铁缺乏及贫血与上皮性卵巢癌顺铂耐药关系的临床研究

Clinical study of relationship between iron deficiency, anemia and cisplatin resistance in epithelial ovarian cancer

目的探讨铁缺乏及贫血与上皮性卵巢癌顺铂耐药的关系。方法选取2011年1月至2014年11月，于长江大学附属第一医院妇科收治并确诊为上皮性卵巢癌的71例患者为研究对象。根据患者对顺铂耐药与否，将其分别纳入顺铂耐药组（n=33，对顺铂治疗耐药）与顺铂敏感组（n=38，对顺铂治疗敏感）。顺铂耐药组与顺铂敏感组患者的纳入标准：经活组织检查确诊为上皮性卵巢癌，符合《妇产科学》（7版）有关上皮性卵巢癌的诊断标准；患者实验室检查结果与基本信息均记录完整。排除标准：伴有溶血、脾功能亢进、营养不良性贫血的上皮性卵巢癌患者。选择同期在本院进行体检的50例健康妇女纳入对照组。对照组受试者纳入标准：无妇科及其他系统肿瘤；排除标准：孕妇及经期妇女。顺铂耐药组与顺铂敏感组患者接受手术及以顺铂为基础的联合化疗治疗。顺铂耐药组与顺铂敏感组患者接受治疗后，以及对照组受试者体检时，空腹采集3组受试者外周静脉血，并检测其血清CA125水平、血清铁水平及血液学指标，统计3组受试者CA125阳性率、铁缺乏发生率及贫血发生率。统计学比较顺铂耐药组、顺铂敏感组及对照组受试者血清CA125水平、血清铁水平、血液学指标，以及CA125阳性率、铁缺乏发生率及贫血发生率。本研究遵循的程序符合长江大学附属第一医院人体试验委员会所制定的伦理学标准，得到该委员会批准。3组受试者年龄、吸烟史、婚姻状况及生育状况等一般临床资料比较，差异均无统计学意义（P〉0．05）。结果①顺铂耐药组、顺铂敏感组及对照组受试者血清CA125水平中位数分别为489．4×10^-3U／L、362．8×10^-3U／L及14．2×10^-3U／L，3组比较，差异有统计学意义（χ^2=74．008，P=0．000）。其中，顺铂耐药组与顺铂敏感组血清CA125水平均显著高于对照组，并且差异均有统计学意义（t=4．576、4．700，P=0．000、0．000）；顺铂耐药组与顺铂敏感组血清CA125水平比较，差异却无统计学意义（t=1．831，P=0．099）。②顺铂耐药组、顺铂敏感组及对照组受试者血清铁水平中位数分别为3．5μmol／L、7．3μmol／L及16．3μmol／L，3组比较，差异有统计学意义（χ^2=77．710，P=0．000）。其中，顺铂耐药组与顺铂敏感组血清铁水平均显著低于对照组，并且差异均有统计学意义（t=52．958、19．268，P=0．000、0．000）；顺铂耐药组血清铁水平显著低于顺铂敏感组，并且差异亦有统计学意义（t=11．63，P=0．002）。③顺铂耐药组、顺铂敏感组及对照组受试者红细胞计数、血红蛋白（Hb）水平、血细胞比容（HCT）、平均血红蛋白浓度（MCHC）比较，差异均有统计学意义[红细胞计数：（3．2±0．5）×10^12／L、（3．6±0．5）×10^12／L及（4．1±0．4）×10^12／L，F=35．991，P=0．000；Hb水平：（92．6±15．3）g／L、（105．7±13．8）g／L及（121．8±12．2）g／L，F=47．329，P=0．000；HCT：（28．3±4．5）％、（31．8±4．0）％及（36．6±3．5）％，F=45．804，P=0．000；MCHC：（326．2±11．7）g／L、（333．O±12．6）g／L及（334．4±8．3）g／L，F=6．116，P=0．003]；3组受试者的平均红细胞体积（MCV）与平均血红蛋白量（MCH）比较，差异却均无统计学意义EMCV：（88．0±9．1）fl、（88．5±5．0）fl与（89．6±4．2）fl，F=0．747，P=0．476；MCH：（28．7±3．3）pg、（29．4±1．8）pg与（29．9±1．6）pg，F=2．942，P=0．057]。其中，顺铂耐药组与顺铂敏感组红细胞计数、Hb水平、HCT均显著低于对照组，并且差异均有统计学意义（均为P=0．000）；顺铂耐药组红细胞计数、Hb水平、HCT均显著低于顺铂敏感组，并且差异亦有统计学意义（P=0．001、0．000、0．000）。顺铂耐药组MCHC低于对照组，且差异有统计学意义（P=0．001）；顺铂敏感组MCHC与对照组相比，差异无统计学意义（P=0．538）；顺铂耐药组MCHC低于顺铂敏感组，差异有统计学意义（P=0．010）。④顺铂耐药组、顺铂敏感组及对照组受试者CA125阳性率、铁缺乏发生率及贫血发生率比较，差异均有统计学意义（CA125阳性率：93．9％、89．5％及4．0％，χ^2=91．144，P=0．000；铁缺乏发生率：81．8％、42．1％及4．0％，χ^2=52．101，P=0．000；贫血发生率：81．8％、57．9％及12．0％，χ^2=42．543，P=0．000）。其中，顺铂耐药组CA125阳性率、铁缺乏发生率及贫血发生率均显著高于对照组，并且差异均有统计学意义（χ^2=67．139、52．958、40．459，P=0．000、0．000、0．000）。顺铂敏感组CA125阳性率、铁缺乏发生率及贫血发生率亦均显著高于对照组，并且差异均有统计学意义（χ^2=65．252、19．268、19．268，P=0．000、0．000、0．000）。顺铂耐药组铁缺乏发生率显著低于顺铂敏感组，并且差异亦有统计学意义（χ^2=11．630，P=0．001）；而顺铂耐药组与顺铂敏感组CA125阳性率及贫血发生率相比，差异却无统计学意义（χ^2=0．455、4．727，P=0．500、0．030）。结论上皮性卵巢癌患者可出现铁缺乏及贫血现象，并且顺铂耐药上皮性卵巢癌患者铁缺乏更为严重。这提示对上皮性卵巢癌患者铁缺乏进行干预，可能是改善其顺铂耐药的潜在途径，而补铁治疗有望成为辅助治疗顺铂耐药上皮性卵巢癌的有效措施。

