树突状细胞治疗联合膀胱灌注表柔比星在TURBT术后的应用研究
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摘要
背景在我国,膀胱癌是泌尿系统最常见的恶性肿瘤,具有复发率较高的临床特点。为预防复发,表浅性膀胱癌及T2a期的浸润性膀胱癌在经尿道膀胱肿瘤切除术(transurethral resection of bladder tumor, TURBT)后常规给予膀胱内灌注丝裂霉素、吡柔比星、表柔比星(epirubicin, EPI)等化疗药物或者卡介苗(Bacillus Calmette-Guerin, BCG),但目前各种灌注治疗药物大都存在着长期疗效不肯定、副作用发生率高甚至出现严重并发症等问题。因此,寻找疗效确切且副作用较小的TURBT术后辅助治疗方案,对提高患者术后生存质量有着重要意义。近年研究表明,树突状细胞(dendritic cells, DC)生物免疫治疗在多种抗肿瘤实验中取得了良好的效果,为肿瘤患者的治疗及康复带来了新的希望。其主要作用机制是通过纠正肿瘤患者的免疫缺陷,建立有效免疫应答,激发自身特异性和非特异性杀瘤反应,达到高效杀伤肿瘤细胞的目的。化疗药物联合免疫增强剂对机体非特异性免疫的刺激和调节,不仅可提高长期疗效,还可避免盲目加大化疗剂量和增加化疗次数而导致的毒副作用增加。
目的评估Dc治疗联合膀胱灌注EPI对膀胱癌TURBT术后2年复发率的影响,观察DC治疗联合膀胱灌注EPI后患者不良反应出现的情况,了解DC治疗后外周血CD3+T淋巴细胞、CD4+T淋巴细胞亚群、CD8+T淋巴细胞亚群以及CD4+/CD8+比值的改变情况,探讨DC联合膀胱灌注EPI降低膀胱癌TURBT术后2年复发率的治疗机制。
方法选取我院2005年1月至2008年8月行TURBT的患者168例,随机分为三组,A组(DC联合治疗组)患者术后1周内给予首次膀胱灌注EPI(30mgEPI溶于50mL生理盐水),灌注后每30min更换体位1次(仰、俯、左、右侧位),保留2h后排出。1次/1周,共6次,然后1次/2周,共6次,1次／月,至2年。同时分别于术后第3、4、6、7周在患者腹股沟区皮内注射106～107个DC,此为第Ⅰ期疗程；术后27周给予第ⅡⅡ期疗程,DC治疗方案同第Ⅰ期疗程。B组(EPI灌注组)患者术后仅采用膀胱灌注EPI (30mgEPI溶于50mL生理盐水),具体灌注方案同前。C组(BCG灌注组)患者术后仅采用膀胱灌注BCG (120mgBCG溶于50mL生理盐水),具体灌注方案同膀胱灌注EPI。所有患者随访至2年或肿瘤复发,观察比较三组患者肿瘤2年复发率及不良反应发生率,并观察DC治疗对外周血T淋巴细胞亚群及比值的影响。
结果三组患者2年复发率分别为10%、25.8%、11.3%,A组与B组、c组与B组间的差异均有统计学意义(P<0.05),A组与C组间的差异无统计学意义(P>0.05)。三组患者不良反应发生率分别为20%、10.6%、40.3%,A组与C组、B组与C组间的差异均有统计学意义(P<0.05),A组与B组间的差异无统计学意义(P>0.05)。A组患者DC治疗后外周血CD3+T淋巴细胞、CD4+T淋巴细胞亚群、CD4+/CD8+比值升高,与DC治疗前相比差异有统计学意义(P<0.05),与同期B组患者相比差异亦有统计学意义(P<0.05)。
结论与单纯膀胱灌注EPI相比,Dc治疗联合膀胱灌注EPI能显著降低TURBT术后患者的2年复发率,其疗效与单纯膀胱灌注BCG相仿,但不良反应发生率远低于单纯膀胱灌注BCG.DC治疗可通过提高外周血CD3+T淋巴细胞、CD4+T淋巴细胞亚群以及CD4+／CD8+比值来增强机体免疫能力,发挥抗肿瘤免疫治疗作用。因此,DC治疗联合膀胱灌注化疗药物为TURBT术后辅助治疗的发展提供了新思路,开拓了新空间。
Background In China, bladder cancer is the most common malignant tumor in urinary system, with a lower grade but a higher recurrence rate. To prevent the recurrence of bladder cancer, patients with superficial bladder cancer or T2a invasive bladder cancer often receive a routine intravesical infusion therapy after transurethral resection of bladder tumor (TURBT). However, almost all the infusion therapy drugs, including BCG and all kinds of chemotherapeutic agents such as mitomycin C, pirarubicin and epirubicin (EPI), have some unresolvable problems, for example, uncertain long-term efficacy, high incidence of side effects and even some serious complication. Recent studies have shown that dendritic cells (DC) immune therapy has achieved good results in a variety of anti-cancer experiments, and brought new hope for the cancer patients. Chemotherapy combined with immune therapy can stimulate and regulate non-specific immune of the body, by this it not only can improve the long-term efficacy, but also can avoid the toxic side effects resulting from heavy dosage of chemotherapeutic agents.
