Single agent versus combination chemotherapy for metastatic breast cancer

  • Review
  • Intervention

Authors


Abstract

Background

Combination chemotherapy regimens are frequently favoured over single agents for the treatment of metastatic breast cancer, in an attempt to achieve superior tumour response rates. It is not known however whether giving more intensive chemotherapy regimens results in better health outcomes, when both survival and toxicity are considered, and whether better response rates and rates of progression free survival actually translate to better overall survival.

Objectives

To compare single agent with combination chemotherapy for the treatment of metastatic breast cancer.

Search methods

We searched the Cochrane Breast Cancer Group Specialised Register November 2008. Handsearching of recent conference proceedings was also undertaken.

Selection criteria

Randomised trials of single agent chemotherapy compared to combination therapy in metastatic breast cancer.

Data collection and analysis

Two authors independently assessed trials for eligibility and quality, and extracted data. Hazard ratios were derived for reported time-to-event outcomes.Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present.

Main results

Forty three eligible trials (48 comparisons) were identified. These included 9742 women, 55% of whom were receiving first-line treatment for metastatic disease. For overall survival there was a statistically significant difference in favour of the combination regimens with no heterogeneity (HR 0.88, 95% CI 0.83-0.93, p<0.00001). Results were very similar when trials of first-line treatment were analysed, and for analyses where the single agent was also included in the combination regimen. Combination regimens showed a statistically significant advantage for survival over single agent taxane (HR 0.82; 95% CI 0.75-0.89, p<0.00001), but not anthracycline (HR 0.94.86-1.02, p=0.15).

Combination regimens were also associated with significantly better time to progression (HR 0.78, 95% CI 0.74 - 0.82, p<0.00001) and response (RR 1.29, 95% CI 1.14 -1.45, p<0.0001) although heterogeneity was statistically significant in both instances and probably due to clinical diversity of the participants and interventions.

Women receiving combination regimens experienced a statistically significant detrimental effect on white cell count, increased alopecia and nausea and vomiting.

Authors' conclusions

Combination chemotherapy regimens show a statistically significant advantage for survival, tumor response and time to progression in women with metastatic breast cancer but they also produce more toxicity. An unresolved question is whether combination regimens are more effective than single agents given sequentially.

摘要

背景

對轉移性乳癌的化療選擇: 單一化療藥物與組合化療藥物

為達到較優腫瘤反應率,組合化療藥物通常被認為治療轉移性乳癌優於單一化療藥物。然而當考慮病人存活與化療藥物毒性,投予更強的化療藥物是否有較好的療效?是否更好的腫瘤反應率與無腫瘤的存活率能改善整體存活率?直至目前仍不清楚。

目標

研究目的是比較單一化療藥物與組合化療藥物治療轉移性乳癌之療效。

搜尋策略

我們檢索考科藍乳癌專業小組2008年11月,也包括手工檢索最近會議資料。

選擇標準

單一化療藥物與組合化療藥物治療轉移性乳癌作隨機試驗。

資料收集與分析

兩位作者獨立評估試驗的合理性與品質並提取數據。時間對事件結果則以危險比率(Hazard ratios)表示。腫瘤反應率則視為二分變項。若該研究有調查統計化療藥物毒性和生活品質,一併分析。

主要結論

有43個適合分析的試驗(48個研究)被確定。 包括9742名婦女,55%的人正在接受第一線治療轉移性乳癌。組合化療藥物治療轉移性乳癌優於單一化療藥物,整體存活率統計有顯著差異(HR 0.88, 95% CI 0.83 – 0.93, p < 0.00001)。當就第一線化療藥物作分析且包括組合化療藥物治療含此第一線化療藥物,則結果十分相似。在統計上,組合化療藥物療效比單一化療藥物taxane有顯著的生存優勢(HR 0.82; 95% CI 0.75 – 0.89, p < 0.00001),但比單一化療藥物anthracyline則沒有顯著的生存優勢(H .94.86 – 1.02, p = 0.15) 雖然臨床參與者與介入者有臨床多樣性使得異質性有顯著不同,組合化療藥物治療轉移性乳癌仍有明顯改善疾病進展時間(HR 0.78, 95% CI 0.74 – 0.82, p < 0.00001)與腫瘤反應率(RR 1.29, 95% CI 1.14 −1.45, p < 0.0001)。接受組合化療藥物治療婦女明顯有較低白血球,且明顯較易脫髮,噁心和嘔吐。