Objective To investigate the relationship between iron deficiency, anemia and cisplatin resistance in epithelial ovarian cancer patients. Methods From January 2011 to November 2014, a total of 71 cases of patients who were diagnosed as epithelial ovarian cancer in First Affiliated Hospital of Yangtze University were collected into this study as study subjects. All the patients were divided into cisplatin resistant group （33 cases） and cisplatin sensitive group （38 cases） according to whether they were resistant to cisplatin or not. Inclusion criteria of cisplatin resistant groups and cisplatin sensitive group： all patients were diagnosed as epithelial ovarian cancer by biopsy, and the results were conformed to diagnosis of epithelial ovarian cancer in Obstetrics and Gynecology （7th edition） ; and all laboratory test results and basic information were recorded completely. Exclusion criteria： epithelial ovarian cancer patients with hemolysis, hypersplenism, malnourished anemia. And 50 cases of healthy female during the same period in the same hospital were collected into control group. Inclusion criteria of control group： without gynecological tumors or other system tumors. Exclusion criteria： pregnant women and menstruating women. Blood sample from these three groups were collected, and CA125 level, serum iron level and indexes of hematology in all patients were tested. Then, CA125 positive rate, incidence of iron deficiency and anemia were calculated. Serum CA125 level, serum iron level, hematology indexes, and CA125 positive rate, incidence of iron deficiency and anemia among cisplatin resistant group, cisplatin sensitive group and control group were statistically analyzed. The study protocol was approved by the Ethical Review Board of Investigation in Human Being at First Affiliated Hospital of Yangtze University. There were no statistically significant differences of patients＇ clinical data such as age, smoking history, marital status, and fertility status among three groups （P〉0.05）. Results ① The median of serum CA125 level of subjects in cisplatin resistant group, cisplatin sensitive group and control group were 489. 4 × 10^-3 U/L, 362. 8×10^-3 U/L and 14.2×10^-3 U/L, respectively. And there was statistically significant difference of CA125 level among three groups（χ^2= 74. 008,P=0. 000）. The median of serum CA125 level of cisplatin resistant group and eisplatin sensitive group were significantly higher than that of control group, and all the differences were statistically significant （t=4.576, 4. 700; P=0. 000, 0. 000）. But there was no statistical significance of serum CA125 level between cisptatin resistant group and cisplatin sensitive group（t=1. 831, P = 0. 099）. ② Serum iron level of subjects in cisplatin resistant group, cisplatin sensitive group and control group were 3.5 μmol/L, 7.3 μmol/L and 16.3 μmol/L, respectively. And there was statistically significant difference of serum iron level among three groups（χ^2= 77. 710, P = 0. 000）. Serum iron level of cisplatin resistant group and cisplatin sensitive group were both significantly lower than that of control group, and the differences were statistically significant（t=52. 958, 19. 268; P=0. 000, 0. 000）. And serum iron level of cisplatin resistant group was significantly lower than that of cisplatin sensitive group（t= 11. 630, P = 0. 