阮寒光,周學(xué)亮,程曉華,鄔蒙
(1.南昌市第三醫(yī)院乳腺腫瘤診治中心乳腺腫瘤內(nèi)科,江西330003;2.南昌大學(xué)江西醫(yī)學(xué)院第一附屬醫(yī)院乳腺外科,江西南昌330015;3.南昌大學(xué)江西醫(yī)學(xué)院第一附屬醫(yī)院藥理研究所,江西南昌330015;4.江西省腫瘤醫(yī)院乳腺腫瘤放射治療科,南昌330029;5.南昌大學(xué)江西醫(yī)學(xué)院研究生院醫(yī)學(xué)部,江西南昌330006)
紫杉醇脂質(zhì)體聯(lián)合卡培他濱治療老年晚期三陰乳腺癌臨床療效觀察
阮寒光1,5,周學(xué)亮2△,程曉華3,鄔蒙4
(1.南昌市第三醫(yī)院乳腺腫瘤診治中心乳腺腫瘤內(nèi)科,江西330003;2.南昌大學(xué)江西醫(yī)學(xué)院第一附屬醫(yī)院乳腺外科,江西南昌330015;3.南昌大學(xué)江西醫(yī)學(xué)院第一附屬醫(yī)院藥理研究所,江西南昌330015;4.江西省腫瘤醫(yī)院乳腺腫瘤放射治療科,南昌330029;5.南昌大學(xué)江西醫(yī)學(xué)院研究生院醫(yī)學(xué)部,江西南昌330006)
目的觀察紫杉醇脂質(zhì)體聯(lián)合卡培他濱(TX)治療老年晚期三陰乳腺癌(TNBC)的療效及發(fā)生不良反應(yīng)情況。方法回顧性分析該院2013年1月至2015年1月收治的54例臨床分期為ⅢA~C、Ⅳ期的原發(fā)性老年晚期TNBC患者的臨床資料,將其分為TX組和紫杉醇脂質(zhì)體聯(lián)合順鉑(TP)組各27例。TX組:紫杉醇脂質(zhì)體150 mg/m2,第1天靜脈滴注,卡培他濱1 000 mg/m2,第1~14天口服,每天2次,同時(shí)給予維生素B630 mg口服,每天3次,預(yù)防手足綜合征,21 d為1個(gè)周期;TP組:紫杉醇脂質(zhì)體150 mg/m2,第1天靜脈滴注,順鉑25 mg/m2,第1~3天靜脈滴注,21 d為1個(gè)周期。2個(gè)周期后評(píng)價(jià)兩組療效,最多不超過6個(gè)周期。待所有患者完成化療后對比分析兩組近期療效及不良反應(yīng)。結(jié)果54例老年晚期TNBC輔助化療中,總有效率為68.5%(37/54)。TP組有效率[63.0%(17/27)]高于TX組[74.1%(20/27)],但差異無統(tǒng)計(jì)學(xué)意義(χ2=0.773,P=0.379);TX組手指足綜合征發(fā)生情況明顯高于TP組,差異有統(tǒng)計(jì)學(xué)意義(χ2=44.220,P=0.000);且TP組惡心、嘔吐反應(yīng)發(fā)生情況明顯高于TX組,差異有統(tǒng)計(jì)學(xué)意義(χ2=14.172,P=0.001);兩組脫發(fā),肝、腎功能異常和血液學(xué)毒性發(fā)生情況比較,差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)。結(jié)論在臨床分期為ⅢA~C、Ⅳ期老年晚期TNBC患者的輔助化療中,TX方案與TP方案近期療效相當(dāng)。TX方案減輕了老年晚期TNBC患者胃腸道反應(yīng)的發(fā)生情況,但手足綜合征的發(fā)生情況增加;因此,在提前預(yù)防手足綜合征的情況下,TX方案可以作為老年晚期TNBC輔助化療方式之一。
乳腺腫瘤;脂質(zhì)體;紫杉酚;卡培他濱;不良反應(yīng)
三陰乳腺癌(TNBC)是指雌激素受體(ER)、孕激素受體和人類表皮生長因子受體-2(HER-2)均為陰性的乳腺癌,此類乳腺癌患者不能從內(nèi)分泌治療和赫賽汀(注射用曲妥珠單抗)靶向治療中獲益。TNBC的治療目前尚無統(tǒng)一的標(biāo)準(zhǔn)方案,有研究結(jié)果顯示,在輔助治療中含鉑方案具有一定優(yōu)勢[1-2]。由于含鉑方案對腎功能的損傷及胃腸道的影響,尤其對于老年患者更為明顯,部分老年患者不能耐受。目前,臨床針對老年晚期TNBC患者的輔助治療報(bào)道較少。本研究回顧性分析了52例老年晚期TNBC的臨床資料,觀察紫杉醇脂質(zhì)體聯(lián)合卡培他濱(TX)對老年晚期TNBC的療效與不良反應(yīng),以便為今后臨床治療方案的制訂提供依據(jù)。
