Hong Qing Zhuang

Radiosensitizing effects of gefitinib at different administration times in vitro.

The optimal administration time for applying epidermal growth factor receptor inhibitors combined with radiotherapy has been unclear. We investigated the efficacy of combining gefitinib with radiation in different treatment schedules. We demonstrated that gefitinib was administered to A549 lung cancer cells in three ways (administration before irradiation, administration upon irradiation, administration after irradiation) to establish the radiosensitizing effect. Cell‐survival rates were evaluated by colony‐forming assays. Cell apoptosis and cell‐cycle distribution were investigated using flow cytometry; meanwhile, the expression of P21, Cdc25c, Bcl‐2, Bax, Rad51 and phosphorylated DNA‐PKcs (phospho‐DNA‐PK) after 6 Gy irradiation and/or gefitinib were determined by Western blot analysis. The sensitizer enhancement ratios of the gefitinib administration before irradiation, administration upon irradiation, and administration after irradiation groups were 2.23, 1.51 and 1.30, respectively. A higher apoptosis rate and G2/M phase arrest were observed in cells at 48 h after exposure to 6 Gy irradiation when gefitinib was administrated before irradiation. Increased cell apoptosis and cell cycle arrest were further supported by the expression changes of Bcl‐2, Bax, P21, Cdc25c, Rad51 and phospho‐DNA‐PK at the same time. The best radiosensitizing effect was obtained when gefitinib was delivered before irradiation. Apoptosis might be an important way of cell killing and G2/M phase arrest might be an important mechanism of apoptosis. The expression proportion changes of P21/Cdc25c proteins may play an important role in G2/M cell cycle arrest. Moreover, the pro‐apoptotic/antiapoptotic and DNA repair factors may be important modulators taking part in the molecular events of the radiosensitizing effect of gefitinib combined with irradiation. (Cancer Sci 2009)

Stereotactic body radiation therapy using the CyberKnife(®) system for patients with liver metastases.

The aim of this study was to evaluate the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in the treatment of patients with liver metastases. Between August 2006 and July 2011, patients with 1–4 liver metastases were enrolled and treated with SBRT using the CyberKnife® system at Tianjin Medical University Cancer Institute and Hospital. The metastases were from different primary tumors, with a maximum tumor diameter of less than 6 cm. The primary endpoint was local control. Secondary endpoints were overall survival, progression-free survival, distant progression-free survival, and adverse events. Fifty-seven patients with 80 lesions were treated with SBRT. The 1-year and 2-year local control rates were 94.4% and 89.7%, respectively. The difference in local control between patients who received adjuvant treatment before SBRT and those who did not reached statistical significance (P=0.049). The median overall survival for the entire cohort was 37.5 months. According to the primary tumor sites, the median overall survival was not reached. The 2-year overall survival rate was 72.2% in the favorable group (primary tumors originating from the colon, breast, or stomach, as well as sarcomas); however, in the unfavorable group (primary tumors originating from the pancreas, lung, ovary, gallbladder, uterus, hepatocellular carcinoma, as well as olfactory neuroblastoma), the median overall survival and 2-year overall survival rates were 37.5 months and 55.9%, respectively (P=0.0001). Grade 1–2 fatigue, nausea, and vomiting were the most common adverse events, and no grade 3 and higher adverse events were observed. With excellent local control in the absence of severe toxicity, SBRT provides an alternative for patients with 1–4 liver metastases who cannot undergo surgery or other treatments.

Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump

Background and aim The aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Patients and methods Between October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0. Results Twenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2 months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8 days (range, 1–14 days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1–2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia. Conclusion SBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely.

A comparison between cyberknife and neurosurgery in solitary brain metastases from non-small cell lung cancer

PURPOSEnTo evaluate the efficacy of cyberknife (CK) and neurosurgery (NS) in patients newly diagnosed as solitary brain metastasis (SBM) from non-small cell lung cancer (NSCLC).nnnMETHODS AND MATERIALSnWe retrospectively analyzed 76 patients between 1990 and 2012 from our institution, including 38 patients performing CK and the other half performing NS. The observation end point was overall survival time (OS), local control of treated metastasis (LC) and intracranial control (IC). Kaplan-Meier OS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LC and IC.nnnRESULTSnThe baseline characteristic between the two groups was not significantly different. The 1-year OS rates were 53.5% and 30.5% in the CK group and NS group, respectively, (p=0.121). The 1-year LC rates were 50.8% and 31.3%, respectively, (p=0.078). The 1-year IC rates were 50.8% and 27.7%, respectively, (p=0.066). In multivariate analysis, improved OS was significantly associated with younger age (p=0.016), better ECOG performance status (p=0.000) and graded prognostic assessment (GPA, 3.5-4.0, p=0.006). The LC was also associated with better ECOG performance status (p=0.000). The IC was associated with both better ECOG performance status (p=0.000) and GPA (3.5-4.0, p=0.005).nnnCONCLUSIONSnThere was no statistical difference between CK and NS for SBM from NSCLC in OS, LC and IC. However, CK is less invasive and may be more acceptable for patients. The result needs randomized trials to confirm and further study.

