晚期上皮性卵巢癌患者初治后正常范围的血清CA125水平对预后的影响分析
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摘要
研究背景卵巢癌是妇科常见的恶性肿瘤之一,而且尤以上皮性卵巢癌复发率、死亡率最高。目前,对于晚期上皮性卵巢癌(advanced epithelial ovarian cancer, adEOC)的治疗原则是以手术治疗为主,并辅助以铂类药物为基础的联合化疗,70-80%的患者可以获得临床完全缓解(CR)。然而,尽管手术技巧的提高可以做到最大程度的肿瘤减灭术,新型化疗药物的临床应用给化学治疗带来多重生机,但是最终还是会有70%-80%患者肿瘤复发。CA125对于上皮性卵巢癌的诊断、监测病情的进展和复发方面具有重要作用,是上皮性卵巢癌应用最广泛的肿瘤标记物。近年来,血清CA125测定对于上皮性卵巢癌的预后判断价值是一个研究重点,有学者从不同角度探讨了血清CA125测定对卵巢癌的预后判断价值,证实了血清CA125是影响卵巢癌预后(无进展生存期和总生存期)的重要因素,可为患者的进一步治疗提供了参考依据。有研究表明,adEOC患者经初治达到完全缓解后(CA125<35u/ml),根据正常范围内的CA125值进行分组,低水平CA125组有更长的无进展生存期和总生存期。
目的探讨晚期上皮性卵巢癌患者初治后正常范围的血清CA125水平与预后的关系。
资料及方法收集2001年8月-2008年12月期间在山东大学齐鲁医院收治的晚期上皮性卵巢癌患者病历资料,随访观察至2009年8月结束。所收集的患者病历和随访资料完整。病例资料的筛选遵循以下标准,1)患者在术前血清CA125值高于正常(>35u／m1),2)完成理想的肿瘤细胞减灭术,3)病理类型为卵巢上皮性癌,4)手术-病理分期为Ⅲ-Ⅳ期,5)术后接受6个疗程以铂类药物为基础的联合化疗,6)初治后得到完全缓解：临床症状消失、血清CA125小于35／ml、体格检查和盆腹腔CT或MRI以及胸部X线片等影像学检查无阳性发现,7)初治后动态监测血清CA125值,至少连续两次小于35／ml。
将研究对象按CA125<10u/ml和10≤CA125<35u/ml两个水平分为A、B两组,进行回顾性研究分析,用卡方检验或Fisher's精确概率法比较组间的分布差异；进一步进行生存分析,采用Kaplan-Meier方法计算生存率,并绘制生存曲线；使用Log-rank test法进行单因素分析,比较两组的生存时间或生存曲线是否相同；采用Cox风险比例回归模型进行影响预后的多因素分析；检验水准取双侧a=0.05,P<0.05有统计学意义。
结果共有86例患者符合病例纳入标准,其中A组(CA125<10u/ml)共34例,B组(10≤CA125<35u/ml)共52例。两组中位无进展生存期(progression-free survival, PFS)分别为46个月和25个月,有显著性差异(P=0.002)；中位总生存期(overall survival, OS)分别为60个月和44个月,有显著性差异(P=0.006)；多因素生存分析表明,adEOC患者经手术和化疗达到完全缓解后,血清CA125水平和化疗方案的选择是影响PFS和OS的重要因素,CA125<10 u/ml和TC化疗方案是独立的预后因素。
结论对于接受理想肿瘤细胞减灭术和规范化疗后达到完全缓解的adEOC患者,低水平CA125和TC化疗方案是adEOC患者独立的预后因素。可以将CA125=10u/ml作为界限,对此类患者作进一步的危险分层,可能为指导adEOC患者的进一步巩固治疗提供依据。
Background Ovarian cancer is one of the most common malignancies in women, especially, advanced epithelial ovarian cancer (adEOC) has high recurrence rate and is the leading cause of gynecologic cancer death. At present, primary treatment for women with adEOC consists of cytoreductive surgery and postoperative platinum based combination chemotherapy administered and about 70-80% of patients can reach the complete clinical remission. Although advances in treatment strategies have improved the median overall survival, the majority of patients(70-80%) will eventually relapse. The serum CA125 concentration has been considered as a tool of great importance in the diagnosis, monitoring of relapse and disease progression for EOC. Thus, it is reasonable to investigate whether CA125 may have utility as a prognostic indicator as well in ovarian cancer. Recently a large number of studies have been carried out to this effect. Several reports have recently indicated that it may be possible to define the risk of relapse and death by dividing patients who have achieved a complete remission(CA125<35u/ml) after primary treatment into different groups based on the CA-125 value. Indeed, nadir values have been associated with an increase in progression-free survival (PFS) and overall survival (OS).
