| Objective:To study the effectiveness and safety of EGFR-Mabs in treatment of head and neck squamous cell carcinoma (HNSCC) patients by using meta-analysis and to investigate the sensitization and potential mechanism of Dihydroartemisinin (DHA), Metformin and AG490 combined with Cetuximab in hypopharyngeal carcinoma Fadu cells on tumor inhibition. Methods:Published studies on the effect of EGFR-Mabs in HNSCC patients were comprehensively searched from the CBM, Pubmed, EMBASE, and CENTRAL databases, and primary outcomes included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Secondary outcomes included serious adverse events (Grade 3-4). The results were expressed as Risk Ratio (RR) or Hazard Rate (HR) with their corresponding 95% Confidence Intervals (95%CI). MTT assay and isobologram were used to evaluate the effects of DHA, Metformin and AG490 respectively combined with Cetuximab on the proliferation of Fadu cells. The expressions of p-STAT3, T-STAT3, p-MAPK, Bcl-xl, Mcl-1, Cyclin D1 and VEGF protein with different medications were detected by Western blot. Apoptosis was detected by flow cytometry. Results: (1)EGFR-Mabs combined with conventional therapy in the treatment of recurrent and/or metastatic (RM) HNSCC patients achieved a significant improvement in therapeutic effect (ORR:RR:1.61,95% CI:1.34-1.92,P<0.001; PFS:HR:0.68,95% CI:0.61-0.76, P<0.001; OS:HR:0.84,95% CI:0.75-0.95, P=0.004). (2)The primary analysis indicated that Mabs did not improve ORR and PFS, except for OS in locoregionally advanced (LA) HNSCC patients (ORR 1.21,0.97-1.49; PFS 0.87,0.75-1.01; OS 0.82,0.71-0.95). (3)There were no significant differences in the 2 year PFS and OS in LA HNSCC patients between Cetuximab therapy or no Cetuximab therapy (PFS:RR=1.02,95% CI 0.92-1.12; P= 0.76; OS:RR=1.06,95% CI 1.00-1.13, P= 0.06). For RM HNSCC patients, the OS, PFS and ORR were significantly superior by Cetuximab therapy compared with those by no Cetuximab therapy (OS:MD=2.41,95% CI0.96-3.86, P=0.001; PFS:MD=2.06,95% CI 1.34-2.77, P<0.00001; ORR:OR=2.38,95% CI 1.60-3.54, P<0.00001). The 1 year survival ratio showed no significant improvement (OR=1.39,95% CI 0.98-1.97,P=0.07). (4)The main adverse reactions such as skin reaction were found in patients with EGFR-Mabs therapy.(5)Antagonistic, additive and synergistic effects were found in DHA, Metformin and AG490 respectively combined with Cetuximab on the proliferation of Fadu cells by using MTT assay and isobologram. The expressions of p-STAT3, Bcl-xl, Mcl-1, Cyclin D1 and VEGF protein treated with Metformin and AG490 respectively combined with Cetuximab were significantly reduced as revealed by Western blot detection. And apoptosis was increased when metformin and AG490 combined with Cetuximab by flow cytometry, respectively. Conclusion:EGFR-Mabs in treatment of HNSCC patients can achieve a total effect with dissatisfactory effectiveness, representing therapeutic resistance. The main adverse reactions (Grade 3-4) such as skin reaction are found in patients with EGFR-Mabs therapy, and the difference is statistically significant. Antagonistic effect is found in DHA combined with Cetuximab therapy, and the underlying mechanism needs to be further studied. Sensitization effect is found in Metformin and AG490 combined with Cetuximab therapies, respectively, which may be attributed to blockade of corresponding signal pathways. |
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