LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women

 

Abstract

Background

Approximately 60% of breast cancers amongst premenopausal women express the nuclear oestrogen receptor (ER+ breast cancer). Adjuvant endocrine therapy is an integral component of care for ER+ breast cancer, exerting its effect by reducing the availability of oestrogen to micrometastatic tumour cells. Endocrine strategies in premenopausal women include oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, or permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Aromatase inhibitors are also available with concurrent suppression of ovarian oestrogen synthesis, either through LHRH agonists, surgery, or radiotherapy. Chemotherapy can also have an endocrine action in premenopausal women by interrupting ovarian oestrogen production, either temporarily or permanently. International consensus statements recommend single agent tamoxifen as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy), and the role of LHRH agonists remains under active investigation.

Objectives

To assess LHRH agonists as adjuvant therapy for women with early breast cancer.

Search methods

The Cochrane Breast Cancer Group Specialised Register was searched on 19 February 2009. This register incorporates references from CENTRAL (The Cochrane Library) (to 2002), MEDLINE (1966 to July 2008), EMBASE (until 2002); and handsearches of abstracts from the San Antonio Breast Cancer Symposium, American Society of Clinical Oncology Annual Meeting, and the Clinical Oncological Society of Australia Annual Meeting. MEDLINE references (from August 2008 to 19th February 2009) were checked by the authors. The reference lists of related reviews were checked. A final check of the list of trials maintained by the Early Breast Cancer Trialists' Collaborative Group was made in January 2008.

Selection criteria

All randomised trials assessing LHRH agonists as adjuvant treatment in premenopausal women with early stage breast cancer were included. Specifically, we included trials that compared:

(A) LHRH agonists (experimental arm) versus another treatment;

(B) LHRH agonists + anti-oestrogen (experimental arm) versus another treatment;

(C) LHRH agonists + chemotherapy (experimental arm) versus another treatment;

(D) LHRH agonists + anti-oestrogen + chemotherapy (experimental arm) versus another treatment.

Data collection and analysis

Data were collected from trial reports. We reported estimates for the differences between treatments on recurrence free survival, overall survival, toxicity and quality of life using data available in the reports of each trial. Meta-analyses were not performed because of variability in the reporting of the trials.

Main results

We identified 14 randomised trials that involved over 13,000 premenopausal women with operable breast cancer, most of whom were ER+. The numbers of trials making the different comparisons were:

(A) i. LHRH versus tamoxifen (three trials),

ii. LHRH versus chemotherapy (four trials);

(B) i. LHRH + tamoxifen versus tamoxifen (two trials),

ii. LHRH + tamoxifen versus LHRH (three trials),

iii. LHRH + tamoxifen versus chemotherapy (two trials),

iv. LHRH + aromatase inhibitor versus LHRH + tamoxifen (one trial);

(C) i. LHRH + chemotherapy versus LHRH (one trial),

ii. LHRH + chemotherapy versus chemotherapy (five trials);

(D) LHRH + tamoxifen + chemotherapy versus chemotherapy (three trials).

The LHRH agonist in most of these trials was goserelin.

For most of the treatment comparisons there are too few trials, too few randomised patients, or too little follow up to draw reliable estimates of the relative effects of different treatments.

(A) LHRH monotherapy: results suggest that adjuvant LHRH agonist monotherapy is similar to older chemotherapy protocols (eg. CMF) in terms of recurrence-free and overall survival in ER+ patients. There are insufficient data to compare LHRH agonist monotherapy to tamoxifen alone, but available results suggest that these treatments are comparable in terms of recurrence-free survival.

(B) LHRH + anti-oestrogen therapy: there are insufficient data to compare the combination of an LHRH agonist plus tamoxifen to tamoxifen alone. Results suggest that the LHRH agonist plus tamoxifen combination may be superior to an LHRH agonist alone or to chemotherapy alone, but the chemotherapy protocols tested are outdated. The data comparing LHRH agonists plus aromatase inhibitors to LHRH agonists plus tamoxifen are currently inconclusive.

(C) LHRH + chemotherapy: there are insufficient data to compare the LHRH + chemotherapy combination to an LHRH agonist alone, although results from a single study suggest comparable efficacy in ER+ patients. There is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus chemotherapy combination in comparison to chemotherapy alone.

(D) LHRH agonist + chemotherapy + tamoxifen: there is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus tamoxifen plus chemotherapy in comparison to chemotherapy alone.

