S-1 Maintenance Therapy in Extensive Stage Small-Cell Lung Cancer-A Randomized Clinical Study.

Small-cell lung cancer (SCLC) is a recalcitrant cancer for its dismal prognosis although extensive research had been done. Four to 6 cycles platinum-based chemotherapy is the mainstay treatment for the extensive-stage disease; but the role of maintenance treatment is not fully understood. This is a phase 2, open-label study. Patients with extensive-stage SCLC reaching an objective response or stable disease (SD) after induction chemotherapy were randomly assigned (1:1) with a minimization procedure. One group received oral S-1 and the other group received placebo as maintenance treatment until disease progression or unacceptable toxicities. The primary end point of this study was progression-free survival (PFS), and the secondary end points were overall survival (OS), response rates, and toxicities. This study was based on earlier work, the preliminary results was reported on 2019 ASCO annual meeting. A total of 89 patients were enrolled, of whom 45 received S-1 maintenance therapy and 44 received placebo. The median PFS and OS were 6.35 months and 10.82 months in the S-1 group, as compared to 5.98 months and 10.09 months in the placebo group. The PFS was 7.2 months and 5.3 months, and OS was 12.9 months and 10.9 months in patients with an objective response compared to in patients with SD after induction chemotherapy, respectively. S-1 maintenance therapy did not prolong PFS or OS in patients with extensive-stage SCLC; tumor regression rate was the prognostic factor of PFS or OS. Further research with novel agents in the maintenance setting is warranted.

A randomized clinical study to compare intrapleural infusion with intravenous infusion of bevacizumab in the management of malignant pleural effusion in patients with non-small-cell lung cancer.

BACKGROUND: To compare the efficiency and toxicity of bevacizumab by intrapleural or intravenous infusion in the management of malignant pleural effusion in patients with non-small-cell lung cancer (NSCLC). METHODS: Sensitizing mutation negative NSCLC patients with malignant pleural effusion were randomized into two groups in 1:1 ratio. The pleural effusion was completely drained in 24 hours; one group received intrapleural infusion and the second group received intravenous infusion of bevacizumab at a dose of 7.5 mg per kg bodyweight. The serum vascular endothelial growth factor (VEGF) was tested before and 72 hours after injection of bevacizumab. Computerized tomography (CT) scan to evaluate pleural effusions was carried out at four weeks for each patient and their survival followed-up. RESULTS: A total of 67 patients were screened and 43 enrolled into the study. The response rate was 80% (16 of 20) in the intrapleural group and 66.7% (14 of 21) in the intravenous group. The median duration of response (DoR) of pleural effusion was 4.50 months and 3.70 months, respectively. The median serum VEGF level at 72 hours decreased 67.25% in the intrapleural group and 57.19% in the intravenous group compared to baseline level (P = 0.276). The median serum VEGF level at 72 hours decreased 52.02% compared to baseline level in patients' DoR less than three months and 68.33% in patients' DoR longer than three months, respectively (P = 0.014). The main side effects noted were mild to moderate hypertension, proteinuria and epistaxis. CONCLUSIONS: Bevacizumab intrapleural infusion had higher efficiency and higher safety than intravenous infusion in the management of malignant pleural effusion caused by NSCLC. The decreased level of serum VEGF at 72 hours after bevacizumab treatment was closely related to the response rate and duration of the response of pleural effusion.

Osimertinib compared docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small-cell lung cancer.

OBJECTIVE: To compare the efficacy and toxicity of osimertinib versus docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. METHODS: In this phase 3, open-label, three-center study, we randomly assigned (1:1) previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients into two groups. These patients had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum. One group received oral osimertinib (80 mg/day) and the other group received intravenous infusion docetaxel (75 mg/m2) and bevacizumab (7.5 mg/kg) every 21 days until disease progression, unacceptable toxic effects or patient death. The primary endpoint of this study was progression-free survival (PFS) and the secondary endpoints were response rates, toxicities and overall survival (OS). This trial was registered with ClinicalTrials.gov, number NCT02959749. RESULTS: A total of 147 patients were treated. Among them, 74 were enrolled in the osimertinib group and 73 were in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months in the osimertinib group versus 2.95 months in the docetaxel-bevacizumab group (hazard ratio 0.23; 95% confidence interval [CI], 0.12-0.38; P < 0.001). The overall response rate in the osimertinib group was significantly better than in the docetaxel-bevacizumab group (61.6%; 95% CI, 55.5-67.7 versus 8.3%; 95% CI, 1.3-15.3; p < 0.001). Because all the progressed patients in the docetaxel-bevacizumab group crossed over to the osimertinib group, there was no significant difference in the median OS between two groups at the time of last follow-up (hazard ratio 0.79; 95% CI, 0.38-1.61; P = .551). The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.4%) in the osimertinib group and alopecia (15.3%), anorexia (12.5%), neutropenia (9.7%) and nausea (8.3%) in the docetaxel-bevacizumab group. CONCLUSIONS: Osimertinib had higher response rate, longer PFS and milder side effects than docetaxel-bevacizumab in third-line therapy in patients with EGFR T790 M positive advanced NSCLC.

Effects of microwave ablation on T-cell subsets and cytokines of patients with hepatocellular carcinoma.

