Adjuvant chemotherapy for advanced endometrial cancer

  • Review
  • Intervention

Authors


Abstract

Background

Approximately 13% of women diagnosed with endometrial cancer present with advanced stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV). The standard treatment of advanced endometrial cancer consists of cytoreductive surgery followed by radiation therapy, or chemotherapy, or both. There is currently little agreement about which adjuvant treatment is the safest and most effective.

Objectives

To evaluate the effectiveness and safety of adjuvant chemotherapy compared with radiotherapy or chemoradiation, and to determine which chemotherapy agents are most effective in women presenting with advanced endometrial cancer (FIGO stage III/IV).

Search methods

We searched the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 2013), MEDLINE and EMBASE up to November 2013. Also we searched electronic clinical trial registries for ongoing trials.

Selection criteria

Randomised controlled trials (RCTs) of adjuvant chemotherapy compared with radiotherapy or chemoradiation in women with FIGO stage III and IV endometrial cancer.

Data collection and analysis

Two review authors selected trials, extracted data, and assessed trials for risk of bias. Where necessary, we contacted trial investigators for relevant, unpublished data. We pooled data using the random-effects model in Review Manager (RevMan) software.

Main results

We included four multicentre RCTs involving 1269 women with primary FIGO stage III/IV endometrial cancer. We considered the trials to be at low to moderate risk of bias. All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy; one trial evaluating 552 women (88% stage III, 12% stage IV) compared two chemotherapy regimens (cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment) in women who had all undergone adjuvant radiotherapy; and one trial contributed no data.

Overall survival (OS) and progression-free survival (PFS) was longer with adjuvant chemotherapy compared with adjuvant radiotherapy (OS: hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.57 to 0.99, I² = 22%; and PFS: HR 0.74, 95% CI 0.59 to 0.92, I² = 0%). Sensitivity analysis using adjusted and unadjusted OS data, gave similar results. In subgroup analyses, the effects on survival in favour of chemotherapy were not different for stage III and IV, or stage IIIA and IIIC (tests for subgroup differences were not significant and I² = 0%). This evidence was of moderate quality. Data from one trial showed that women receiving adjuvant chemotherapy were more likely to experience haematological and neurological adverse events and alopecia, and more likely to discontinue treatment (33/194 versus 6/202; RR 5.73, 95% CI 2.45 to 13.36), than those receiving adjuvant radiotherapy. There was no statistically significant difference in treatment-related deaths between the chemotherapy and radiotherapy treatment arms (8/309 versus 5/311; Risk Ratio (RR) 1.67, 95% CI 0.55 to 5.00).

There was no clear difference in PFS between intervention groups in the one trial that compared CDP versus CD (552 women; HR 0.90, 95% CI 0.69 to 1.17). We considered this evidence to be of moderate quality. Mature OS data from this trial were not yet available. Severe haematological and neurological adverse events occurred more frequently with CDP than CD.

We found no trials to include of adjuvant chemotherapy versus chemoradiation in advanced endometrial cancer; however we identified one ongoing trial of this comparison.

Authors' conclusions

There is moderate quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy in stage III and IV endometrial cancer. There is limited evidence that it is associated with more adverse effects. There is some uncertainty as to whether triplet regimens offer similar survival benefits over doublet regimens in the long-term. Further research is needed to determine which chemotherapy regimen(s) are the most effective and least toxic, and whether the addition of radiotherapy further improves outcomes. A large trial evaluating the benefits and risks of adjuvant chemoradiation versus chemotherapy in advanced endometrial cancer is ongoing.