1.1一般資料收集南昌市第三醫(yī)院2013年1月至2015年1月臨床分期為ⅢA~C、Ⅳ期[依據(jù)2003版美國腫瘤聯(lián)合會(huì)(AJCC)乳腺癌分期標(biāo)準(zhǔn)進(jìn)行分期]的原發(fā)性TNBC老年患者54例的臨床資料,且均為女性,年齡60~78歲,中位年齡67歲;輔助化療前均經(jīng)粗針活檢病理結(jié)果確診及免疫組織化學(xué)明確ER、孕激素受體、HER-2表達(dá)水平;卡氏評(píng)分(KPS評(píng)分)為70分以上;臨床具有可測量的病灶?;熐八谢颊呔?jīng)肝臟、肺部CT片和全身核素骨顯像檢查是否遠(yuǎn)處轉(zhuǎn)移及轉(zhuǎn)移的部位數(shù)量明確M分期?;颊邊^(qū)域淋巴結(jié)腫大經(jīng)粗針活檢病理結(jié)果確診,明確N分期,其中TX組27例,浸潤性導(dǎo)管癌12例,浸潤性小葉癌10例,其他5例;ⅢA~C期15例,Ⅳ期12例。紫杉醇聯(lián)合順鉑(TP)組27例,浸潤性導(dǎo)管癌15例,浸潤性小葉癌8例,其他4例;ⅢA~C期13例,Ⅳ期14例。所有患者在化療前均行血常規(guī),肝、腎功能,心電圖,心臟彩色多普勒超聲檢查,排除心、肝、腎功能嚴(yán)重?fù)p害。兩組患者在年齡、病理類型、臨床分期及KPS評(píng)分等方面比較,差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)。見表1。
1.2方法
1.2.1治療方法TX組:于化療前30min給予地塞米松10 mg靜脈注射及苯海拉明20 mg肌內(nèi)注射預(yù)防過敏反應(yīng),紫杉醇脂質(zhì)體150 mg/m2,第1天靜脈滴注,卡培他濱1 000 mg/m2,第1~14天口服,每天2次,同時(shí)給予維生素B630 mg口服,每天3次,預(yù)防手足綜合征,21 d為1個(gè)周期。TP組:紫杉醇脂質(zhì)體150 mg/m2,第1天靜脈滴注,順鉑25 mg/m2,第1~3天,靜脈滴注,21d為1個(gè)周期。每2個(gè)周期對兩組患者進(jìn)行療效評(píng)價(jià),治療有效化療持續(xù)至第6個(gè)周期。如疾病進(jìn)展(PD),則停止該方案治療?;熎陂g監(jiān)測兩組患者血常規(guī)及肝、腎功能。若臨床出現(xiàn)Ⅲ度以上不良反應(yīng),化療藥物劑量減量20%。
1.2.2療效判斷標(biāo)準(zhǔn)采用實(shí)體瘤治療療效評(píng)價(jià)(RECIST)標(biāo)準(zhǔn),乳腺腫瘤原發(fā)病灶及轉(zhuǎn)移病灶最大直徑縮小大于或等于30%為部分緩解(PR),增大大于或等于20%為PD。所有患者均由同一組醫(yī)生對腫瘤原發(fā)病灶及轉(zhuǎn)移病灶進(jìn)行評(píng)價(jià),化療后出現(xiàn)PD時(shí)終止化療。療效分為臨床完全緩解(CR)、PR、疾病穩(wěn)定(SD)及PD,臨床有效率(RR)=CR+PR。毒性反應(yīng)按WHO分級(jí)標(biāo)準(zhǔn)分為0、Ⅰ、Ⅱ、Ⅲ、Ⅳ級(jí)進(jìn)行評(píng)價(jià)。
表1 兩組患者臨床特征比較
1.3統(tǒng)計(jì)學(xué)處理應(yīng)用SPSS17.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)分析,采用Pearson χ2檢驗(yàn)或Fisher′s精確檢驗(yàn)。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
2.1兩組患者近期療效比較所有患者行2個(gè)及2個(gè)以上周期化療,最多不超過6個(gè)周期,共完成278個(gè)周期化療,平均5.15個(gè)周期。其中TX組完成143個(gè)周期,TP組完成135個(gè)周期。TX組2例患者因Ⅲ度手足綜合征經(jīng)2個(gè)周期化療后終止治療,而TP組1例患者出現(xiàn)Ⅳ度惡心、嘔吐后終止治療;TX組3例患者完成4個(gè)周期后出現(xiàn)PD改用其他方案治療,TP組2例患者4周期化療后因疾病進(jìn)展更改方案。54例老年晚期TNBC輔助化療中,總有效率為68.5%(37/54),TP組有效率[74.1%(20/27)]高于TP組[63.0%(17/27)],但差異無統(tǒng)計(jì)學(xué)意義(χ2=0.773,P=0.379)。見表2。未完成6個(gè)周期化療的患者評(píng)估其體力狀況及心、肺、肝、腎功能,決定是否采用繼續(xù)化療或最佳支持治療。而完成6個(gè)周期化療患者選擇繼續(xù)口服卡培他濱維持治療或觀察等待處理。
