畢書(shū)婷

[摘要] 目的 對(duì)培美曲塞聯(lián)合順鉑治療晚期非小細(xì)胞肺癌(NSCLC)進(jìn)行臨床療效和毒性評(píng)價(jià)。方法 45例經(jīng)病理組織學(xué)和/或細(xì)胞學(xué)檢查確診NSCLC,均為初治患者,其中男性28例,女性17例;年齡31~76歲,中位年齡58歲,鱗癌12例,腺癌30例,腺鱗癌3例,TNM分期:ⅢA7例,ⅢB16例,Ⅳ22例,應(yīng)用培美曲塞聯(lián)合順鉑治療,即培美曲塞500mg/m2,順鉑75mg/m2,21d為一周期,至少接受2個(gè)周期化療。按照WHO標(biāo)準(zhǔn)評(píng)價(jià)臨床療效和毒性。結(jié)果 45例患者中,無(wú)完全緩解(CR)病例,部分緩解(PR)10例,穩(wěn)定(SD)13例,進(jìn)展(PD)22例,有效率(CR+PR)22.22%,臨床獲益率(CR+PR+SD)51.11%,主要毒性反應(yīng)為骨髓抑制,胃腸道反應(yīng)。結(jié)論 培美曲塞聯(lián)合順鉑治療晚期NSCLC療效可靠,毒性反應(yīng)小,與國(guó)內(nèi)外文獻(xiàn)報(bào)道的緩解率及有效率類(lèi)似。

[關(guān)鍵詞] 培美曲塞;順鉑;晚期非小細(xì)胞肺癌;化療

[中圖分類(lèi)號(hào)] R734.2 [文獻(xiàn)標(biāo)識(shí)碼] A [文章編號(hào)] 1673-9701(2009)36-54-03

Pemetrexed Combined with Oxaliplatin in Treatment of Advanced Non-small Cell Lung Cancer:A Clinical Observation of 45 Cases

BI Shuting

Department of Respiratory,Nanjing Municipal Chest Hospital,Nanjing 210029,China

[Abstract]Objective To observe the clinical efficacy and adverse effects of pemetrexed combined with oxaliplatin to treat advanced non-small cell lung cancer. Methods Forty-five cases aged 31~76 years(a median age of 58 years)were newly diagnosed as advanced non-small cell lung cancer by histopathological and/or cytology,28 cases were male and 17 female,and in 45 cases,12 cases were squamous cell carcinoma,30 were adenocarcinoma and 3 were adenosquamous carcinoma. TNM staging showed 7 cases of ⅢA,16 cases of Ⅲ B and 22cases of Ⅳ. Pemetrexed 500mg/m2 and cisplatin 75mg/m2 were used for at least 2 cycles of chemotherapy with 21 days as a cycle. Based on WHO criteria,the clinical efficacy and toxicity were evaluated. Results In 45 patients,there were no cases of complete remission(CR),10 cases of partial remission(PR)13 cases of stablility(SD)and 22 cases of progress(PD). The effective rate(CR+PR)was 22.22% and the clinical benefit rate(CR+PR+SD) was 51.11%,and the main side effects were myelosuppression and gastrointestinal tract reaction. Conclusion The combination of pemetrexed and oxaliplatin in the treatment of advanced non-small cell lung cancer has reliable efficacy and fewer side effects,showing similar remission rate and effective rate reported in the literature at home and abroad.

[Key words] Pemetrexed;Cisplatin;Advanced non-small cell lung cancer;Chemotherapy