摘要

輔助化療對於晚期的子宮內膜癌

背景

被診斷出子宮內膜癌時,約有13%的人是屬於晚期的階段(世界級婦科聯盟(International Federation of Gynecology and Obstetrics),分期3~4)。標準的治療末期子宮內膜癌,包含減積手術後放射線治療、化學療法或是雙重療法。近期對於輔助性治療方式的安全性和有效性,仍是具有爭議的。

目的

評估輔助性化療和放射線治療或是話放線治療其安全性及有效性。並決定對於末期的子宮內膜癌病患,那一種的化學療藥物是最有效的治療方式。

搜尋策略

我們搜尋)Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL)(第10期2013年)。Medline和EMBASE至2013年11月。同時,我們搜尋電子臨床試驗註冊為正在進行的試驗。

選擇標準

針對診斷被世界級婦科聯盟分期為第三期或是第四期的子宮內膜癌的女性患者,運用隨機對照試驗(Randomised controlled trials)對輔助性化療和放射線治療或是化療放射性治療相比較。

資料收集與分析

二位回顧作者會去選擇試驗,萃取數據並評估試驗的偏差風險。必要時,我們將接觸試驗的研究者,以收集相關未公佈的數據。我們匯集在Review Manager (RevMan) 軟體上,利用隨機效果的模型。

主要結果

這包含四個複合中心隨機對照試驗,含有1269位女性罹患有世界級婦科聯盟分期為第三、四期的子宮內膜癌症病患。因考慮到低到中等的偏差風險。全部的參與者都有接受減積手術。其中二個試驗,評估620位女性患者(83%第三期,17%第四期)。第一個為比較輔助性化學治療方式和輔助性放射性治療,另一個是包含552位女性患者(88%第三期,12%第四期)相比較二種化學治療的療程(cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment)及正在接受輔助性放射性治療的患者和一個試驗沒有貢獻其數據。

整體存活率(Overall survival)和無惡化的生存率(progression-free survival),輔助性化療較輔助放射線治療長久(整體存活率:危險比(hazard ratio)0.75,95%可信賴區間(confidence interval)0.57〜0.99,β= 22%;和PFS :危險比 0.74,95%信賴區間為0.59〜0.92,β= 0%)。敏感性分析使用調整和未經調整的整體存活率數據,有相似的結果。在亞組分析,對生存有利的化學治療效果,在分期為第3和第4或是分期3a 和3b並沒有不同(測試亞組差異不顯著和I²= 0%)。這一個證據是中等品質。從一個試驗數據中顯示,接受輔助化療的女性,相較於接受輔助放射線治療,更容易出現血液、神經系統的副作用反應或是掉髮,而且更容易中斷治療(33/194 v.s 6/202; 危險率(Risk Ratio )5.73,95%信賴區間為2.45至13.36)。與治療相關的致死率,在化學治療組別和放射線治療組別之間,並沒有統計上意義的不同(8/309 v.s 5/311; 風險率1.67, 95% 信賴區間 0.55 to 5.00)。

在其中的一個試驗中,無惡化的生存率,在CDP 和 CD組比較之下沒有明顯的差異(552 女性; 危險比 0.90, 95% 信賴區間 0.69 to 1.17)。我們認為這個證據是中等品質。成熟的整體存活率數據尚未公佈。 CDP組相較於CD組有較頻繁的嚴重的血液和神經系統副作用。

我們沒有發現任何試驗有涵括,對晚期子宮內膜癌的輔助性化療和放射化療做比較;然而,我們有確認一個正在進行此種比較的試驗。

作者結論

中等品質的證據顯示,化療將增加手術後的存活時間,相對於約25%放射線治療第3到4期的子宮內膜癌。有限的證據顯示與更多的有關。副其關聯性。在長期下,不確定三療法提供優於雙重療法類似的生存優勢。需要進一步的研究以確定哪些化療方案(多個)是最有效和毒性最小,並確定是否在加入放射線治療能進一步提高其效果。一個評估輔助性化放療與化學治療的益處與風險,對於末期子宮內膜癌的大型試驗研究正進行中。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Plain language summary

Chemotherapy after surgery for stage III and IV endometrial cancer

The issue: Advanced endometrial cancer (FIGO stage III and IV) is cancer of the womb which has spread beyond the womb to the ovaries, vagina, other adjacent tissues, draining lymph nodes, or other organs. Women are usually treated by surgery to remove as much of the tumour as possible. They are then offered adjuvant (meaning 'added') radiotherapy (high energy x-rays and other rays that destroy cancer cells), or chemotherapy (anti-cancer drugs), or both. There is uncertainty as to which treatment (radio- or chemotherapy or both) after surgery has the greatest effect on survival, and which anti-cancer drugs work best.

