Meng-Zhong Liu

Randomized controlled trials have failed to report any survival advantage for WBRT combined with SRS in the management of brain metastases, despite the enhanced local and distant control in comparison to each treatment alone. Literature review have revealed important role of primary histology of the tumor when dealing with brain metastases. NSCLC responds better to combined approach even when there was only single brain metastasis present while breast cancer has registered better survival with SRS alone probably due to better response of primary tumor to advancement in surgical and chemotherapeutic agents. Furthermore, mutation status (EGFR/ALK) in lung cancer and receptor status (ER/PR/HER2) in breast cancer also exhibit diversity in their response to radiotherapy. Radioresistant tumors like renal cell carcinoma and melanoma brain metastases have achieved better results when treated with SRS alone. Secondly, single brain metastasis may benefit from local and distant brain control achieved with combined treatment. These diverse outcomes suggest a primary histology-based analysis of the radiotherapy regimens (WBRT, SRS, or their combination) would more ideally establish the role of radiotherapy in the management of brain metastases. Molecularly targeted therapeutic and immunotherapeutic agents have revealed synergism with radiation therapy particularly SRS in treating cancer patients with brain metastases. Clinical updates in this regard have also been reviewed.

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.

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 < 0.00001]), ORR (Overall OR 6.59 [4.86, 8.94; p < 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 < 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 < 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 < 0.00001]) and time to CNS progression (HR 0.25 [0.13, 0.46; p < 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.

Recently, immune checkpoint inhibitors have shown survival advantage over chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). This meta-analysis was conducted to gather and analyze the available evidence (Evidence level I; Randomized Controlled Trials) comparing efficacy and safety of anti-programmed cell death-1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies and chemotherapy in the treatment of advanced NSCLC. A search strategy was devised to identify the randomized controlled trials (RCTs) using electronic databases of PubMed, Cochrane Library, and Web of Science. Hazard ratios or odds ratios obtained for overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment related adverse events (TRAEs) were analyzed using fixed effect model or random effects model. Additionally, subgroup analysis was also performed. A total of seven RCTs (n = 3867) were identified and selected for inclusion in this meta-analysis. Anti-PD1/PD-L1 therapies (nivolumab, pembrolizumab, atezolizumab) resulted in better OS (HR 0.72 [95% confidence interval [CI] 0.63, 0.82; P < .00001]), PFS (HR 0.84 [95% CI 0.72, 0.97; P < .02]), and ORR (odds ratio [OR] 1.52 [95% CI 1.08, 2.14; P < .02]) in comparison to chemotherapy in advanced NSCLC. Improved safety was observed with anti-PD1/PD-L1 therapies (OR 0.31 [95%CI 0.26, 0.38; P < .00001]). Subgroups analysis revealed Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (HR 0.76 [95%CI 0.62, 0.93; P = .007]), squamous cell type (HR 0.76 [95% CI 0.63, 0.92; P = .005]), current/former smoker (HR 0.76 [95% CI 0.63, 0.92; P = .005]), epidermal growth factor receptor (EGFR) wild type (HR 0.67 [95% CI 0.60, 0.76; P < .00001]), Kirsten rat sarcoma oncogene mutation (KRAS) mutant (HR 0.60 [95% CI 0.39, 0.93; P < .02]), and absence of central nervous system (CNS) metastases (HR 0.71 [95% CI 0.63, 0.80; P < .00001]) were associated with better overall survival. Anti-PD1/PD-L1 therapies are safe and effective treatment option in advanced non-small cell lung cancer and can be recommended selectively.

To analyze the failure pattern and clinical efficacy of elective nodal irradiation in patients with esophageal squamous cell carcinoma who received neoadjuvant chemoradiotherapy. We retrospectively analyzed 173 esophageal squamous cell carcinoma patients who received neoadjuvant chemoradiotherapy including elective nodal irradiation from 2002 to 2015. Failure pattern, survival and recurrence sites were analyzed. For patients with regional recurrences, the recurrence sites were analyzed in relation to an imaginary field of involved field irradiation. After a median follow-up of 55.5 months, 58 patients (33.5%) developed recurrences. Among 22 patients with regional recurrences, infield failure occurred in 19 patients (86.4%) and outfield failure occurred in 3 patients (13.6%), of whom only 1 patient had an outfield failure without synchronous distant metastasis. Compared with the involved field irradiation field, 6 patients’ failure sites (27.3%) were located in the involved field irradiation field and 13 patients’ failure sites (59.1%) were out of the involved field irradiation field but within the elective nodal irradiation field. Since only a minority of patients had outfield regional recurrences, neoadjuvant chemoradiotherapy with elective nodal irradiation yields satisfactory infield control. More than half of the regional recurrences occurred within the elective nodal irradiation field but out of the involved field irradiation field. Prospective evaluation of whether elective nodal irradiation could lead to an improved survival outcome is necessary.