2.2兩組患者不良反應(yīng)發(fā)生情況比較兩組患者均出現(xiàn)不同程度骨髓抑制,如中性粒細(xì)胞、血小板及血紅蛋白減少,TX組Ⅲ+Ⅳ度骨髓抑制稍高于TP組,但差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)。在腎功能損傷方面,兩組患者不良反應(yīng)均較輕,可能與患者年齡均偏大、化療前及化療中預(yù)先給予相應(yīng)的處理措施有關(guān)。TX組發(fā)生手足綜合征明顯高于TP組,因發(fā)生Ⅲ度手足綜合征2個(gè)周期后終止治療的患者2例,兩組比較,差異有統(tǒng)計(jì)學(xué)意義(χ2=44.220,P=0.000);而TP組發(fā)生惡心、嘔吐明顯高于TX組,差異有統(tǒng)計(jì)學(xué)意義(χ2=14.172,P=0.001),且TP組1例患者出現(xiàn)Ⅳ度惡心、嘔吐后終止治療,兩組患者發(fā)生腹瀉均較低,差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)。兩組患者脫發(fā),肝、腎功能異常發(fā)生情況比較,差異均無統(tǒng)計(jì)學(xué)意義(P>0.05)。見表3。
表2 兩組患者近期療效比較
表3 兩組患者化療不良反應(yīng)發(fā)生情況比較(n)
臨床根據(jù)乳腺癌患者病理組織的免疫組織化學(xué)、腫瘤細(xì)胞形態(tài)及基因表達(dá)產(chǎn)物的不同,把乳腺癌分為4種亞型:Luminal A型、Luminal B型、HER-2過表達(dá)型和其他型。TNBC是指ER、孕激素受體和HER-2均為陰性乳腺癌。TNBC患者和“基底樣”患者有近80%的重合,但前者還包含一些特殊組織學(xué)類型,如低危(典型)髓樣癌及腺樣囊性癌。此類乳腺癌患者不能從內(nèi)分泌治療和赫賽汀靶向治療中獲益[3-5]。晚期TNBC包括局部晚期及轉(zhuǎn)移性乳腺癌,目前臨床治療手段仍是以化療為主的綜合治療為指導(dǎo)。已有大量研究證實(shí),紫杉醇類藥物及卡培他濱在乳腺癌的輔助治療中有效[6-12]。紫杉醇藥物加入脂蛋白后患者外周血液和肝臟毒性反應(yīng)明顯減弱,且顯著減弱對骨髓的抑制作用,其對血壓的影響及相關(guān)不良反應(yīng)發(fā)生率也明顯低于單純紫杉醇注射液,明顯提高了機(jī)體對紫杉醇的耐受性。本品在部分臟器中水平明顯增高,且呈靶向性??ㄅ嗨麨I是新一代氟尿嘧啶類口服治療藥物,具有應(yīng)用方便、生物利用度高等優(yōu)點(diǎn)??ㄅ嗨麨I作用于細(xì)胞S期,其特點(diǎn)是選擇性腫瘤內(nèi)活化,所以腫瘤組織中氟尿嘧啶濃度高而全身氟尿嘧啶濃度低,降低了全身毒性。而主要不良反應(yīng)為手足綜合征、惡心、嘔吐等[13]。本研究結(jié)果顯示,二者聯(lián)合治療不良反應(yīng)輕、療效肯定,且與蒽環(huán)類藥無交叉耐藥性。
本研究將TX方案應(yīng)用于老年晚期TNBC輔助治療中,取得了較好的效果,TP組有效率稍高于TX組,但差異無統(tǒng)計(jì)學(xué)意義(χ2=0.773,P=0.379)。一項(xiàng)臨床Ⅱ期研究結(jié)果顯示,卡培他濱聯(lián)合紫杉醇類藥物用于晚期乳腺癌的新輔助治療中,患者CR發(fā)生率為19.0%~22.0%。且總有效率達(dá)72.0%~97.6%[14-16]。而有研究結(jié)果顯示,卡培他濱單藥用于晚期乳腺癌的一線治療是安全、有效的[17-18]。與其他藥物聯(lián)合使用,總有效率達(dá)30.0%~70.0%[19],與本研究結(jié)果相似。在不良反應(yīng)方面,TX組主要表現(xiàn)為手足綜合征,3例患者發(fā)生Ⅲ度以上手足綜合征,且發(fā)生率為11.1%(3/27),其中2例患者因該不良反應(yīng)放棄治療,1例患者通過治療后堅(jiān)持治療完成整個(gè)療程。而TP組主要不良反應(yīng)為腎功能損傷,胃腸道中的惡心、嘔吐不適。Ⅲ度以上惡心、嘔吐發(fā)生率明顯高于TX組。