Objective To assess the influence of DC therapy combined with intravesical perfusion of EPI on 2 years recurrence rate of bladder cancer. Observe the adverse reaction in patients after DC therapy combined with intravesical perfusion of EPI.Make clear the changes of CD3+, CD4+, CD8+ and CD4+/CD8±levels in peripheral blood of the patients who have received DC therapy and explore the immune mechanism of DC anti-tumor therapeuty.
Methods Select 168 bladder cancer patients who received TURBT in our hospital from January 2005 to August 2008. All the tumors were resected completely including the tissues 2cm away from the tumor and all the pathological examinations showed no cancer cells on the edge of the tumor. The patients were randomly divided into three groups. Group A (DC combination therapy group) were given the first intravesical infusion of EPI (30mg EPI dissolved in 50mL saline) within the first week after TURBT, changing body position (supine, prone, left lateral and right lateral position) every 30min after infusion and discharge the perfusate after 2h. One time per week for six times, then one time every two weeks for six times, finally one time every month for 19 months. During the above chemotherapy course, all members in Group A also received intradermal injection of 106~107 DC on the groin area at the 3th、4th、6th、7th week after TURBT. This was the first course of DC treatment and the patients in Group A received their second course of DC treatment from the 27th week after TURBT, which was the same as the first one. Group B (EPI infusion group) were treated only with EPI bladder perfusion after TURBT, the infusion method was same with Group A. Group C (BCG infusion group) were treated only with BCG bladder perfusion after TURBT, the infusion method was same with EPI bladder perfusion. All patients in three groups were followed up for 2 years to observe and compare the tumor recurrence rate, adverse reactions and the influence of DC on T lymphocyte subsets.
Results The two-year recurrence rates of three groups were 10%,25.8% and 11.3% respectively, the difference between Group C and Group B as well as the difference between Group A and Group B was statistically significant (P<0.05), while the difference between Group A and Group C was not statistically significant (P>0.05). The adverse reaction rates of three groups were 20%,10.6% and 40.3% respectively, the difference between Group B and Group C as well as the difference between Group A and Group C was statistically significant(P<0.05),while the difference between Group A and Group B was not statistically significant (P>0.05). The peripheral blood CD3, CD4and CD4/CD8 ratio of Group A increased after DC treatment, the differences were significant compared with those before DC treatment(P<0.05), the differences were also statistically significant compared with the Group B at the same time(P <0.05).
Conclusion Compared with EPI infusion group, DC therapy combined with intravesical perfusion of EPI can effectively reduce two-year recurrence rate of bladder cancer. The anti-tumor effect is similar with BCG infusion group while the adverse reaction rate was far below BCG infusion group. DC vaccination can increase peripheral blood CD3, CD4 and CD4/CD8 ratio so as to improve the patients'body immunity in short time. Therefore, DC immune therapy combined with intravesical chemotherapy provides a new way for the adjuvant treatment of bladder cancer.
目的评估Dc治疗联合膀胱灌注EPI对膀胱癌TURBT术后2年复发率的影响,观察DC治疗联合膀胱灌注EPI后患者不良反应出现的情况,了解DC治疗后外周血CD3+T淋巴细胞、CD4+T淋巴细胞亚群、CD8+T淋巴细胞亚群以及CD4+/CD8+比值的改变情况,探讨DC联合膀胱灌注EPI降低膀胱癌TURBT术后2年复发率的治疗机制。
方法选取我院2005年1月至2008年8月行TURBT的患者168例,随机分为三组,A组(DC联合治疗组)患者术后1周内给予首次膀胱灌注EPI(30mgEPI溶于50mL生理盐水),灌注后每30min更换体位1次(仰、俯、左、右侧位),保留2h后排出。1次/1周,共6次,然后1次/2周,共6次,1次／月,至2年。同时分别于术后第3、4、6、7周在患者腹股沟区皮内注射106～107个DC,此为第Ⅰ期疗程；术后27周给予第ⅡⅡ期疗程,DC治疗方案同第Ⅰ期疗程。B组(EPI灌注组)患者术后仅采用膀胱灌注EPI (30mgEPI溶于50mL生理盐水),具体灌注方案同前。C组(BCG灌注组)患者术后仅采用膀胱灌注BCG (120mgBCG溶于50mL生理盐水),具体灌注方案同膀胱灌注EPI。所有患者随访至2年或肿瘤复发,观察比较三组患者肿瘤2年复发率及不良反应发生率,并观察DC治疗对外周血T淋巴细胞亚群及比值的影响。
结果三组患者2年复发率分别为10%、25.8%、11.3%,A组与B组、c组与B组间的差异均有统计学意义(P<0.05),A组与C组间的差异无统计学意义(P>0.05)。三组患者不良反应发生率分别为20%、10.6%、40.3%,A组与C组、B组与C组间的差异均有统计学意义(P<0.05),A组与B组间的差异无统计学意义(P>0.05)。A组患者DC治疗后外周血CD3+T淋巴细胞、CD4+T淋巴细胞亚群、CD4+/CD8+比值升高,与DC治疗前相比差异有统计学意义(P<0.05),与同期B组患者相比差异亦有统计学意义(P<0.05)。
结论与单纯膀胱灌注EPI相比,Dc治疗联合膀胱灌注EPI能显著降低TURBT术后患者的2年复发率,其疗效与单纯膀胱灌注BCG相仿,但不良反应发生率远低于单纯膀胱灌注BCG.DC治疗可通过提高外周血CD3+T淋巴细胞、CD4+T淋巴细胞亚群以及CD4+／CD8+比值来增强机体免疫能力,发挥抗肿瘤免疫治疗作用。因此,DC治疗联合膀胱灌注化疗药物为TURBT术后辅助治疗的发展提供了新思路,开拓了新空间。
