口服Iloprost顯示可有效恢復戒菸者的呼吸道損傷

作者：Barbara Boughton  
出處：WebMD醫學新聞

　　August 6, 2009(加州舊金山) — 根據發表於國際肺癌研究協會第13屆肺癌世界研討會中的研究，口服一般用來治療肺動脈高壓的一種藥物iloprost，顯示可有效預防肺癌以及恢復戒菸者的抽菸相關呼吸道損傷。
　　
　　在這個包括152名戒菸者與抽菸者的多中心第2期研究中，6個月的iloprost療程對於戒菸者的氣管內再生不良產生顯著的改善。不過，此藥物對於抽菸者的呼吸道沒有效果。
　　
　　主要研究者、科羅拉多大學醫學院內科副教授Robert Keith醫師表示，iloprost是一個很有效的製劑，它即將進行第3期的預防性試驗。雖然需要更多研究以釐清iloprost的效果和副作用。Keith醫師相信，它可以有潛力用來預防肺癌且改善戒菸者的氣管內再生不良。
　　
　　該研究中，痰細胞學檢查出現異常、菸齡至少20年且每天抽一包菸、呼吸道出現抽菸相關傷害的抽菸者和戒菸者，被隨機分派接受iloprost或安慰劑，且接受六處不同位置的氣管切片。在6個月的治療期間結束之後，進行第二次的支氣管鏡檢和再度氣管切片。使用世界衛生組織的規定，切片評分從1(正常)到6(嚴重再生不良)。
　　
　　研究者接著使用三個不同評分來分析組織：最差切片評分、平均切片評分、再生不良指數—所有切片中出現4分(輕微再生不良)以上的切片百分比。開始時，抽菸者的平均分數顯著高於戒菸者(3.0 vs 2.1；P< .001)。不過，結果顯示，在重複進行支氣管鏡檢之後，與安慰劑組相比，隨機分配接受iloprost的戒菸者，在三種組織檢查中都有最明顯的改善。Keith醫師表示，該研究提出在你戒菸之後，你是否可以矯正呼吸道中發生之問題的議題。
　　
　　副作用皆很輕微且未引起退出研究；最常見的副作用是頭痛與熱潮紅。
　　
　　Keith醫師在老鼠的肺高壓研究，發現接受prostacyclin的老鼠不會產生肺癌之後，對於iloprost的預防效果產生興趣。在組織研究中，prostacyclin顯示可以產生新的血管、預防細胞不正常分化而預防腫瘤；動物研究中，接受iloprost的老鼠不會發生癌症。Keith醫師解釋，iloprost很類似prostacyclin。
　　
　　主持研究發表會議的溫哥華英屬哥倫比亞癌症局Stephen Lam醫師指出，雖然iloprost的預防試驗相當令人振奮，仍有一些限制。他表示，我們需瞭解這只是一個次組分析，且只適用於戒菸者—整個試驗中的57個研究對象而已。他指出，也還不清楚用於更多嚴重再生不良之戒菸者時的風險降低效果如何。
　　
　　Lam醫師認為，第3期的試驗可能是不切實際的；研究者花了5年才招募到71個願意接受二度支氣管鏡檢的戒菸者。他也指出，你無法忽視iloprost的副作用。他表示，之前其他可明顯降低再生不良之藥物的研究，都因為輕微但令人困擾的副作用而未能進行第3期試驗。
　　
　　國家癌症研究中心以及退伍軍人事務部資助本研究。Keith醫師與Lam醫師均宣告沒有相關財務關係。
　　
　　國際肺癌研究協會第13屆肺癌世界研討會(WCLC)：摘要D1.6。發表於2009年8月4日。

Oral Iloprost Shows Promise for Reversing Airway Damage in Former Smokers

By Barbara Boughton
Medscape Medical News

August 6, 2009 (San Francisco, California) — Oral iloprost, a medication usually used to treat pulmonary arterial hypertension, has shown promise as a preventative agent for lung cancer and for reversing smoking-related damage in the airways of former smokers, according to a study presented here at the 13th World Conference on Lung Cancer, organized by the International Association for the Study of Lung Cancer.

In the multicenter phase?2 study of 152 former and current smokers, a 6-month course of iloprost produced significant improvements in endobronchial dysplasia in former smokers. However, the drug had no effect on the airways of current smokers.

"Iloprost is a very promising agent, and it could progress to phase?3 prevention trials," said lead researcher Robert Keith, MD, associate professor of medicine at the University of Colorado School of Medicine in Denver. Although acknowledging that more research needs to be done to clarify the benefits and adverse effects of iloprost, Dr. Keith maintained that it has the potential to prevent lung cancer and improve endobronchial dysplasia — at least in former smokers.

In the study, current and former smokers with abnormal sputum cytology, at least a 20-year history of smoking a pack of cigarettes per day, and smoking-related damage in their central airways were randomized to iloprost or placebo, and underwent bronchoscopies, with biopsies at 6 different sites. A second bronchoscopy and repeat biopsies were taken at the end of the 6-month treatment period. Using World Health Organization criteria, biopsies were scored from 1 (normal) to 6 (severe dysplasia).

The researchers then analyzed histology using 3 different scores: the worst-biopsy score, the average-biopsy score, and the dysplasia index — the percent of total biopsies with a score of more than 4 (mild dysplasia). At baseline, current smokers had a significantly higher average score than former smokers (3.0 vs 2.1; P?< .001). However, results indicated that after repeat bronchoscopies, former smokers randomized to iloprost showed significantly greater improvement in all 3 histology measures than those randomized to placebo. "The study poses the question of whether you can modulate what happens in the airways after you stop smoking," Dr. Keith said.

Adverse effects were mild and did not cause any of the subjects to withdraw from the study. The most common were an increase in headaches and flushing.

Dr. Keith became interested in the preventive effects of iloprost after discovering through animal research in pulmonary hypertension that mice receiving prostacyclin did not develop lung cancer. In tissue studies, prostacyclin has been shown to prevent tumors from creating new blood vessels and to prevent cells from dividing abnormally; in animal studies, mice receiving iloprost were protected from developing cancer. Iloprost is very similar to prostacyclin, Dr. Keith explained.

Although the iloprost prevention trial is "very exciting," it had some limitations, noted Stephen Lam, MD, from the British Columbia Cancer Agency in Vancouver, who moderated the session at which the study was presented. "We need to realize that this is only a subgroup analysis and it only applies to former smokers — 57 subjects in all," he said. It was also unclear from the trial what the magnitude of risk reduction might be in a larger group of ex-smokers with serious or severe dysplasia, he added.

Dr. Lam suggested that a phase?3 trial might be unrealistic; it took the researchers 5 years to recruit just 71 former smokers willing to undergo repeat bronchoscopies. He also pointed out that "you can't ignore the side effects of iloprost." Previous studies with other drugs that have produced a significant reduction in dysplasia have not led to phase?3 trials because of mild but bothersome adverse effects, he said.

The study was funded by the National Cancer Institute and the Department of Veterans Affairs. Dr. Keith and Dr. Lam have disclosed no relevant financial relationships.

13th World Conference on Lung Cancer (WCLC): Abstract D1.6. Presented August 4, 2009.