Stereotactic radiation therapy for oligometastases or oligorecurrence within mediastinal lymph nodes

Aims This study evaluated the safety and efficacy of stereotactic radiation therapy (SRT) for the treatment of patients with oligometastases or oligorecurrence within mediastinal lymph nodes (MLNs) originating from different tumors. Methods Between October 2006 and May 2015, patients with MLN oligometastases or oligorecurrence were enrolled and treated with SRT at our hospital. The primary endpoint was MLN local control (LC). Secondary endpoints were time to symptom alleviation, overall survival (OS) after SRT, and toxicity using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Results Eighty-five patients with 98 MLN oligometastases or oligorecurrences were treated with SRT. For the entire cohort, the 1-year and 5-year actuarial LC rates were 97% and 77%, respectively. Of 53 symptomatic patients, symptom alleviation was observed in 47 (89%) after a median of 5 days (range, 3-30 days). The median OS was 27.2 months for all patients. For patients with non-small cell lung cancer, univariate and multivariate analyses revealed that a shorter interval between diagnosis of primary tumors and SRT and larger MLN SRT volume were associated with worse OS. CTCAE v4.0 ≥ Grade 3 toxicities occurred in six patients (7%), with Grade 5 in three patients (all with RT history to MLN station 7). Conclusions SRT is a safe and efficacious treatment modality for patients with oligometastases or oligorecurrence to MLNs originating from different tumors, except for patients who received radiotherapy to MLN station 7. Further investigation is warranted to identify the patients who benefit most from this treatment modality.

Research progress on criteria for discontinuation of EGFR inhibitor therapy

The clinical success of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is “until progression”, based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer.

Celecoxib-erlotinib combination treatment enhances radiosensitivity in A549 human lung cancer cell

BACKGROUNDnRadiosensitivity by blocking the epidermal growth factor receptor and cyclooxygenase-2 pathways with erlotinib and celecoxib in A549 human lung cancer cell was investigated.nnnMETHODSnMTT assays were used to detect the antitumor effects of erlotinib and celecoxib in A549 cells. Colony formation assays were used to evaluate the antitumor effects. Flow cytometry analysis was used to assess the cell cycle and cell apoptosis, and western blotting analysis was performed to evaluate the expression of AKT and phosphorylated AKT.nnnRESULTSnEither erlotinib or celecoxib inhibited the A549 cell proliferation in a dose-dependent manner. Combining Erlotinib or celecoxib with radiation can suppress the cell colony formation and the Dq, D0, SF2 of the combining erlotinib or celecoxib with radiation was lower than in the combinations either erlotinib or celecoxib with radiation (t= 6.62, P< 0.05). The SER of radiation with celecoxib or erlotinib and celecoxib and erlotinib were 1.299, 1.503 and 2.217, respectively. The Flow cytometry analysis results showed that either celecoxib or erlotinib could induce G0/G1 arrest, and reduction of S phase cell proportion, especially when combinations erlotinib-celecoxib with radiation. Either celecoxib or erlotinib could enhance radiation-induced apoptosis, especially significant when combinations erlotinib-celecoxib with radiation. Moreover, radiation can promote the expression of pAKT, and the pAKT was remarkably lowest in the combinations erlotinib-celecoxib with radiation group (t= 4.89, P< 0.05).nnnCONCLUSIONSnBlocking both EGFR- and COX-2-related pathways could enhance the antitumor effect of radiation. The underlying mechanisms including the enhancement of apoptosis and radiation-induced G0/G1 arrest, possibly via inhibiting the PI3K/AKT signaling pathway.

Late course accelerated hyperfractionation radiotherapy for locally advanced esophageal squamous cell carcinoma

Late course accelerated hyperfractionation radiotherapy (LCAHR) is used as a standard treatment option for locally advanced esophageal squamous cell carcinoma (LAESCC) in China, but concerns remain regarding its efficacy and safety. The purpose of this paper was to evaluate the efficacy and safety of LCAHR. The comparisons examined were as follows: LCAHR versus conventional fractionation radiotherapy (CFR) and LCAHR plus chemotherapy (CT) versus LCAHR alone.