作者結論

接受組合化療藥物治療轉移性乳癌婦女明顯有較好存活率、腫瘤反應及疾病進展時間,但他們也接受更多藥物毒性。是否組合化療藥物治療優於單一藥物有順序地投予仍是是否組合化療藥物治療優於單一藥物有順序地投予仍是一個未解決的問題。

翻譯人

本摘要由中山醫學大學附設醫院李秋香翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

轉移性乳癌是癌細胞已擴散操超過乳腺和局部淋巴結。儘管許多婦女將度過晚期疾病生活多年,治療的目的是在減輕症狀,而不是治癒。晚期疾病治療的藥物選擇要看激素狀態(是否有雌激素和孕激素刺激腫瘤生長),以及是否有人類表皮增長因子感受器官2 (human epidermal growth factor receptor2 (HER2))來決定是否可以trastuzumab (herceptin)來治療。多?晚期疾病婦女將接受眾多化療藥物之一作為他們的第一線治療,因為腫瘤對某一種化療藥物或組合兩種或兩種以上之化療藥物有抵抗性。本綜合回顧文獻研究的目地在比較治療轉移性乳癌是否組合化療藥物優於單一化療藥物。我們確定43個合格試驗(48個比較,因為某些試驗有一個以上的比較)。這些試驗包括9742女性,55%的人是第一次接受化療治療轉移性疾病。本綜合回顧文獻研究發現所有試驗皆顯示組合化療藥物比單一化療藥物有較高存活率。當就第一線化療藥物作分析且包括組合化療藥物治療是否含此第一線化療藥物的試驗也顯示一樣的結果。組合化療藥物治療轉移性乳癌仍有明顯改善疾病進展時間(治療後,直至疾病進展的時間)與腫瘤反應率(腫瘤是否由於治療?得小)。接受組合化療藥物治療婦女明顯有較低白血球,且明顯較易脫髮,噁心和嘔吐。對婦女作出有關治療的決定,值得注意的是,本綜合回顧文獻研究未能解決的問題是是否組合化療藥物治療優於單一藥物有順序地投予。一些個別的試驗提出了一種可能性方案,多種有次序的從一個化療藥物立即直接給予下一種化療藥物可能比同時一起給予有較高存活率。治療婦女晚期疾病有一個重要的考慮是在治療的好處與化療藥物副作用之間取得平衡。可惜只有11個試驗報告有關生活品質的訊息。一般來說,接受組合化療藥物治療的婦女必須承受更大藥物毒性及付出心理和社會因素生活品質之代價。本綜合回顧文獻研究沒有足夠的數據判定以婦女的觀點來看這二個治療選擇的整體臨床效益。因此晚期疾病婦女需要?找信息有關轉移性乳癌的化療藥物所具潛在的好處與對他們生活品質影響多大,以便他們做決定治療的選擇。

アブストラクト

転移性乳癌に対する単剤化学療法と多剤併用化学療法との比較

背景

より良い奏効率を達成する目的で、転移性乳癌の治療として多剤併用化学療法レジメンがしばしば単剤よりも好んで用いられる。しかし、生存率および毒性の両方を考慮した場合に強力な化学療法レジメンであるほど、健康へのアウトカムが良好となるかどうか、また奏効率および無増悪生存率が良好であるほど、全生存が良いと言えるのかどうかは不明である。

目的

転移性乳癌治療のための単剤化学療法を多剤併用化学療法と比較する。

検索戦略

2008年11月にCochrane Breast Cancer Group Specialised Registerを検索した。さらに最新の学会予稿集をハンドサーチした。

選択基準

転移性乳癌において単剤化学療法を多剤併用化学療法と比較しているランダム化試験。

データ収集と分析

2名のレビューアが独自に試験の適格性と質を評価し、データを抽出した。報告されたイベント発生までの期間のアウトカムについてハザード比を導き出した。奏効率は二値変数として解析した。毒性および生活の質データがある場合はこれらを抽出した。