肺癌的發(fā)病率和死亡率在過(guò)去的一個(gè)世紀(jì)快速上升,至20 世紀(jì)末已經(jīng)成為世界范圍內(nèi)最重要的人群死因之一。肺癌是我國(guó)第三大惡性腫瘤,發(fā)病率也日益上升,目前已居城市中常見(jiàn)惡性腫瘤的首位。到2010 年我國(guó)肺癌患者將達(dá)到60 萬(wàn)。肺癌的新發(fā)病例中,非小細(xì)胞肺癌(NSCLC)約占85%,其中大部分為局部晚期(Ⅲ期)或轉(zhuǎn)移性(Ⅳ期)肺癌。除了極少部分Ⅲ期患者可以通過(guò)綜合治療手段獲得治愈以外,大部分晚期患者的治療目的是延長(zhǎng)生存期和提高生活質(zhì)量,化療在其中起到了重要作用。培美曲塞(pemetrexed,PEM)是一種新型的多靶點(diǎn)抗葉酸制劑,作用于葉酸依賴(lài)性代謝途徑中的多個(gè)酶,包括胸苷酸合成酶(TS),二氫葉酸還原酶(DHFR)和甘氨酰胺核苷甲?；D(zhuǎn)移酶(GARFT)等,從而抑制腫瘤細(xì)胞的生長(zhǎng)。由于其耐受性較好,不良反應(yīng)小,與鉑類(lèi)藥物聯(lián)合應(yīng)用治療晚期非小細(xì)胞肺癌(NSCLC)目前受到推崇[1-3]。從2006年6月起,我們觀(guān)察了培美曲塞、順鉑方案聯(lián)合治療晚期初治非小細(xì)胞肺癌患者45例,現(xiàn)報(bào)道如下。

1資料與方法

1.1一般資料

選取我院2006 年6月~2009 年6月經(jīng)病理組織學(xué)和/或細(xì)胞學(xué)檢查確診的晚期非小細(xì)胞肺癌患者45例,其中纖支鏡確診16例,經(jīng)皮肺穿刺確診13例,鎖骨上淋巴結(jié)活檢9例,痰細(xì)胞學(xué)確診4例,胸腔鏡下胸膜活檢確診3例,Karnofsky 評(píng)分≥60 分,預(yù)計(jì)生存時(shí)間3個(gè)月以上,可評(píng)估近期療效;肝腎功能及血常規(guī)均正常;均有可測(cè)量病灶。其中,ⅢA期7例,ⅢB期16例,Ⅳ期22例;年齡31~76 歲,中位年齡58歲;其中男性28例,女性17例;腺癌30例,鱗癌12例,腺鱗癌3例;均化療2個(gè)周期以上。

1.2 給藥方法

用藥前1 周開(kāi)始補(bǔ)充維生素B12、葉酸;給藥前1d、當(dāng)天及用藥后1d給予地塞米松口服。培美曲塞(美國(guó)禮來(lái)公司,力比泰Alimta)500mg/m2,10min靜脈注射,順鉑75mg/m2,21d為1個(gè)周期。每用藥2 個(gè)周期后進(jìn)行評(píng)價(jià)療效。

1.3療效和毒性反應(yīng)評(píng)價(jià)

療效評(píng)價(jià)按世界衛(wèi)生組織(WHO)1981年統(tǒng)一評(píng)價(jià)標(biāo)準(zhǔn),判定為完全緩解(CR),部分緩解(PR),穩(wěn)定(SD)和進(jìn)展(PD),近期有效率為(CR+PR)/總例數(shù)×100%,臨床獲益率為(CR+PR+ SD)/總例數(shù)×100%。毒性反應(yīng)按WHO化療藥物急性與亞急性毒性表現(xiàn)和分度標(biāo)準(zhǔn)進(jìn)行觀(guān)察和判斷,分為0～Ⅳ度。

2 結(jié)果

2.1 療效

45例患者均按計(jì)劃完成了相應(yīng)的治療,共化療112個(gè)周期,無(wú)中途退出及治療相關(guān)死亡發(fā)生。PR 10例,SD 13例,PD 22例。近期有效率22.22%,臨床獲益率51.11%,見(jiàn)表1。

2.2 不良反應(yīng)

骨髓抑制:以白細(xì)胞下降為主,其中Ⅰ～Ⅱ度的白細(xì)胞下降9例(20.00%),Ⅲ度1例(2.22%);血紅蛋白降低8例(17.78%);血小板降低5例(11.11%);胃腸道反應(yīng):由于化療前對(duì)胃腸道反應(yīng)有預(yù)處理,Ⅰ度惡心嘔吐6例,占13.33%;Ⅱ度惡心嘔吐3例,占6.67%;有9 例發(fā)生靜脈炎,占20.00%;5例末梢神經(jīng)炎,占11.11%;7例肝功能損害,占15.56%;4例輕度腎臟毒性發(fā)生,占8.89%;心電圖異常6例,占13.33%;皮疹2例,占4.44%;口腔炎3例,占6.67%;無(wú)治療相關(guān)性死亡。見(jiàn)表2。