There are insufficient data to assess the effect of the addition of LHRH agonists to the current standard treatment of chemotherapy plus tamoxifen.

Endocrine therapy with LHRH agonists appears to have fewer side-effects than the forms of chemotherapy assessed. The optimal duration of LHRH therapy in the adjuvant setting is unclear.

Authors' conclusions

Overall, the data from currently published clinical trials of LHRH agonists in the adjuvant setting for premenopausal women with endocrine-sensitive breast cancer are supportive of clinical benefit. Nonetheless, definitive comparisons against current clinical standards of care that include third generation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. The authors conclude that the current data strongly support the continuation of current trials that definitively compare a variety of combinations of LHRH agonists and anti-oestrogenic strategies to the current standard of five years of tamoxifen.

 

Plain language summary

Ovarian suppression with LHRH agonists (such as goserelin) for treating premenopausal women with early breast cancer

More than half of the premenopausal women who develop breast cancer have a type of cancer that is sensitive to hormones, termed 'oestrogen receptor positive' or ER+ disease. To slow the growth of any cancer cells that remain after surgery, hormonal therapy can be used to reduce the availability of the natural hormone oestrogen to the cells. This can be done by blocking the oestrogen receptors on the cells with drugs such as tamoxifen, by suppressing the production of oestrogen by drugs called luteinising hormone releasing hormone (LHRH) agonists, or by removing the ovaries with surgery or impairing their ability to produce hormones using radiotherapy. A new class of drugs called aromatase inhibitors work by stopping the production of oestrogen, but can only be safely used in premenopausal women if their ovarian cycling is suppressed (either by LHRH agonists, surgery, or radiotherapy). Chemotherapy, designed to kill cancer cells, can also have a hormonal action by bringing on early menopause. This review examined the role of LHRH agonists for women with early stage breast cancer. It looked at comparisons of LHRH agonists versus other types of hormonal treatment and versus chemotherapy. We also examined the role of combined LHRH agonist plus tamoxifen therapy, combined LHRH agonist plus chemotherapy, and combined LHRH agonist plus tamoxifen plus chemotherapy. A total of 14 randomised trials that involved over 13,000 women were found, but only a small number of these were relevant to each of the comparisons in this review. The LHRH agonist in the trials was usually goserelin, used for a couple of years.

We found seven trials comparing LHRH agonist therapy (alone) to other treatments. There is not enough evidence to compare LHRH agonists directly to tamoxifen. Four of the trials compared an LHRH agonist to a now superseded chemotherapy regimen. For ER+ women, these trials showed no significant differences between LHRH agonists and chemotherapy on recurrence and death, but LHRH agonists had fewer side effects.

Six trials compared LHRH agonists in combination with tamoxifen to other treatments. There is currently insufficient information to reliably compare this combination with tamoxifen alone. The LHRH agonist plus tamoxifen combination may reduce the risk of breast cancer recurrence, but not death, when compared to an LHRH agonist alone or chemotherapy alone. There is insufficient evidence to know whether an LHRH agonist plus an aromatase inhibitor is better or worse than an LHRH agonist plus tamoxifen.

Three trials compared combining an LHRH agonist plus chemotherapy plus tamoxifen to chemotherapy alone. There was a reduction in the risk of breast cancer recurrence, and possibly death, with the combination treatment.

It is important to note that the current standard of care for premenopausal women with ER+ breast cancer is five years of tamoxifen, often with chemotherapy. We found no trials of LHRH agonist-containing regimens versus this standard. The women in the trials in this review need to continue to be followed up so that the longer-term effects can be investigated, to 10 and more years after diagnosis. More research is also needed to help choose between different types of LHRH agonist, and to find out if the length of time that the drug is used makes a difference. It is also unknown whether there are important differences between the effects of LHRH agonists and ovarian ablation by surgery or radiotherapy.

