晚期攝護腺癌病人接受新型荷爾蒙治療的認知功能損傷之文獻回顧、統合分析與臨床試驗計畫書

Cognitive impairment in men with advanced prostate cancer treated with novel hormonal agents: a systematic review, meta-analysis and clinical trial protocol

陳麗琴(Li-Chin Chen)

指導教授 ： 蒲永孝

國立臺灣大學/醫學院/臨床醫學研究所/碩士(2021年)

https://doi.org/10.6342/NTU202102322

摘要

重要性
臨床上廣泛的研究已知，攝護腺癌患者接受雄性素剝奪療法會造成認知功能損傷。然而，晚期攝護腺癌患者除了接受傳統雄性素剝奪療法之外，再接受新型荷爾蒙療法(novel hormonal agents)，是否會造成認知功能的進一步損傷，還沒有人發表過相關的統合分析。
主要目標
收集已發表之前瞻性臨床研究論文，進行晚期攝護腺癌患者，接受新型荷爾蒙療法與認知功能損傷關聯性的文獻回顧與統合分析。
資料來源
從以下數據資料庫中搜尋相關的研究。資料庫包括EMBASE, PubMed, CINAHL, Web of Science (WoS), Scopus, clinicaltrials.gov, and European Medicines Agency。
研究篩選、資料擷取以及統合分析
符合納入統合分析的資料，為晚期攝護腺癌患者接受傳統雄性素剝奪療法外，再加上新型荷爾蒙療法的前瞻性臨床研究。新型荷爾蒙療法包含四種藥品(abiraterone acetate, enzalutamide, apalutamide, and darolutamide)。對照組包括安慰劑和/或標準治療。研究篩選是經由本論文之研究生執行，檢查研究標題與摘要是否符合統合分析之需要。本研究生與另一名獨立之審查員，依照 Cochrane 偏差風險評估工具(risk-of-bias tool)，對欲納入的研究進行偏差風險評估。文獻回顧與統合分析，係根據隨機效應模式(random-effect)進行資料統整。
主要結果與評估
主要研究終點 (primary endpoint) 是臨床研究中使用之NCI CTCAE評估標準，所通報認知功能損傷的不良事件。
結果
本統合分析研究共納入有8個隨機分組的臨床研究。包含10,560名病人，其中有5,913病人接受新型荷爾蒙療法，4,647病人接受對照組治療。平均年齡中位數為70.5歲(range 33-97 years)，平均研究追蹤期中位數是32.5個月 (range 14-52 months)。統合分析結果顯示，新型荷爾蒙療法與對照組相比，有顯著升高的認知功能損傷風險(odds ratio (OR) 2.15; 95% confidence interval (CI) 1.47 - 3.14, P <0.0001)，各估計值之間存在中等異質性(I2 = 60%)。次分析為每個新型荷爾蒙療法比上對照組後的風險。依照次分析族群，顯示新型荷爾蒙療法對於認知功能造成不同程度的風險，結果為：1)每種新型荷爾蒙療法造成認知功能損傷風險對比值由大到小，依序為：enzalutamide (OR 3.52; 95% CI 2.53 - 4.89)、 apalutamide (OR 1.75; 95% CI 0.4 - 2.96)、abiraterone acetate (OR 1.71; 95% CI 1.13 - 2.60)、以及 darolutamide (OR 0.93; 95% CI 0.42 - 2.06)。2)不同癌症期別的風險，轉移性去勢敏感性前列腺癌 (mCSPC) (OR 2.75; 95% CI 1.70 - 4.43)和非轉移性去勢抵抗性前列腺癌 (nmCRPC) (OR 1.88; 95% CI 0.85 - 4.18) ，都可看到新型荷爾蒙療法比對照組造成更多之認知功能損傷。3)不同年齡層風險，患者年齡小<70 歲 (OR 2.32；95% CI 1.29 - 4.20) 和 ≥ 70 歲 (OR 1.98；95% CI 1.13 - 3.47) ，也可看到新型荷爾蒙療法造成較多之認知功能損傷。 4)研究追蹤期間的中位數不管是< 24 個月（OR 1.91；95% CI 1.26 - 2.91）或 ≥ 24 個月（OR 2.25；95% CI 1.24 - 4.08），皆可看到新型荷爾蒙療法比對照組，造成較多之認知功能損傷。
此統合分析的缺陷，還是缺乏直接比較兩種或多種新型荷爾蒙療法藥品對於認知功能改變的數據資料。建議未來若要了解不同新型荷爾蒙療法對於認知功能改變之間的區別，應該進行直接比較之研究。
結論
晚期攝護腺癌患者在傳統荷爾蒙療法加上新型荷爾蒙療法，相對於傳統荷爾蒙療法加上對照組，達到統計顯著的差異(OR 2.15; 95% CI 1.47 - 3.14, P <0.0001)，造成更多的認知功能損傷。因此，建議臨床醫師在開立新型荷爾蒙療法處方時，應記住此種治療相關的不良反應，評估不同新型荷爾蒙療法，所造成認知功能損傷風險之程度，並依照患者情況選擇合適藥品。

