Analysis About The Efficacy And Safety Of Gemcitabine In Advanced NPC Based On EBM

BackgroundNasopharyngeal carcinoma(NPC) is one of the most common malignant tumors of head and neck in the South-east Asia.About 90%of them are undifferentiated or poorly differentiated squamous cell carcinoma,which are highly malignant,fast growing and with high occurrence of lymph node and distant metastasis.Seventy-five percent of new diagnostic cases areⅢorⅣstage.Radiotherapy is one of the most common used treatment methods for NPC.The curative rate is around 50%.The failure in the treatment is mainly due to distant metastasis and reoccurrence.In the recent years,chemotherapy in NPC has made a very big progress,it plays vital role both in combined modality of chemo-radiotherapy for locally advanced disease as well as in treatment of metastatic disease.Platinumbased combination regime (typically cisplatin +5-fluorouracil) is the most commonly used chemotherapy regime, but there is no consensus on secondline chemotherapy treatmentfor patients who are already treated with platinumbased regimen.The primary mechanism of tumor is the abnormal of cell cycle regulation.The disorders of tumor cell cycle regulation is usually manifested over-expression of positive regulatory cell cycle protein and deactivation of negative regulatory cell cycle kinase inhibitor.NSCLC,pancreatic cancer,breast cancer and head and neck squamous cell carcinoma(oral cavity, nasopharynx and larynx squamous cell carcinoma) are usually lead to change of cell cycle regulation because of the both disorder.Gemcitabine(Gemzar;Eli-lilly Pharmaceuticals,Inc,USA) is a pyrimidine analog,a ribonucleotide??uctase inhibitor that competes with deoxycytidine triphosphate(dCTP) for incorporation into DNA.Gemcitabine had been proven its efficiency in many types of tumors like NSCLC,pancreatic and breast cancer,but there is few report on treatment of advanced NPC using gemcitabine and the conclusions of different researchers are different,even contradictory.Therefore,it is extreme necessarily to take a scientific evaluation for expanding the indications of gemcitabine.The evaluation should not only depend on personal experience,expert advice and public view.It must be based on profound scientific research and abundant clinical evidence.Systematic review of evidence-based medicine is considered the most rational,scientific and comprehensive evaluation method.We take the systematic review by means of collecting randomized and semi-randomized controlled trials on treatment of advanced NPC using gemcitabine which has been published or ongoing all over the world before march 2008.The goal of this study is to evaluate the efficacy and safety profile of gemcitabine in advanced NPC patients and to identify the status of gemcitabine-based chemotherapy in the treatment of advanced NPC.Objective1,To survey and analysis the current clinical application of gemcitabine in our hospital.2,To identify the feasibility of gemcitabine in the treatment of advanced NPC.3,To take a comprehensive and scientific systematic review to evaluate the efficacy and safety of gemcitabine in advanced NPC based on theory of EBM.4,To guide clinical practice with scientific research findings.Method1,Survey and analysis of clinical application of gemcitabine2,Determine criteria for i??ded studies and excluded studies.3,Designing search strategies.Up to march 2008,we searched the Cochrane Central Register of Controlled Trials(CENTRAL)(The Cochrane Library Issue3, 2007),MEDLINE(1994 to March 2008),EMBASE(1994 to March 2008), EBSCO(1996 to March 2008),OVID(1996 to March 2008),CBM and CNKI.4,Assessment of study quality.Two reviewers checked the following information.Method of randomisation and whether the randomizing was blind to the treatment allocation;Method of measuring outcome and whether the adjudication of outcome were done independently,blindly,or both,to treatment allocation;Number of exclusions and losses to follow up.A-class was rated when all quality standards were satisfied.B-class was rated when all quality standards were only partially meet. C-class was rated when all quality standards were completely unsatisfied.5,Data collection and analysis.Two review authors selected trials for inclusion, and independently assessed trial quality and extracted data.Methods of statistical analysis included types of data and effect measures,summarizing effects across studies,identifying and measuring heterogeneity,sensitivity analyses,calculation of relative treatment effects as well as confidence interval estimates.6,Keeping track of identified studies.If the conclusion of meta analysis could not judge exactly,we would track continuously on research progress of treatment of advanced NPC using gemcitabine.Statistical methods1,Part one:Quantitative data were expressed as the form of((?)