Smorenburg等[20]進(jìn)行了一項(xiàng)臨床Ⅲ期試驗(yàn),將單藥脂質(zhì)體阿霉素或卡培他濱應(yīng)用于老年晚期乳腺癌的一線治療,兩組患者中位生存期分別為5.6、7.7個(gè)月,手足綜合征發(fā)生率分別為10.0%、16.0%,該結(jié)果與本研究報(bào)道的不良反應(yīng)發(fā)生情況相似。在老年乳腺癌患者中大多數(shù)年齡偏大,胃腸道反應(yīng)不適影響其進(jìn)食及營養(yǎng)吸收,從而導(dǎo)致該類患者體質(zhì)量下降,耽誤治療。而手足綜合征大多數(shù)表現(xiàn)為表面皮膚顏色改變及瘙癢、皸裂等,通常不影響患者營養(yǎng)狀態(tài)及內(nèi)臟功能。作者認(rèn)為,通過適當(dāng)?shù)膶ΠY治療,大部分發(fā)生手足綜合征的患者仍可以克服其不良反應(yīng),從而繼續(xù)治療。
本研究表明,TX方案對老年晚期TNBC有較好療效,且不良反應(yīng)通過相應(yīng)的對癥治療后可以克服,且藥物使用方便,因此,該方法可成為老年晚期TNBC的治療方案。
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Observation on clinical efficacy of docetaxel liposo me combined with capecitabine in treating elderly advanced 3-negative breast cancer
Ruan Hanguang1,5,Zhou Xueliang2△,Chen Xiaohua3,Wu Meng4(1.Department of Breast Oncology,DiagnosisandTreatmentCenterofBreastTumor,NanchangMunicipalThirdHospital,Jiangxi330003,China;2.Department of Breast Surgery,F(xiàn)irst Affiliated Hospital of Jiangxi Medical College,Nanchang University,Nanchang,Jiangxi 330015,China;3.Research Institute of Pharmacology,F(xiàn)irst Affiliated Hospital of Jiangxi Medical College,Nanchang University,Nanchang,Jiangxi330015,China;4.Department of Breast Oncology Radiotherapy,Jiangxi Provincial Tumor Hospital,Nanchang 330029,China;5.Department of Medicine,Postgraduate School,Jiangxi Medical College,Nanchang University,Nanchang,Jiangxi330006,China)
ObjectiveToobservetheefficacyandadversereactionsofdocetaxelliposomecombinedwithcapecitabine(TX)in the treatment of elderly advanced 3-negative breast cancer(TNBC).MethodsThe clinical data in 54 cases of clinical stageⅢA~C,Ⅳof elderly advanced TNBC in this hospital from January 2013 to January 2015 were retrospectively analyzed.All patients were divided into the TX group and docetaxel liposome combined with cisplatin group(TP),27 cases in each group.TX group was given docetaxel liposome 150 mg/m2by intravenous drip on 1 d and oral TX 1 000 