Objective To evaluate the prognostic value of normal serum CA125 level in advanced epithelial ovarian cancer patients with complete clinical remission after primary treatment.
Methods A retrospective analysis was conducted on advanced EOC patients with stageⅢ-Ⅳwho had received primary treatment in Qilu hospital of ShanDong university during October 2001 to December 2008,followed up to October 2009. The eligible criteria were:1) an elevated CA-125 at time of diagnosis (>35u/ml),2) Underwent optimal cytoreductive surgery,3) histological diagnosis of adEOC,4) FIGO stagesⅢandⅣ,5) a combination of platinum based chemotherapy administered,6) achieved clinically defined complete remission (CR) after the initial therapy (ie, no cancer-related symptoms; CA-125<35u/ml; normal physical examination, computed tomography or MRI scan of the abdomen/pelvis and chest x-ray) and 7) at least two serial serum CA-125 level determinations remained within the normal range (<35u/ml).
All patients were divided into 2 arbitrary groups according to the serum CA-125 levels after 6 cycles of the chemotherapy: group A, CA125< 10 U/ml; group B,10≤CA125< 35 U/ml. The Chi-Square/Fisher's exact test was used to examine patients' characteristics for categorical variables. Survival analysis was performed by Kaplan-Meier method with long-rank test for determining statistical significance. Cox proportional hazards regression was used in multivariate analysis to determine the prognosis significance of all factors. All P-values presented were two-sided, and associations were considered significant if the P-value was<0.05.
Results Eighty six patients were consistent with eligible criteria in this study. Among them, there were 32 patients in group A (CA125<10u/ml) and 54 in group B (10progression-free survival (PFS) was 46 and 25 months for groups A and B, respectively (P= 0.002). Median overall survival (OS) was 60 and 44 months for groups A and B, respectively (P=0.006). The Cox model showed a highly significant impact on PFS and OS in relation to CA-125 nadir levels and TC chemotherapy regiment.
Conclusions The low CA125 level within normal range and TC chemotherapy regiment are independent prognostic factors for patients with adEOC who achieved complete clinical remission after primary therapy. When the cut-off value is set to 10 u/ml, CA125 nadir may be an important factor for identifying patients for whom maintenance chemotherapy is effective.