 

摘要

背景

停經前婦女的早期乳腺癌以促黃體素釋放激素激動劑(LHRH agonists)為輔助治療

大約 60％的停經前婦女乳腺癌以核雌激素受體(ER +乳腺癌)表現。內分泌輔助治療對ER +的乳腺癌是一個不可分割的治療，充分發揮其作用可減少可用性雌激素的腫瘤細胞微轉移。在停經前婦女的內分泌輔助治療戰略包括雌激素受體阻斷劑他莫昔芬，其可暫時抑制卵巢雌激素合成的促黃體激素釋放激素(LHRH)激動劑，或永久性阻斷卵巢雌激素合成的卵巢切除術或放射治療。芳香?抑製劑也可通過釋放激素激動劑，手術或放療同時抑制卵巢雌激素的合成。化療也有內分泌輔助治療的作用，無論是暫時或永久性的阻斷停經前婦女卵巢雌激素的生產。國際共識一致聲明建議單劑的他莫昔芬作為當前停經前婦女(通常先化療)的標準輔助內分泌治療和促黃體素釋放激素激動劑的作用仍在積極調查。

目標

為了評估促黃體素釋放激素激動劑作為早期女性乳腺癌的輔助治療。

搜尋策略

2009年2月19日我們檢索了Cochrane乳癌團隊專業註冊資料。註冊資料結合參考文獻來自CENTRAL(Cochrane圖書館)(至2002年)，MEDLINE(1966年至2008年7月)，EMBASE資料庫(至2002年)，聖安東尼奧乳癌研討會的手工檢索摘要，美國臨床腫瘤學會年會，和澳大利亞臨床腫瘤學協會的年會。 作者檢查MEDLINE的參考文獻(從 2008年8月至2009年2月19日)。審查列舉相關的參考文獻。最後審查列表的檢查維持是採用自2008年1月早期乳癌研究試驗共同團隊提出。

選擇標準

所有的隨機試驗評估黃體素釋放激素激動劑作為停經前婦女早期乳腺癌患者的輔助治療。具體來說，我們比較試驗包括： (一)促性腺激素釋放激素激動劑(實驗臂)與另一種治療; (二)釋放激素激動劑 +抗雌激素(實驗臂)與另一種治療; (三)促黃體素釋放激素激動劑 +化療(實驗臂)與另一種治療; (四)促黃體素釋放激素激動劑 +抗雌激素+化療(實驗臂)與另一種治療。

資料收集與分析

數據是從試驗報告中收集。我們評估所有報告中每個試驗提供的使用數據處理對無復發存活率，總存活率，毒性及生活品質之間的差異。由於試驗報告的變異性，不會執行統合分析(Metaanalysis)

主要結論

我們確定了14項隨機試驗，總括13000多可作乳腺癌手術的停經前婦女，其中大部分是ER陽性。這些試驗數字不同的比較有： (A)一，促性腺激素釋放激素與他莫昔芬(三項試驗)， 二，促性腺激素釋放激素與化療(四項試驗); (B)一，促黃體素釋放激素+他莫昔芬與他莫昔芬(二項試驗)， 二，促黃體素釋放激素+他莫昔芬與促黃體素釋放激素(三項試驗)， 三，促黃體素釋放激素+他莫昔芬與化療(二項試驗)， 四，促黃體素釋放激素+芳香?抑製劑與促黃體素釋放激素+他莫昔芬(一項試驗); (C)一，促黃體素釋放激素+化療與促黃體素釋放激素(一項試驗) 二，促黃體素釋放激素+化療與化療(五項試驗); (D)促黃體素釋放激素+他莫昔芬+化療與化療(三項試驗)。 促黃體素釋放激素激動劑在大多數的這些試驗是使用戈舍瑞林(goserelin)。 對於大多數的治療比較中試驗太少，隨機病人太少，或是太少制定可靠的不同治療相對影響的追蹤。 (A)促黃體素釋放激素單一療法：結果建議，促黃體素釋放激素激動劑單一輔助療法在無復發存活率和總存活率在ER +的乳腺癌患者類似舊化療方案(如CMF)。沒有足夠的數據來比較促黃體素釋放激素激動劑單獨對他莫昔芬，但現有的結果建議，這些療法可比較其無復發存活率。 (B)促黃體素釋放激素+抗雌激素治療：沒有足夠的數據來比較相聯合的促黃體素釋放激素激動劑加他莫昔芬單獨對他莫昔芬。結果建議，聯合促黃體素釋放激素激動劑加他莫昔芬，可能優於單獨一促黃體素釋放激素激動劑或單純化療，但化療方案分別是過時的。數據對比較促黃體素釋放激素激動劑加芳香?抑製劑，對促黃體素釋放激素激動劑加他莫昔芬，目前尚無定論。 (C)促黃體素釋放激素+化療：沒有足夠的數據來比較釋放激素+化療相結合，對單一促黃體素釋放激素激動劑，儘管從單一的研究結果顯示相同的療效在ER +的乳癌患者。接受聯合促黃體素釋放激素加化療的患者對單純化療的患者相比可提高無復發存活率和總存活率。 (四)促黃體素釋放激素激動劑+化療+他莫昔芬：接受聯合促黃體素釋放激素加他莫昔芬加化療的患者對單純化療的患者相比可提高無復發存活率和總存活率。 沒有足夠的數據來評估促黃體素釋放激素激動劑加入到當前標準化療加他莫昔芬的效果。 賀爾蒙治療與促黃體素釋放激素激動劑比化療形式似乎有較少的副作用。目前還不清楚促黃體素釋放激素療法的最佳輔助治療時間。

