閉経前女性の化学療法による早発卵巣不全の予防を目的とした、ゴナドトロピン放出ホルモンアナログの併用
Abstract
Background
This is an update of the original review published in the Cochrane Database of Systematic Reviews 2011, Issue 11, and updated in 2015, Issue 4.
Chemotherapy has significantly improved prognosis for women with malignant and some non‐malignant conditions. This treatment, however, is associated with ovarian toxicity. The use of gonadotropin‐releasing hormone (GnRH) analogues, both agonists and antagonists, may have a protective effect on the ovaries. The primary mechanism of action of GnRH analogues is to suppress the gonadotropin levels to simulate pre‐pubertal hormonal milieu and subsequently prevent primordial follicles from maturation and therefore decrease the number of follicles that are more vulnerable to chemotherapy.
Objectives
To assess the efficacy and safety of GnRH analogues given before or in parallel to chemotherapy to prevent chemotherapy‐related ovarian damage in premenopausal women with malignant or non‐malignant conditions.
Search methods
The search was run for the original review in July 2011, and for the first update in July 2014. For this update we searched the following databases in November 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the Chinese Biomedicine Database (CBM).
Selection criteria
Randomised controlled trials (RCTs), in all languages, which examined the effect of GnRH analogues for chemotherapy‐induced ovarian failure in premenopausal women, were eligible for inclusion in the review.
Data collection and analysis
Two review authors independently extracted data and assessed trial quality using the Cochrane 'Risk of bias' tool. We analysed binary data using risk ratios (RRs) with 95% confidence intervals (CI) and for continuous data, we used the standardized mean difference (SMD) to combine trials. We applied the random‐effects model in our analyses. We used the GRADE approach to produce a 'Summary of findings' table for our main outcomes of interest.
Main results
We included 12 RCTs involving 1369 women between the ages of 12 and 51.1 years. Participants were diagnosed with breast malignancy, ovarian malignancy, or Hodgkin's lymphoma, and most of them received alkylating, or platinum complexes, based chemotherapy. The included studies were funded by a university (n = 1), research centres (n = 4), and pharmaceutical companies (n = 1). Trials were at high or unclear risk of bias.
Comparison 1: GnRH agonist plus chemotherapy versus chemotherapy alone
The incidence of menstruation recovery or maintenance was 178 of 239 (74.5%) in the GnRH agonist group and 110 of 221 (50.0%) in the control group during a follow‐up period no longer than 12 months (RR 1.60, 95% CI 1.14 to 2.24; 5 studies, 460 participants; I2 = 79%; low‐certainty evidence), with an overall effect favouring treatment with GnRH agonist (P = 0.006). However, we observed no difference during a follow‐up period longer than 12 months between these two groups (P = 0.24). In the GnRH agonist group, 326 of 447 participants had menstruation recovery or maintenance (72.9%) in comparison to the control group, in which 276 of 422 participants had menstruation recovery or maintenance (65.4%) during a follow‐up period longer than 12 months (RR 1.08, 95% CI 0.95 to 1.22; 8 studies, 869 participants; I2 = 56%; low‐certainty evidence).
The incidence of premature ovarian failure was 43 of 401 (10.7%) in the GnRH agonist group and 96 of 379 (25.3%) in the control group (RR 0.44, 95% CI 0.31 to 0.61; 4 studies, 780 participants; I2 = 0%; moderate‐certainty evidence), with an overall effect favouring treatment with GnRH agonist (P < 0.00001).
The incidence of pregnancy was 32 of 356 (9.0%) in the GnRH agonist group and 22 of 347 (6.3%) in the control group (RR 1.59, 95% CI 0.93 to 2.70; 7 studies, 703 participants; I2 = 0%; low‐certainty evidence), with no difference between groups (P = 0.09). However, we are cautious about this conclusion because there were insufficient data about whether the participants intended to become pregnant.
The incidence of ovulation was 29 of 47 (61.7%) in the GnRH agonist group and 12 of 48 (25.0%) in the control group (RR 2.47, 95% CI 1.43 to 4.26; 2 studies, 95 participants; I2 = 0%; low‐certainty evidence) with an overall effect favouring treatment with GnRH (P = 0.001).
The most common adverse effects of GnRH analogues included hot flushes, vaginal dryness, urogenital symptoms, and mood swings. The pooled analysis of safety data showed no difference in adverse effects between GnRH agonist group and control group.