±s). Comparison of efficiency and the total incidence of adverse reactions were carried out by Chi-square test.All data were analysis by software of Statistical Package for Social Science.2,Part two:We used the cochrane collaboration software review manager (RevMan 4.2) to analysis.Result1,First-line chemotherapy for advanced NPC in our hospital was mainly PF (fluorouracil+cisplatin) regimen,as well as TPF(Taxotere+fluor??cil+cisplatin) regimen.Gemcitabine chemotherapy used in advanced NPC was uncommon.2,Retrospective survey showed the efficiency of gemcitabine had no significant statistical difference compared with first-line regimen of guideline when used as first-line treatment in non-small cell lung cancer(x~2=1.0,P=0.593),pancreatic cancer(x~2=0.709,P=0.450),breast cancer(x~2=1.0,P=0.521),and also used as second-line treatment in bladder cancer(x~2=0.415,P=0.305) and ovarian cancer (x~2=0.68,P=0.407).3,Gemzar,whether combined with carboplatin(x~2=10.019,P=0.002) or cisplatin(x~2=10.949,P=0.001),was significantly better than zefei in efficiency.The incidence of adverse reactions of them had no significant statistical difference(x~2=0.076,P=0.783),(x~2=0.000,P=1.0).The efficiency of gemzar +cisplatin regimen was better than gemzar+carboplatin regimen,but had no significant statistical difference.(x~2=0.189,P=0.664).The efficiency of zefei+ cisplatin regimen was better than zefei+carboplatin regimen,but had no significant statistical difference(x~2=0.01,P=0.921).The efficiency and the incidence of adverse reactions of combination chemotherapy regimen was better than monotherapy regimen,and had significant statistical difference(x~2=10.068, P=0.002),(x~2=14.199,P＜0.001).The efficiency of 3 weeks therapy was higher than 4 weeks therapy and the incidence of adverse reactions of 3 weeks therapy were lower than 4 weeks therapy,but the statistical difference was not significant(x~2= 0.982,P=0.386),(x~2=1.065,P=0.571).DUI of gemzar was less than 1 and DUI of zefei was more than 1.T test show that it was no significant statistical difference between them(t=1.476,P=0.2 ).Cost-effectiveness analysis showed that total drug costs and costs of one course treatment of gemzar were higher than that of zefei.Cost-effective of gemzar was significantly lower than zefei(Z=-2.405,P= 0.016).4,Meta-analyses showed th?? and 3-year survival rate of GP(gemcitabine+ cisplatin) regimen had no significant difference compared with PF regimen (fluorouracil+cisplatin)[RR=1.12,95%CI,(0.88,1.42),P=0.37],[RR=1.40, 95%CI(0.95,2.07),P=0.09],but had higher remission rate[RR=1.13,95% CI(1.22,1.26) P=0.02]and slighter myelosuppression and gastrointestinal reactions[RR=0.47,95%CI(0.26,0.86),P=0.01],[RR=0.47,95%CI(0.30,0.75), P=0.001],[RR=0.23,95%CI(0.04,0.86),P=0.03];The response rate and 1 year survival rate of GC(gemcitabine+cisplatin) regimen were higher than that of monotherapy with gemcitabine[RR=1.81,95%CI(1.06,3.08),P=0.03],[RR=1.78, 95%CI(1.03,3.06),P=0.04],but it had no significant difference between the two regimens in 3 year survival rate[RR=2.01,95%CI(0.80,5.05),P=0.14].GC regimen were higher myelosuppression and gastrointestinal reactions than that of monotherapy with gemcitabine[RR=1.77,95%CI(1.09,2.86),P=0.02],[RR=2.08,95%CI (1.21,3.57),P=0.008],[RR=1.91,95%CI(1.04,3.50),P=0.04];The remission rate of GEM+CBP(gemcitabine+carboplatin) regimen had significant higher compared with DOC+DDP regimen(paclitaxel+cisplatin)[P＜0.01].Compared with mode of venous administration,there was higher response rate(P=0.013),1-year survival rate (P=0.018)and longer median survival time(P=0.030) when gemcitabine were administered by artery.Conclusion1,Gemcitabine when used as first-line chemotherapy in non-small cell lung cancer,pancreatic cancer,breast cancer,bladder cancer had certain advantages compared to common first-line chemotherapy of clinic in our hospital,but no obvious advantage for ovarian cancer.2,There were no significant difference in efficacy and adverse reactions whatever gemcitabine was combined with carboplatin or cisplatin.Gemzar were more effective than zefei.Cost-effective of gemzar was significantly lower than zefei. Gemzar co??ning chemotherapy was the best treatment.3,Gemcitabine was an effective agent for advanced NPC when used as monotherapy or incombined treatment,and toxic and side-effect was slight.Although it had been recommended as a second-line agent for recurrence of sensitive NPC, more clinical trials were needed to define its role in first-line treatment.Due to a high risk of selection bias and detection bias in included studies,the evidence was insufficient to determine the effect of gemcitabine.Further large-scale trials were required to define the role of gemcitabine in the treatment of advanced NPC.