作者結論

總體而言，從目前公佈的在停經前婦女內分泌敏感乳腺癌的促黃體素釋放激素激動劑輔助治療的臨床試驗數據是有效益。然而，對目前比較明確的臨床照護標準，包括第三代化療和他莫昔芬前，須在輔助治療設置可以適當界定。作者得出結論，以目前的數據強力支持繼續進行比較各種聯合促黃體素釋放激素激動劑和抗雌激素加進符合現行標準使用5年他莫昔芬策略的試驗。

翻譯人

本摘要由中山醫學大學附設醫院陳幹珍翻譯。

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

總結

促黃體素釋放激素激動劑(如戈舍瑞林)的卵巢抑制用於治療停經前婦女的早期乳癌，超過一半的停經前婦女患乳腺癌都有激素敏感類型的癌症，稱為「雌激素受體陽性」或「ER +疾病」。為了在任何手術後仍然存在的癌細胞的生長減緩，可以使用賀爾蒙治療，以減少自然雌激素供應的細胞。這可以通過阻斷細胞對雌激素受體的藥物如他莫昔芬，通過抑制雌激素產生的藥品如同所謂的促黃體激素釋放激素(LHRH)激動劑，或通過手術取出卵巢或用放射治療阻斷產生激素的能力。 一類新的藥物稱為芳香?抑製劑，作用是停止生產雌激素，但只能使用於卵巢循環是抑制的停經前婦女(雌激素激動劑，手術或放療任一種治療)。 化療的目的是殺死癌細胞，但也造成了賀爾蒙的變化而提早了停經期。 這項研究為婦女早期乳癌檢討促黃體素釋放激素激動劑的作用。它比較促黃體素釋放激素激動劑與其他類型的激素治療和化療相比。我們還研究了促黃體素釋放激素激動劑合併作用加他莫昔芬治療，合併促性腺激素釋放激素激動劑加化療，以及合併促性腺激素釋放激素激動劑加他莫昔芬加化療。總共有14個隨機試驗並總括13,000多名婦女，但只有少數研究與這次審查相關。促黃體素釋放激素激動劑的試驗是使用戈舍瑞林，已用數年。 我們發現七個試驗比較促黃體素釋放激素激動劑療法(單獨)對其他治療。沒有足夠的證據來比較促黃體素釋放激素激動劑與他莫昔芬。四個試驗比較促黃體素釋放激素激動劑為現行化學療程。對於ER陽性的婦女，這些試驗顯示促黃體素釋放激素激動劑和化療對復發和死亡並無顯著差異，但促黃體素釋放激素激動劑有較少的副作用。 6個試驗比較結合促黃體素釋放激素激動劑和他莫昔芬對其他治療方法。目前尚沒有足夠的資料比較這種組合單獨與他莫昔芬。相較於單獨促黃體素釋放激素激動劑或單純化療，促黃體素釋放激素激動劑以及他莫昔芬的組合，可減少乳腺癌復發的風險，但不是死亡。沒有足夠的證據比較促黃體素釋放激素激動劑加芳香?抑製劑和促黃體素釋放激素激動劑加他莫昔芬是好還是壞。 3項試驗比較了結合促黃體素釋放激素激動劑加化療加他莫昔芬對單純化療。這綜合治療可減少乳癌復發的風險，或可能死亡。 重要的是要注意到目前的標準照護停經前婦女ER+乳癌為5年的他莫昔芬與化療。我們沒有發現任何試驗比較促黃體素釋放激素激動劑含處方與這個標準。 在試驗中的婦女需要繼續跟進，使確診後10或多年之後可以進行調查較長期的影響。還需要更多的研究來幫助選擇不同類型的促黃體素釋放激素激動劑，以及尋找該藥物是否使用更長時間的一個區別。影響促黃體素釋放激素激動劑和卵巢切除以手術或放射治療重要的差別也是未知的。