OBJECTIVES: To investigate the effects of microwave ablation on T-lymphocyte subsets and cytokines in patients with hepatocellular carcinoma. MATERIAL AND METHODS: Peripheral blood was collected from 45 patients with hepatocellular carcinoma treated by microwave ablation before treatment, one week and one month after treatment. T cells (CD3+, CD4+ and CD8+ cells), CD4+ CD25+ Tregs, and CD16+ CD56+ NK cells were analyzed by flow cytometry. Levels of cytokines (IL-2, IFN-γ, TNF-α, IL-12, IL-4, IL-6, IL-8, and IL-10) were determined by a Luminex 200 analyzer. RESULTS: Compared with before treatment, CD3+ cells, CD4+ cells and IL-12 increased significantly at one month after the microwave ablation treatment, while IL-4, IL-10 decreased significantly. CONCLUSIONS: Microwave ablation could relieve the suppression of immune function caused by tumors, promote the deviation of Th2/Th1, and improve immune dysfunction in patients with hepatocellular carcinoma.

Artificial pneumothorax: a safe and simple method to relieve pain during microwave ablation of subpleural lung malignancy.

BACKGROUND: Microwave ablation has been extensively used for eliminating pulmonary tumors; however, it is usually associated with severe pain under local anesthesia. Decreasing the power and shortening the ablation time can help to relieve the pain; however, this leads to incomplete ablation and an increasing recurrence rate. This research aims to employ an artificial pneumothorax to increase both the curative effect and pain relief during the ablation procedure. MATERIAL AND METHODS: From July 2013 to January 2015, nine patients presenting with 10 subpleural lung tumors (age: 44-78 years) with a high possibility of severe pain underwent the artificial pneumothorax during microwave ablation. The pain assessment scores and complications induced by the artificial pneumothorax were recorded and analyzed by a CT scan follow-up. RESULTS: The tumors of the nine patients were eliminated successfully using microwave ablation with artificial pneumothorax under local anesthesia. The pain caused by the ablation was relieved to a great extent with an average rate of 94.66% (range: 63.3%-100%) and all tumors were ablated completely. No severe complications occurred after the operation. CONCLUSIONS: The artificial pneumothorax is a reliable therapy to improve the curative effect of microwave ablation under local anesthesia by relieving the pain of the patients.

Effects of combining transarterial chemoembolization with percutaneous microwave coagulation therapy for hepatocellular carcinoma abutting the diaphragm.

OBJECTIVE: This study aims to explore the clinical effectiveness of a combination therapy of transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) in treating hepatocellular carcinoma (HCC) abutting the diaphragm. MATERIAL AND METHODS: Six cases with HCC were treated with TACE followed by PMCT one month later with the aid of artificial pneumothorax. RESULTS: CT/MRI revealed complete necrosis in the tumor lesions and the treated tumor margins (≥ 5 mm). Serum alpha-fetoprotein (AFP) levels markedly declined in patients who originally had higher serum AFP levels. Postoperative complications such as fever, mild hepatic dysfunction and pleural effusion were alleviated within a short period of time. All patients were closely monitored through follow-up; all patients survived, except for one patient who received a liver transplantation. CONCLUSIONS: As lesions are either invisible or poorly visible in sonography, determining an effective treatment for HCC abutting the diaphragm remains a particular challenge. TACE and PMCT combined therapy with the aid of artificial pneumothorax proved to be an available treatment option.

Chronopharmacology and mechanism of antitumor effect of erlotinib in Lewis tumor-bearing mice.

The epidermal growth factor receptor (EGFR), a ubiquitously expressed receptor tyrosine kinase, is recognized as a key mediator of tumorigenesis in many human epithelial tumors. Erlotinib is tyrosine kinase inhibitor approved by FDA for use in oncology. It inhibits the intracellular phosphorylation of tyrosine kinase associated with the EGFR to restrain the development of the tumor. To investigate the antitumor effect of erlotinib at different dosing times and the underlying molecular mechanism via the PI3K/AKT pathway, we established a mouse model of Lewis lung cancer xenografts. The tumor-bearing mice were housed four or five per cage under standardized light-dark cycle conditions (light on at 7:00 AM, 500 Lux, off at 7:00 PM, 0 Lux) with food and water provided ad libitum. The mice were observed for quality of life, their body weight and tumor volume measured, and the tumor growth curves drawn. After being bled, the mice were sacrificed by cervical dislocation. The tumor masses were removed at different time points and weighed. The mRNA expression of EGFR, AKT, Cyclin D1 and CDK-4 were assayed by quantitative real-time PCR (qRT-PCR). Protein expression levels of AKT, P-AKT and Cyclin D1 were determined by Western blot analysis. The results suggest that erlotinib has a significant antitumor effect on xenografts of non-small cell lung cancer in mice, and its efficacy and toxicity is dependent on the time of day of administration. Its molecular mechanism of action might be related to the EGFR-AKT-Cyclin D1-CDK-4 pathway which plays a crucial role in the development of pathology. Therefore, our findings suggest that the time of day of administration of Erlotinib may be a clinically important variable.

Sorafenib in liver function impaired advanced hepatocellular carcinoma.

OBJECTIVE: To explore the efficacy and safty of sorafenib in Child-Pugh class B to class C hepatocellular carcinoma (HCC). METHODS: In this three-center open-label study from November 2011 to May 2013, we randomly assigned 189 patients with advanced Child-Pugh class B or C HCC patients into two groups, one group with 95 patient to receive sorafenib (400 mg a time, twice a day) and the other group with 94 patients to receive best supportive care. The primary end points were progression-free survival and overall survival. RESULTS: The median progression-free survival was 2.2 months and 1.9 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.55; 95% confidence interval, 0.40-0.75; P=0.002). The median overall survival was 4.0 months and 3.5 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.48; 95% confidence interval, 0.35-0.68; P<0.001). The main adverse effect of sorafenib was rash and acne of the skin (in 51.7% patients). The incidences of severe rash, diarrhea, and dry skin were 5.6%, 5.6%, and 2.2% in the sorafenib group. One patient reached partial response in the sorafenib group. CONCLUSIONS: Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.