sulfophenyl)-2 H-terazolium (MTT) assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM) added 30 min prior to radiation (pre-irradiation sorafenib) of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib) on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. Results The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9%) than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P  Conclusions Sorafenib combined with irradiation exerted a schedule-dependent effect in HCC cells in vitro, which has significant implications for the combined use of sorafenib and radiotherapy for HCC patients.</p

Indoleamine 2,3-dioxygenase 1 and Programmed Cell Death-ligand 1 Co-expression Predicts Poor Pathologic Response and Recurrence in Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy

This study aimed to investigate the impact of indoleamine 2,3-dioxygenase 1 (IDO1) expression, programmed cell death-ligand 1 (PD-L1) expression, CD8+ tumor-infiltrating lymphocyte (TIL) status, and their combination on pathologic complete response (pCR) and recurrence in esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (CRT). Indoleamine 2,3-dioxygenase 1, PD-L1, and CD8+ TIL statuses were evaluated by immunohistochemical analysis on pre-CRT biopsies of 158 patients. Sixty-eight patients (43.0%) achieved pCR after neoadjuvant CRT and 48 patients (30.4%) developed recurrences after surgery. IDO1 and PD-L1 proteins were co-expressed in 28 patients (17.7%). Indoleamine 2,3-dioxygenase 1 positive patients showed a significantly lower pCR rate than IDO1 negative patients (28.6% vs. 51.0%, P = 0.007). Similarly, PD-L1 high expression was significantly negatively correlated with pCR rate (27.3% vs. 51.5%, P = 0.004). On multivariate analysis, IDO1 expression was an independent prognostic factor for developing recurrences. Stratification analysis revealed that patients with co-expression of IDO1 and PD-L1 were significantly associated with a lower pCR rate and worse recurrence-free survival than those with one or none positive protein. In conclusion, IDO1 and PD-L1 co-expression could predict poor pathologic response and high risk of recurrence in ESCC after neoadjuvant CRT, indicating a subset of patients who may benefit from CRT combined with immunotherapy

Overexpression of amplified in breast cancer 1 (AIB1) gene promotes lung adenocarcinoma aggressiveness in vitro and in vivo by upregulating C-X-C motif chemokine receptor 4

Abstract Background We previously found that overexpression of the gene known as amplified in breast cancer 1 (AIB1) was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. However, the role of AIB1 in that malignancy remains unknown. The present study aimed to investigate the function of AIB1 in the process of lung adenocarcinoma cell metastasis. Methods A series of in vivo and in vitro assays were performed to elucidate the function of AIB1, while real-time PCR and Western blotting were utilized to identify the potential downstream targets of AIB1 in the process of lung adenocarcinoma metastasis. Rescue experiments and in vitro assays were performed to investigate whether the invasiveness of AIB1-induced lung adenocarcinoma was mediated by C-X-C motif chemokine receptor 4 (CXCR4). Results The ectopic overexpression of AIB1 in lung adenocarcinoma cells substantially enhanced cell migration and invasive abilities in vitro and tumor metastasis in vivo, whereas the depletion of AIB1 expression substantially inhibited lung adenocarcinoma cell migration and invasion. CXCR4 was identified as a potential downstream target of AIB1 in lung adenocarcinoma. The knockdown of AIB1 greatly reduced CXCR4 gene expression at both the transcription and protein levels, whereas the knockdown of CXCR4 in cells with AIB1 ectopic overexpression diminished AIB1-induced migration and invasion in vitro and tumor metastasis in vivo. Furthermore, we found a significant positive association between the expression of AIB1 and CXCR4 in lung adenocarcinoma patients (183 cases), and the co-overexpression of AIB1 and CXCR4 predicted the poorest prognosis. Conclusions These findings suggest that AIB1 promotes the aggressiveness of lung adenocarcinoma in vitro and in vivo by upregulating CXCR4 and that it might be usable as a novel prognostic marker and/or therapeutic target for this disease