目的探讨晚期上皮性卵巢癌患者初治后正常范围的血清CA125水平与预后的关系。
资料及方法收集2001年8月-2008年12月期间在山东大学齐鲁医院收治的晚期上皮性卵巢癌患者病历资料,随访观察至2009年8月结束。所收集的患者病历和随访资料完整。病例资料的筛选遵循以下标准,1)患者在术前血清CA125值高于正常(>35u／m1),2)完成理想的肿瘤细胞减灭术,3)病理类型为卵巢上皮性癌,4)手术-病理分期为Ⅲ-Ⅳ期,5)术后接受6个疗程以铂类药物为基础的联合化疗,6)初治后得到完全缓解：临床症状消失、血清CA125小于35／ml、体格检查和盆腹腔CT或MRI以及胸部X线片等影像学检查无阳性发现,7)初治后动态监测血清CA125值,至少连续两次小于35／ml。
将研究对象按CA125<10u/ml和10≤CA125<35u/ml两个水平分为A、B两组,进行回顾性研究分析,用卡方检验或Fisher's精确概率法比较组间的分布差异；进一步进行生存分析,采用Kaplan-Meier方法计算生存率,并绘制生存曲线；使用Log-rank test法进行单因素分析,比较两组的生存时间或生存曲线是否相同；采用Cox风险比例回归模型进行影响预后的多因素分析；检验水准取双侧a=0.05,P<0.05有统计学意义。
结果共有86例患者符合病例纳入标准,其中A组(CA125<10u/ml)共34例,B组(10≤CA125<35u/ml)共52例。两组中位无进展生存期(progression-free survival, PFS)分别为46个月和25个月,有显著性差异(P=0.002)；中位总生存期(overall survival, OS)分别为60个月和44个月,有显著性差异(P=0.006)；多因素生存分析表明,adEOC患者经手术和化疗达到完全缓解后,血清CA125水平和化疗方案的选择是影响PFS和OS的重要因素,CA125<10 u/ml和TC化疗方案是独立的预后因素。
结论对于接受理想肿瘤细胞减灭术和规范化疗后达到完全缓解的adEOC患者,低水平CA125和TC化疗方案是adEOC患者独立的预后因素。可以将CA125=10u/ml作为界限,对此类患者作进一步的危险分层,可能为指导adEOC患者的进一步巩固治疗提供依据。
Background Ovarian cancer is one of the most common malignancies in women, especially, advanced epithelial ovarian cancer (adEOC) has high recurrence rate and is the leading cause of gynecologic cancer death. At present, primary treatment for women with adEOC consists of cytoreductive surgery and postoperative platinum based combination chemotherapy administered and about 70-80% of patients can reach the complete clinical remission. Although advances in treatment strategies have improved the median overall survival, the majority of patients(70-80%) will eventually relapse. The serum CA125 concentration has been considered as a tool of great importance in the diagnosis, monitoring of relapse and disease progression for EOC. Thus, it is reasonable to investigate whether CA125 may have utility as a prognostic indicator as well in ovarian cancer. Recently a large number of studies have been carried out to this effect. Several reports have recently indicated that it may be possible to define the risk of relapse and death by dividing patients who have achieved a complete remission(CA125<35u/ml) after primary treatment into different groups based on the CA-125 value. Indeed, nadir values have been associated with an increase in progression-free survival (PFS) and overall survival (OS).
Objective To evaluate the prognostic value of normal serum CA125 level in advanced epithelial ovarian cancer patients with complete clinical remission after primary treatment.
Methods A retrospective analysis was conducted on advanced EOC patients with stageⅢ-Ⅳwho had received primary treatment in Qilu hospital of ShanDong university during October 2001 to December 2008,followed up to October 2009. The eligible criteria were:1) an elevated CA-125 at time of diagnosis (>35u/ml),2) Underwent optimal cytoreductive surgery,3) histological diagnosis of adEOC,4) FIGO stagesⅢandⅣ,5) a combination of platinum based chemotherapy administered,6) achieved clinically defined complete remission (CR) after the initial therapy (ie, no cancer-related symptoms; CA-125<35u/ml; normal physical examination, computed tomography or MRI scan of the abdomen/pelvis and chest x-ray) and 7) at least two serial serum CA-125 level determinations remained within the normal range (<35u/ml).
All patients were divided into 2 arbitrary groups according to the serum CA-125 levels after 6 cycles of the chemotherapy: group A, CA125< 10 U/ml; group B,10≤CA125< 35 U/ml. The Chi-Square/Fisher's exact test was used to examine patients' characteristics for categorical variables. Survival analysis was performed by Kaplan-Meier method with long-rank test for determining statistical significance. Cox proportional hazards regression was used in multivariate analysis to determine the prognosis significance of all factors. All P-values presented were two-sided, and associations were considered significant if the P-value was<0.05.