關鍵字

攝護腺癌 ； 認知功能 ； 智能損傷 ； 澤珂 ； 安列康 ； 安可坦 ； 諾博戈 ； 新型荷爾蒙療法

並列摘要

Importance:
Androgen deprivation therapy (ADT)-induced cognitive impairment in men with prostate cancer (PC) was widely observed in clinical studies. However, there have been no meta-analyses on cognition effect in men with PC receiving novel hormonal agents (NHAs).
Objective:
To investigate the cognitive impairment in prospective clinical studies of NHAs plus conventional androgen-deprivation therapy (ADT) in men with advanced prostate cancer (aPC).
Data Sources:
Studies were searched from inception through February 1st, 2021 in bibliographic databases including EMBASE, PubMed, CINAHL, Web of Science (WoS), Scopus, clinicaltrials.gov, and European Medicines Agency (EMA).
Study Selection, Data Extraction and Synthesis:
Qualified studies were prospective clinical studies assessing the addition of NHAs (abiraterone acetate, apalutamide, enzalutamide, or darolutamide) to conventional ADT in men with aPC. The comparators included matched placebos and/or standard of care. The graduate student (LCC) performed the screening. Two independent reviewers (LCC HYC) performed the risk of bias assessment using the Cochrane risk-of-bias tool. Data were pooled using the random-effect model, following systematic review and meta-analysis guidelines.
Main Outcome and Measures:
Cognitive impairment was assessed by reported adverse events in clinical studies in terms of common terminology criteria for adverse events (CTCAE).
Results:
A total of 8 randomized controlled trials were included in the systematic review and meta-analysis. The total number of the enrolled patients was 10,560 men (median age (range): 70.5 years (33-97), with 5,913 in the NHAs group and 4,647 in the comparator group, respectively. The median follow-up time for the 8 studies was 32.5 months (range 14-52 months). The results showed that NHAs significantly impaired the cognitive function compared to comparators when studies of the four NHAs were pooled (odds ratio (OR) 2.15; 95% confident interval (CI) 1.47 - 3.14) with moderate heterogeneity between estimates (I2 = 60%). With respect to each NHA, the cognitive impairment results compared to comparators for each agent were as follows: enzalutamide (OR 3.52; 95% CI 2.53 - 4.89), apalutamide (OR 1.75; 95% CI 1.04 - 2.96), abiraterone acetate (OR 1.71; 95% CI 1.13 - 2.60), and darolutamide (OR 0.93; 95% CI 0.42 - 2.06). The cognitive impairment effect, if 4 NHAs were pooled, for men with metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) were both significantly more common with NHAs than with comparators (for mCSPC and nmCRPC, OR 2.75; 95% CI 1.70 - 4.43 and OR 1.88; 95% CI 0.85 - 4.18, respectively). Both men of age < 70 years (OR 2.32; 95% CI 1.29 - 4.20) and ≥ 70 years (OR 1.98; 95% CI 1.13 - 3.47) have had significantly impaired cognitive function if treated with NHAs compared to comparators. Similarly, the cognitive impairment effect was seen in studies with a median follow-up of both < 24 months (OR 1.91; 95% CI 1.26 - 2.91) and ≥ 24 months (OR 2.25; 95% CI 1.24 - 4.08).
One of the limitations of the meta-analysis is the lack of direct head-to-head comparison among NHAs. Future studies of the direct comparison of these NHAs are needed to better understand which is better than the others in terms of cognitive function preservation.
Conclusions:
In general, NHAs, compared to comparators, had significant negative impact on cognitive function in men with aPC receiving conventional ADT. Each individual NHA had varied degrees of cognitive impairment effect. Clinicians should always bear in mind the potential harm in cognitive function when prescribing these NHAs.

並列關鍵字

prostate cancer ； cognitive function ； mental impairment ； abiraterone acetate ； apalutamide ； enzalutamide ； darolutamide ； novel hormonal agents

參考文獻

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