3討論

培美曲塞是一種新型的抗代謝藥物,結(jié)構(gòu)上含有核心為吡咯嘧啶基團(tuán)的抗葉酸制劑,表現(xiàn)為多靶點(diǎn)抗葉酸代謝,能夠抑制幾種與嘌呤和嘧啶分泌相關(guān)的葉酸依賴(lài)性酶,抑制細(xì)胞復(fù)制,從而抑制腫瘤的生長(zhǎng)。已表現(xiàn)出對(duì)多種腫瘤的抗癌活性,包括大腸癌、乳腺癌、肺癌、胰腺癌、間皮瘤及胃癌等[4]。但值得注意的是,PEM 組骨髓抑制的發(fā)生率和嚴(yán)重程度明顯低于現(xiàn)在較為流行的一線(xiàn)化療藥物如多西他賽、吉西他濱等。該藥已被美國(guó)FDA批準(zhǔn)二線(xiàn)治療NSCLC[5],隨著培美曲塞廣泛用于臨床,其療效較好,較低的累積毒性及副反應(yīng)得到了廣泛的應(yīng)用。有鑒于此,FDA于2008年9月30日又正式批準(zhǔn)增加培美曲塞的適應(yīng)證,允許其與順鉑聯(lián)用作為局部惡化和轉(zhuǎn)移并伴有非鱗狀組織學(xué)特性的非小細(xì)胞肺癌(NSCLC)的一線(xiàn)治療方案。而PEM 與鉑類(lèi)藥物聯(lián)合治療晚期NSCLC的Ⅱ期臨床研究[6-7]表明,PEM/鉑類(lèi)聯(lián)合方案的療效與其他常用的含鉑兩藥方案相似,而毒性反應(yīng)的發(fā)生率則明顯較低[8]。本組治療45 例晚期患者,近期有效率22.22%,臨床獲益率51.11%,與報(bào)道[9-10]結(jié)果相近。

培美曲塞主要毒副作用為Ⅲ～Ⅳ度白細(xì)胞減少、皮疹、貧血以及肝功能異常,血小板減少少見(jiàn)。補(bǔ)充葉酸和維生素能夠降低骨髓毒性的發(fā)生率,口服地塞米松可預(yù)防皮疹的發(fā)生。本組病人均予以地塞米松口服及補(bǔ)充葉酸和維生素,未有皮疹發(fā)生,Ⅲ～Ⅳ度白細(xì)胞下降也極為罕見(jiàn)。Ⅱ度白細(xì)胞下降和Ⅰ～Ⅱ度的非血液學(xué)毒性,經(jīng)升白細(xì)胞治療等對(duì)癥處理后可好轉(zhuǎn)。順鉑的主要副作用表現(xiàn)為胃腸道反應(yīng)、脫發(fā)等,經(jīng)鎮(zhèn)吐等對(duì)癥處理可改善。部分患者還存在有靜脈炎,可能與藥物濃度及給藥速度有關(guān),選深靜脈、增大稀釋比例和迅速?zèng)_洗靜脈可減少其發(fā)生率。綜上所述,PEM/鉑類(lèi)聯(lián)合化療方案使用未見(jiàn)嚴(yán)重的毒副反應(yīng)及治療相關(guān)死亡,而且以上毒性大多能在下一周期化療前恢復(fù)。

總之,培美曲塞與順鉑聯(lián)合治療晚期非小細(xì)胞肺癌可獲較高療效,且毒性低,耐受性、安全性好,是目前擁有較為理想近期療效的方案,值得在臨床中加以應(yīng)用。但該方案出現(xiàn)時(shí)間并不長(zhǎng),其中遠(yuǎn)期療效還有待進(jìn)一步大規(guī)模隨訪(fǎng)、統(tǒng)計(jì)并加以總結(jié)。

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(收稿日期:2009-09-24)