Results Eighty six patients were consistent with eligible criteria in this study. Among them, there were 32 patients in group A (CA125<10u/ml) and 54 in group B (10
Conclusions The low CA125 level within normal range and TC chemotherapy regiment are independent prognostic factors for patients with adEOC who achieved complete clinical remission after primary therapy. When the cut-off value is set to 10 u/ml, CA125 nadir may be an important factor for identifying patients for whom maintenance chemotherapy is effective.
引文
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13. Riedinger JM, Wafflart J, Ricolleau G, Eche N, Larbre H, Basuyau JP, Dalifard I, Hacene K, Pichon MF:CA125 half-life and CA 125 nadir during induction chemotherapy are independent predictors of epithelial ovarian cancer outcome: results of a French multicentric study. Ann Oncol 2006,17:1234-1238.
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21. Riedinger JM, Bonnetain F, Basuyau JP, Eche N,Larbre H,Dalifars I,Wafflart J,Ricolleau G,Pichon MF:Change in CA 125 levels after the first cycle of induction chemotherapy is an independent predictor of epithelial ovarian tumour outcome. Ann Oncol 2007,18:881-885.
22. Gadducci A, Zola P, Landoni F, Maggino T, Sartori E,Bergamino T; Cristofani R: Serum half-life of CA125 during early chemotherapy as an independent prognostic variable for patients with advanced epithelial ovarian cancer: results of a multicentric Italian study. Gynecol Oncol 1995,58:42-7.
23. Ron IG, Inbar M, Gelernter I:Use of CA125 response to predict survival parameters of patients with advanced ovarian carcinoma. Acta Obstet Gynecol Scand 1994,73:658-662.
24. Mogensen O:Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 1992,44:207-212.
25. Yedema CA, Kenemans P, Voorhorst F, Bon G, Schijf C, Beex L, Verstraeten A, Hilgers J, Vermorken J:CA 125 half-life in ovarian cancer: a multivariate survival analysis. Br J Cancer 1993,67:1361-1367.
26.蓝春燕,黄鹤,刘继红：晚期卵巢上皮性癌患者初次治疗过程中血清CA125水平变化与其预后的关系.中华妇产科杂志.2008,10：732-736.
27. Rocconi RP, Matthews KS, Kemper MK, Hoskins KE, Huh WK, Michael Straughn J.The timing of normalization of CA125 levels during primary chemotherapy is predictive of survival in patients with epitheal ovarian cancer. Gynecol Oncol 2009,114:242-245.
28. Buller RE, Berman ML, Bloss JD, Manetta A, DiSaia PJ. CA 125 regression:a model for epithelial ovarian cancer response. Am J Obstet Gynecol 1991,165: 360-367.
29. Gadducci A, Cosio S, Fanucchi A, Negri S, Cristofani R, Genazzani AR: The predictive and prognostic value of serum CA 125 half-life during paclitaxel/platinum-based chemotherapy in patients with advanced ovarian carcinoma. Gynecol Oncol 2004,93:131-136.
30. Hunter VJ, Daly L, Helms M, Soper JT, Berchuck A, Clarke-Pearson DL, Bast RC Jr: The prognostic significance of CA 125 half-life in patients with ovarian cancer who have received primary chemotherapy after surgical cytoreduction. Am J Obstet Gynecol 1990,163:1164-1167.
31. De la Cuesta R, Maestro ML, Solana J, Vidart JA, Escudero M, Iqlesias E, Valor R: Tissue quantification of CA 125 in epithelial ovarian cancer. Int J Biol Markers 1999,14:106-114.
32. Hφgdall EV, Christensen L, Kjaer SK, Blaakaer J, Kjaerbye-Thygesen A, Gayther S, Jacobs IJ, Hogdall CK: CA125 expression pattern, prognosis and correlation with serum CA125 in ovarian tumor patients. From The Danish "MALOVA" Ovarian Cancer Study. Gynecol Oncol 2007; 104:508-515.
33. Kumar B, De Silva M, Venter DJ, Armes JE. Tissue microarrays:a practical guide. Pathology 2004; 36:295-300.