The aim of the review: We aimed to determine whether chemotherapy after surgery is effective compared to radiotherapy, in women with advanced cancer of the womb.

How was the review conducted? We searched the literature from 1966 to November 2013 for relevant randomised controlled trials (RCTs). We included four RCTs which were at low to moderate risk of bias and involved 1269 women. We wrote to the investigators of three trials for unpublished data. Three of the four trials compared similar interventions (chemotherapy versus radiotherapy after surgery). We pooled survival data (including the unpublished data) from two trials and await unpublished data for the third trial. The fourth trial compared two types of chemotherapy treatments after all women had received surgery and radiotherapy.

What are the main findings? Women who received chemotherapy after surgery (starting within eight weeks of surgery) survived approximately 25% longer than those receiving radiotherapy after surgery. Assuming that 60% of women with stage III endometrial cancer usually survive at least five years after surgery and radiotherapy, this would increase to 75% if they receive surgery and chemotherapy instead, depending on other risk factors, such as age. The risk of death which might have been caused by treatment was low with both chemotherapy and radiotherapy but we could not be sure if one was more harmful than the other. Chemotherapy may be associated with more side-effects (low blood counts, nerve damage and hair loss) compared with radiotherapy.

In the trial that compared two different chemotherapy treatments, there was no clear evidence that using three anti-cancer drugs was better than using two. However, the final overall survival results of this trial have not yet been reported. Severe side-effects were much more common in women treated with three anti-cancer drugs than two drugs.

What are the conclusions? Chemotherapy appears to be more effective than radiotherapy after surgery for women with stage III and IV endometrial cancer but may cause more side-effects. More research is needed to determine whether the addition of radiotherapy to chemotherapy improves outcomes and which anti-cancer drugs are best.

Laički sažetak

Kemoterapija nakon operacije za treći i četvrti stadij karcinoma endometrija

Problem: uznapredovali rak endometrija (FIGO stadij III i IV) je rak maternice koji se proširio izvan maternice na jajnike, rodnicu, druga susjedna tkiva, limfne čvorove ili druge organe. Žene se obično podvrgavaju operaciji kako bi se uklonilo što više tumora je moguće. Često im se nudi adjuvantna (dodatna) terapija zračenjem - radioterapija (visokoenergetske X-zrake i ostale zrake koje uništavaju tumorske stanice) ili kemoterapija ili oboje. Nije sigurno koja terapija (radio- ili kemoterapija ili obje) nakon operacije imaju najbolji učinak na preživljenje i koji antitumorski lijekovi najbolje djeluju.

Cilj pregleda: utvrditi je li kemoterapija nakon operacije učinkovita u usporedbi s radioterapijom u žena s uznapredovalim rakom maternice.

Kako je sustavni pregled proveden? Pretražena je literatura objavljena od 1966. do studenog 2013. kako bi se pronašle randomizirane kontrolirane studije (engl. randomised controlled trials, RCTs). Uključene su ukupno četiri studije koje su imale niski ili srednji rizik pristranosti i uključivale 1269 žena. Voditelji tri studije su kontaktirani kako bi se pokušali dobiti neobjavljeni podatci. Tri od četiri studije uspoređivale su slične intervencije (kemoterapija u usporedbi s radioterapijom nakon operacije). Zbirno su analizirani podatci o preživljenju (uključujući neobjavljene podatke) iz dvije studije, a u tu analizu će se moći uključiti i neobjavljeni podatci iz treće studije kad ih autori dostave. Četvrta studije je uspoređivala dvije vrste kemoterapije nakon što su sve žene podvrgnute operaciji i radioterapiji.