mg/m2on 1-14 d twice daily,meanwhile oral vitamin B630 mg,3 times daily,for preventing hand-foot syndrome,with 21 d as 1 cycle;the TP group was given docetaxel liposome 150 mg/m2by intravenous drip on 1 d and cisplatin 25 mg/m2by intravenous drip on 1-3 d,with 21 d as 1 cycle.The efficacy was evaluated after 2 cycles,not more than 6 cycles.The short-term efficacy and adverse reactions were analyzed and compared between the two groups after finishing chemotherapy in all the cases.ResultsIn the adjuvant chemotherapy of 54 cases of elderly advanced TNBC,the total effective rate was 68.5%(37/54),the effective rate in the TP group was higher than that in the TX group without statistical difference[63.0%(17/27)vs.74.1%(20/27),χ2=0.773,P=0.379];the occurrence rate of hand-foot syndrome in the TX group was significantly higher than that in the TP group,the difference was statistically significant(χ2=44.220,P=0.000),moreover the occurrence rates of nausea and vomiting in the TP group was significantly higher than that in the TX group,the difference was statistically significant(χ2=14.172,P=0.001);but the occurrence of hair loss,liver and kidney function abnormality and hematological toxicology had no statistically significant difference between the two groups(P>0.05).Conclusion
In the adjuvant chemotherapy of clinical stageⅢA-C andⅣof elderly advanced TNBC,the TX regimen and TP regimen have the same short-term effect.The TX regimen alleviates the occurrence of gastrointestinal reactions,but the occurrence of hand-foot syndrome is increased;therefore in that case of preventing this complication in advance,the TX regimen may serve as one of adjuvant chemotherapeutic regimens in elderly advanced TNBC.
Breast neoplasms;Liposomes;Paclitaxel;Capecitabine;Side effects
10.3969/j.issn.1009-5519.2016.19.006
A
1009-5519(2016)19-2954-03
阮寒光(1982-),博士研究生,主治醫(yī)師,主要從事乳腺腫瘤放、化療的研究?!?/p>
,E-mail:jxcancer@163.com。
(2016-05-16)