002）. ③There were statistically significant differences of red blood cell count, hemoglobin （Hb） level, hematocrit （HCT） and mean corpuscular hemoglobin concentration （MCHC） among cisplatin resistant group, cisplatin sensitive group and control group[red blood cell count： （3. 2±0.5）×10^12/L, （3. 6±0.5）×10^12/L and （4.1±0.4）×10^12/L, F=35. 991, P=0. 000; Hb level：（92.6±15.3）g/L,（105.7±13.8）g/L and （121.8±12.2）g/L, F=47.329, P=0.000; HCT： 28.3%±4.5%, 31.8%±4.0% and 36.6%±3.5%, F=45.804, P= 0. 000; MCHC：（326.2±11.7）g/L,（333.0±12.6）g/L and（334.4±8.3）g/L, F=6.116, P=0. 003]. But there were no statistical significances of mean corpuscular volume （MCV） and mean corpuscular hemoglobin （MCH） among three groups[-MCV： （88.05±9.1）fl, （88.55±5.0）fl and （89.6±4.2）fl, F=0. 747,P= 0.476; MCH：（28.7±3.3）pg,（29.4±1.8）pg and（29.95±1.6）pg, F=2.942, P=0.0571. Red blood cell count, Hb level and HCT of cisplatin resistant group and cisplatin sensitive group were all significantly lower than those of control group （P = 0. 000）. And these indexes of cisplatin resistant group were significantly lower than those of cisplatin sensitive group（P=0. 001, 0. 000, 0. 000）. MCHC of cisplatin resistant group was significantly lower than that of control group（P = 0. 001）; but there was no statistical significance of MCHC between cisplatin sensitive group and control group（P=0. 538）; MCHC of cisplatin resistant group was significantly lower than that of cisplatin sensitive group （P= 0. 010）. ④There were statistically significant differences of CA125 positive rate, incidence of iron deficiency and anemia among cisplatin resistant group, cisplatin sensitive group and control group（CA125 positive rate： 93.9%, 89.5% and 4.0%, χ^2= 91. 144, P = 0. 000; incidence of iron deficiency： 81.8 %, 42.1% and 4.0 %, χ^2= 52. 101, P=0. 000;incidence of anemia：81.8%, 57.9% and 12.0% ,χ^2=42. 543,P=0. 000）. CA125 positive rate, incidence of iron deficiency and anemia of cisplatin resistant group were significantly higher than those of control group（χ^2 =67. 139, 52. 958, 40. 459; P=0. 000, 0. 000, 0. 000）. And these indexes of cisplatin sensitive group were significantly higher than those of control group （χ^2 = 65. 252, 19. 268, 19. 268; P = 0. 000, 0. 000, 0. 000）. The incidence of iron deficiency in cisplatin resistant group were significantly lower than those of cisplatin sensitive group（χ^2= 11. 630, P= 0. 001）, while there were no statistical differences of CA125 positive rate and incidence of anemia between cisplatin resistant group and cisplatin sensitive group （χ^2=0. 455, 4. 727; P=0. 500, 0. 030）. Conclusions Iron deficiency and anemia can be found in epithelial ovarian cancer patients, and those symptoms will be more severe in cisplatin resistant patients with epithelial ovarian cancer. It may indicate that iron deficiency intervention can be the potential method to improve epithelial ovarian cancer patients＇ sensitivity to cisplatin, while the iron supplement is expected to become an effectively auxiliary measure for the treatment of epithelial ovarian cancer eisplatin resistance.