Comparison 2: GnRH agonist‐antagonist cotreatment plus chemotherapy versus chemotherapy alone
Only one RCT discussed GnRH agonist‐antagonist cotreatment. The limited evidence showed the incidence of menstruation recovery or maintenance was 20 of 25 (80%) in both cotreatment group and control group during a 12‐month follow‐up period (RR 1.00, 95% CI 0.76 to 1.32; 50 participants; very low‐certainty evidence), with no difference between groups (P = 1.00). In the cotreatment group, 13 of 25 participants had menstruation recovery or maintenance (52.0%) in comparison to the control group, in which 14 of 25 participants had menstruation recovery or maintenance (56.0%) during a follow‐up period longer than 12 months (RR 0.93, 95% CI 0.56 to 1.55; 50 participants; very low‐certainty evidence), with no difference between groups (P = 0.78). The incidence of pregnancy was 1 of 25 (4.0%) in the cotreatment group and 0 of 25 (0%) in the control group (RR 3.00, 95% CI 0.13 to 70.30; 50 participants; very low‐certainty evidence), with no difference between groups (P = 0.49).
Authors' conclusions
GnRH agonist appears to be effective in protecting the ovaries during chemotherapy, in terms of maintenance and resumption of menstruation, treatment‐related premature ovarian failure and ovulation. Evidence for protection of fertility was insufficient and needs further investigation. Evidence was also insufficient to assess the effect of GnRH agonist and GnRH antagonist cotreatment on ovarian protection against chemotherapy. The included studies differed in some important aspects of design, and most of these studies had no age‐determined subgroup analysis. Large and well‐designed RCTs with longer follow‐up duration should be conducted to clarify the effects of GnRH analogues in preventing chemotherapy‐induced ovarian failure, especially on different age groups or different chemotherapy regimens. Furthermore, studies should address the effects on pregnancy rates and anti‐tumour therapy.
PICOs
一般語訳
卵巣癌に対する化学療法を受けている女性に用いる、ゴナドトロピン放出ホルモン（性腺刺激ホルモン放出ホルモン）アナログ
レビューの論点
本レビューは、コクランの系統的レビューのデータベース（2011年第11号）のレビューを初めて改訂したものである。
化学療法は、癌患者や時に癌を患っていない人々の予後を改善するが、女性においては、この治療が卵巣機能障害をもたらすことがある。ゴナドトロピン放出ホルモン（GnRH、性腺刺激ホルモン放出ホルモン）とよばれるホルモンは、GnRHアゴニストとGnRHアンタゴニストのどちらもが、化学療法で用いる抗がん剤の卵巣に対する影響を少なくできる可能性がある。本レビューでは、GnRHアナログ（GnRHに類似した構造を持つ薬剤）が、閉経前の女性が癌やその他の疾患の治療のために化学療法を受けた場合に、化学療法による卵巣の障害を予防できるかどうかについて、結論付けることを目的としている。
研究の特性
2018年11月までの医学文献を検索し、目的に合致したランダム化比較試験（RCT）を選択した。すなわち、化学療法を受ける前後にGnRHアナログを投与することで、化学療法による卵巣の障害が予防できたかどうかを調べるために、女性を2群かそれ以上にランダムに割り付けて実施された試験である。レビューに含まれた試験は、大学や研究センター、あるいは製薬会社の資金供給を受けていた。しかしながら、これらの試験は方法論的な質は低かった。
主要な結果
本レビューには、化学療法を受けた1369名の女性を含んだ12のRCTを含めた。これらの試験には、GnRHアゴニスト（GnRHと似た働きをするGnRHアナログ）と化学療法の併用と化学療法単独を比較したもの（グループ1）と2種のGnRHアナログ（GnRHアゴニストとGnRHアンタゴニスト）と化学療法の併用と化学療法単独を比較したもの（グループ2）があった。（訳者注：GnRHアンタゴニストとはGnRHに拮抗する働きをするGnRHアナログ）
グループ1では、GnRHアゴニストは卵巣機能を保護する効果を認め、具体的には、早発卵巣不全の頻度を下げる（エビデンスの質は中程度）ことと排卵する率を上げる（エビデンスの質は低度）ことが示された。12か月間のフォローアップ期間における月経（生理）の回復あるいは維持できた率は、GnRHアゴニストを投与された群では対照群より高かった。しかし、12か月以上の観察期間をとると、その率には差が認められなかった（エビデンスの質は低度）。併用群と対象群において、妊娠率には差がなかった（エビデンスの質は低度）。しかしながら、女性が妊娠しようとしていたかどうかは明らかではなかった。また、ほてりや腟の乾燥、頭痛、うつ状態を含んだ副作用についても、2群における差は認めなかった（エビデンスの質は非常に低度～中程度）。
グループ2に対するエビデンスは、RCT1つのみから得られたものであり、限定的である。それによると、GnRHアゴニストとGnRHアンタゴニストを併用して投与しても、月経の回復や維持、妊娠率の観点から卵巣への保護的作用が認められなかった（エビデンスの質は非常に低度）。
結論
GnRHアゴニストは、月経の回復や維持、早発卵巣不全、排卵の点で化学療法中の卵巣を保護する効果があるようだ。妊娠率に対するエビデンスは不十分なので、さらなる調査が必要である。化学療法時にGnRHアゴニストとGnRHアンタゴニストを併用する治療の卵巣機能に対する効果を評価するには、エビデンスがまだ不十分であった。