主な結果

43件の適格な試験(48の比較)を同定した。これらの試験は9,742例の女性を対象とし、このうち55%に転移性乳癌に対してファーストライン治療が施行されていた。全生存については、併用レジメンに有利な統計学的有意差があり、異質性はなかった(HR 0.88、95%CI 0.83~0.93、p<0.00001)。ファーストライン治療に関する試験を解析したところ、また単剤も併用レジメンに含めて解析したところ、結果は非常に類似した。併用レジメンは、生存に関してタキサン単剤よりも統計学的に有意に利益があったが(HR 0.82、95%CI 0.75~0.89、p<0.00001)、アントラサイクリン単剤に対してはそれを上回る利益はなかった(HR 0.94.86~1.02、p=0.15)。併用レジメンは無増悪期間(HR 0.78、95%CI 0.74~0.82、p<0.00001)および腫瘍縮小効果(RR 1.29、95%CI 1.14~1.45、p<0.0001)が有意に良好であったが、両者とも異質性が統計学的に有意であり、おそらく参加者および介入の臨床的多様性によるものと思われた。併用レジメンが投与された女性では、白血球数、脱毛症増加、悪心・嘔吐に対して統計学的に有意な有害作用がみられた。

著者の結論

転移性乳癌の女性に対する多剤併用化学療法レジメンは生存、腫瘍縮小効果、無増悪期間に統計学的に有意な利益を示すが、より多くの毒性が引き起こされる。併用レジメンが単剤の逐次投与よりも有効であるかどうかについては依然として疑問が残る。

訳注

監  訳: 大神 英一,2009.9.15

実施組織: 厚生労働省委託事業によりMindsが実施した。

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Plain language summary

Single agent versus combination chemotherapy for metastatic breast cancer

Metastatic breast cancer is cancer that has advanced and spread beyond the breast and regional lymph nodes. Although many women will live with advanced disease for many years, treatment is aimed at the alleviation of symptoms rather than cure. The first choice of treatment for advanced disease is dependent on hormone status (whether the tumour is stimulated to grow by oestrogen and progesterone) or whether the tumour overexpresses human epidermal growth factor receptor-2 (HER-2) and can be treated with trastuzumab (herceptin). Most women with advanced disease will however receive chemotherapy (anti-cancer agents) either as their first treatment, because their disease has become resistant to some treatments, or in combination with other types of treatments. Chemotherapy drugs can be given alone (single agent) or two or more drugs can be given together (combination chemotherapy). The aim of this review was to compare whether using a more intensive regimen (more than one drug) was better than the single agent treatment for women with advanced disease. We identified 43 eligible trials (48 comparisons- as some trials tested more than one comparison). These trials included 9742 women, 55% of whom were receiving their first treatment with chemotherapy for metastatic disease. The review found a benefit for the combination chemotherapy for survival (all trials). This was also the case when trials of first-line treatment only were analysed, and whether the single agent was also included in the combination or not. Combination treatments were also associated with significantly better time to progression (time after treatment until the disease progressed) and response (whether the tumour gets smaller as a result of the treatment). Women receiving combination treatment however experienced more adverse effects of treatment including a decrease in their white cell count, increased hair loss and nausea and vomiting. For women making a decision about treatment, it should be noted that this review was not able to address the issue of whether combination regimens are more effective than sequential treatment with different single agents. Some individual trials raised the possibility that giving a multiagent regimen sequentially with immediate cross-over from one agent to the next on progression may result in survival times similar to that seen when all the agents are given together

An important consideration for women with advanced disease is the balance between the benefit of treatment and the harms or adverse effects that these treatments may have. Unfortunately only 11 trials in this review reported information relating to quality of life. In general, survival gains with combination therapy came at the cost of a significant increase in toxicity and impact on other psychological and social factors which are known to contribute to a sense of quality of life for this group of women. There were insufficient data in this review to comment on the overall impact of the two treatment options on net clinical benefit from the women's perspective. Women with advanced disease will therefore need to seek the information to allow them to make decisions about the potential benefits of additional treatments (small survival gains) in progressing metastatic disease and the impact this can have on their quality of life.

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