Background In China, bladder cancer is the most common malignant tumor in urinary system, with a lower grade but a higher recurrence rate. To prevent the recurrence of bladder cancer, patients with superficial bladder cancer or T2a invasive bladder cancer often receive a routine intravesical infusion therapy after transurethral resection of bladder tumor (TURBT). However, almost all the infusion therapy drugs, including BCG and all kinds of chemotherapeutic agents such as mitomycin C, pirarubicin and epirubicin (EPI), have some unresolvable problems, for example, uncertain long-term efficacy, high incidence of side effects and even some serious complication. Recent studies have shown that dendritic cells (DC) immune therapy has achieved good results in a variety of anti-cancer experiments, and brought new hope for the cancer patients. Chemotherapy combined with immune therapy can stimulate and regulate non-specific immune of the body, by this it not only can improve the long-term efficacy, but also can avoid the toxic side effects resulting from heavy dosage of chemotherapeutic agents.
Objective To assess the influence of DC therapy combined with intravesical perfusion of EPI on 2 years recurrence rate of bladder cancer. Observe the adverse reaction in patients after DC therapy combined with intravesical perfusion of EPI.Make clear the changes of CD3+, CD4+, CD8+ and CD4+/CD8±levels in peripheral blood of the patients who have received DC therapy and explore the immune mechanism of DC anti-tumor therapeuty.
Methods Select 168 bladder cancer patients who received TURBT in our hospital from January 2005 to August 2008. All the tumors were resected completely including the tissues 2cm away from the tumor and all the pathological examinations showed no cancer cells on the edge of the tumor. The patients were randomly divided into three groups. Group A (DC combination therapy group) were given the first intravesical infusion of EPI (30mg EPI dissolved in 50mL saline) within the first week after TURBT, changing body position (supine, prone, left lateral and right lateral position) every 30min after infusion and discharge the perfusate after 2h. One time per week for six times, then one time every two weeks for six times, finally one time every month for 19 months. During the above chemotherapy course, all members in Group A also received intradermal injection of 106~107 DC on the groin area at the 3th、4th、6th、7th week after TURBT. This was the first course of DC treatment and the patients in Group A received their second course of DC treatment from the 27th week after TURBT, which was the same as the first one. Group B (EPI infusion group) were treated only with EPI bladder perfusion after TURBT, the infusion method was same with Group A. Group C (BCG infusion group) were treated only with BCG bladder perfusion after TURBT, the infusion method was same with EPI bladder perfusion. All patients in three groups were followed up for 2 years to observe and compare the tumor recurrence rate, adverse reactions and the influence of DC on T lymphocyte subsets.
Results The two-year recurrence rates of three groups were 10%,25.8% and 11.3% respectively, the difference between Group C and Group B as well as the difference between Group A and Group B was statistically significant (P<0.05), while the difference between Group A and Group C was not statistically significant (P>0.05). The adverse reaction rates of three groups were 20%,10.6% and 40.3% respectively, the difference between Group B and Group C as well as the difference between Group A and Group C was statistically significant(P<0.05),while the difference between Group A and Group B was not statistically significant (P>0.05). The peripheral blood CD3, CD4and CD4/CD8 ratio of Group A increased after DC treatment, the differences were significant compared with those before DC treatment(P<0.05), the differences were also statistically significant compared with the Group B at the same time(P <0.05).
Conclusion Compared with EPI infusion group, DC therapy combined with intravesical perfusion of EPI can effectively reduce two-year recurrence rate of bladder cancer. The anti-tumor effect is similar with BCG infusion group while the adverse reaction rate was far below BCG infusion group. DC vaccination can increase peripheral blood CD3, CD4 and CD4/CD8 ratio so as to improve the patients'body immunity in short time. Therefore, DC immune therapy combined with intravesical chemotherapy provides a new way for the adjuvant treatment of bladder cancer.
引文
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