Stereotactic radiosurgery provides effective local control, but high recurrence rate are observed while ipilimumab have shown promising improvements in survival in the treatment of melanoma brain metastases. This meta-analysis was done to review the clinical evidence regarding the combination of stereotactic radiosurgery and ipilimumab in the treatment of brain metastases from melanoma. Comprehensive research of the electronic databases (PubMed and Cochrane Library) was carried out in April 2017. Different combination of MESH headings and words were used. Review Manager was used to analyze the outcome data of interest. According to heterogeneity, fixed effects model or random effects model was adapted. Six retrospective studies comparing stereotactic radiosurgery plus ipilimumab with stereotactic radiosurgery alone were found. Total of 411 participants were included in this meta-analysis. Of that, 128 patients had received stereotactic radiosurgery + ipilimumab, while 283 patients had received stereotactic radiosurgery only. Stereotactic radiosurgery plus ipilimumab significantly improved survival when compared to stereotactic radiosurgery alone (hazard ratio: 0.74 [95% confidence interval: 0.56-0.99, P = .04]), with no significant increase in the incidence of adverse events (odds ratio 0.57 [95% confidence interval: 0.28-1.17, P = .12]). Stereotactic radiosurgery with ipilimumab is safe and effective treatment option and can be recommended for the treatment of brain metastases in patients with melanoma.

Purpose: To compare the clinical outcomes of induction chemotherapy (IC) followed by chemoradiotherapy (CRT) versus chemoradiotherapy alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC).

The optimal concurrent chemotherapy regimen with radiotherapy for esophageal cancer is unknown. Here, we compared the survival outcomes and toxicity of definitive chemoradiotherapy with either cisplatin/5-fluorouracil (PF) or docetaxel/cisplatin (DP) in patients with unresectable esophageal squamous cell carcinoma (ESCC). In this study, we identified 317 patients with ESCC who received PF or DP concurrently with definitive radiotherapy. PF group patients received two cycles of cisplatin (60 mg/m2) and 5-fluorouracil (300 mg/m2) at 4-week intervals during radiotherapy. DP group patients received a concurrent three-weekly schedule of docetaxel (60 mg/m2) and cisplatin (80 mg/m2) or cisplatin (25 mg/m2) and docetaxel (25 mg/m2) weekly. The overall survival (OS) and progression-free survival (PFS) were compared using propensity score (–adjusted, –weighted, –stratified, and –matched) analyses. A sensitivity analysis was performed to examine the impact of unmeasured confounders. Inverse probability of treatment weighting for propensity score demonstrated an improvement in OS and PFS with DP group in comparison with PF group (hazard ratio, 0.700; 95% CI, 0.577-0.851) and similar results were achieved with propensity score matching and stratification. Grade 3-4 esophagitis was more common (16/102 vs. 4/102) and grade 3-4 thrombopenia and skin toxicity were less common (3/102 vs. 10/102; 7/102 vs. 19/102; respectively) in the PF group than the DP group. In conclusion, concurrent chemoradiotherapy with the DP regimen resulted in better OS and PFS compared to concurrent PF regimen with tolerable toxicities in ESCC patients. Prospective randomized trials are required to confirm the efficacy of the DP regimen.

Insulin-like growth factor binding protein-3 (IGFBP-3) plays an essential role in radiosensitivity of esophageal squamous cell carcinoma (ESCC). However, the underlying mechanism is not completely understood. Here, we observed that IGFBP-3 had favorable impact on the tumorigenicity of ESCC cells in nude mice by using an in vivo imaging system (IVIS) to monitor tumor growth treated with ionizing radiation (IR). Downregulation of IGFBP-3 expression enhanced tumor growth, inhibited anti-proliferative and apoptotic activity and result in IR resistance in vivo. Cell cycle antibody array suggested that silencing IGFBP-3 promoted transition from G0/G1 to S phase, perhaps though influencing Smad3 dephosphorylation and retinoblastoma protein (Rb) phosphorylation. Downregulation of P21 and P27 and upregulation of p-P27 (phospho-Thr187), cyclin-dependent kinase 2 (CDK2) and cyclin E1 might contribute to the G0/G1 to S phase transition promoted by IGFBP-3. Our results suggest that Smad3-P27/P21-cyclin E1/CDK2-phosphorylated retinoblastoma protein pathways might be involved in this IGFBP-3 mediated radiosensitivity transition in ESCC.

Insulin-like growth factor-binding protein-3 (IGFBP-3) is suggested to predict the radiosensitivity and/or prognosis of patients with esophageal squamous cell carcinoma (ESCC). The present study was designed to investigate the clinical and prognostic effects of IGFBP-3 on ESCC. IGFBP-3 was detected by immunohistochemistry in paraffin-embedded tissues from 70 ESCC patients treated with radiotherapy alone and further examined by western blotting analysis in 10 pairs of fresh ESCC tissues and adjacent non-malignant esophageal specimens. Receiver operating characteristic (ROC) analysis was used to determine cut-off scores for tumor positivity and to evaluate patient survival status. The χ2 test was performed to analyze the association of IGFBP-3 expression with clinical characteristics and radiotherapy response. Associations between prognostic outcomes and IGFBP-3 expression were investigated using Kaplan–Meier analysis and the Cox proportional hazards model. The threshold for IGFBP-3 positivity was set to greater than 65% [area under the ROC curve (AUC) = 0.690, P < 0.019]. Of the 70 ESCC patient tissues tested, 32 (45.7%) were defined as having high IGFBP-3 expression. The levels of IGFBP-3 protein expression were decreased in 70.0% (7 of 10) of ESCC tissues compared with adjacent non-malignant esophageal tissue. In addition, IGFBP-3 expression was associated with pathologic classification (P < 0.05 for T, N, and M categories and clinical stage). Patients with elevated protein level of IGFBP-3 in the tumor had an improved radiotherapy response and prolonged overall survival (P < 0.001). High level of IGFBP-3 expression in ESCC associates with early clinical stages and are predictive for favorable survival of the patients treated with radiotherapy.