Koji su glavni rezultati? Žene koje su primile kemoterapiju nakon operacije (s početkom unutar osam tjedana nakon operacije) imale su oko 25% dulje preživljenje od onih koje su primale radioterapiju. Uz pretpostavku da 60% žena u trećem stadiju raka endometrija obično prežive barem pet godina nakon operacije i radioterapije, taj postotak bi se popeo na 75% ako su podvrgnute operaciji i kemoterapiji umjesto toga, ovisno o faktorima rizika, poput dobi. Rizik od smrti koja bi mogla biti izazvana terapijom je bio nizak i za kemoterapiju i za radioterapiju, ali ne možemo biti sigurni da je jedna terapija sigurnija od druge. Kemoterapija može biti povezana sa više nuspojava (niski broj krvnih stanica, oštećenja živaca i gubitak kose) u usporedbi s radioterapijom.

Studija koja je uspoređivala različite kemoterapijske režime nije našla jasne dokaze da je korištenje tri antitumorska lijeka bolje od korištenja dva. Završni rezultati preživljenja te studije još nisu objavljeni. Ozbiljne nuspojave su bile češće u žena koje su primale tri antitumorska lijeka od onih koje su primale dva.

Koji su zaključci? Kemoterapija se čini učinkovitija od radioterapije nakon operacije za žene sa trećim i četvrtim stadijem raka endometrija, ali može izazvati više nuspojava. Potrebno je još istraživanja kako bi se utvrdilo jesu li ishodi bolji dodatkom radioterapije kemoterapiji i koji su antitumorski lijekovi najbolji.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

淺顯易懂的口語結論

針對第三期及第四期的內宮內膜癌,在手術後的化學治療

議題: 末期的子宮內膜癌(世界級婦科聯盟,分期第三期及第四期)是一個子宮性的癌症,這是一個已經擴散到卵巢陰道或是其他組織的淋巴結,或甚至是擴散到其他器官。多數女姓患者是採取外科手術,盡可能地切除腫瘤。此外,還會有合併放射線的治療(高能量的放射線治療及其他可以破壞癌細胞的放射線)或是化學治療(抗癌症藥物)或合併以上的治療。在外科手術後,哪一種治療方式可以有效的提高生存率還不是很明確,而哪一種抗癌症藥物的作用是最為有效的也還不清楚。

此回顧的目標: 我們的目標是將決定出,對於罹患末期子宮內膜癌病患而言,在手術後,接受化學治療或是放射線治療哪一種是有效的。

此回顧是如何進行? 我們搜尋了從1966年到2013年11月的相關隨機對照試驗。包含從低風險到中等風險的四個隨機系統,回顧含有1269位女性。我們寫信給三個未發表數據的試驗調查人員。在第四項中的三項試驗,比較了類似的介入措施(化療與放療手術後)。我們從兩個試驗中匯集的生存數據(包括未發表的數據),並等待第三個未公佈的數據的試驗。第四個試驗,比較所有手術和放療後的患者,接受兩種不同種類化療的效果。

主要成果? 手術後(八個星期接受過手術)接受化療婦女,存活率比手術後接受放療的,約多於25%。假設第三期的子宮內膜癌病患通常存活在手術和放療的至少五年後存活率是60%,這增加至75%。如果他們接受手術和而非化療,端看其危險因素,如年齡。死亡的風險性,會造成化學治療和放射線治療二者的低的治療意願,但我們也不能肯定,哪一個比另一個更有其毒性。化療像較於放射線治療有其更多的副作用(低血細胞數量、神經損傷和掉髮)。

在這種比較了兩種不同的化療試驗,也沒有明確的證據顯示,結合使用三個抗癌藥物比使用兩個更有其療效。然而,該試驗最終總體存活結果還沒有被報導。合併使用三種抗癌症藥物相較於使用二種抗癌藥物,有嚴重的副作用。

什麼結論? 對於手術後的第三到四期的子宮內膜癌,化療似乎比放療後更有效的,但可能會導致更多的副作用。更多的研究試驗是被需要的,以確在化療後增加放射線治療是否能改善其預後,或是哪一種的抗癌藥物是有其最佳的療效。

譯註

翻譯者:臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw