荷尔蒙替代疗法与肺癌死亡风险有关


  September 29, 2009 — 根据9月20日在线初版The Lancet期刊中对「Women's Health Initiative (WHI)」试验之资料分析结果,使用雌激素和黄体素的荷尔蒙替代疗法(HRT)与增加肺癌死亡风险有关。Medscape Oncology报导了初步发表于美国临床肿瘤协会第45届年会中的这些结果。
  
  加州大学洛杉矶分校、洛杉矶生物医学研究中心的Rowan T. Chlebowski与WHI的研究伙伴写道,在WHI试验的后介入期中,指派接受雌激素加黄体素治疗的女性,发生癌症的风险高于安慰剂组;结果也显示,并用两种荷尔蒙治疗会增加肺癌死亡率。为了评估此关联是否存在,我们对于该试验完整追踪期间有肺癌诊断者进行事后分析。
  
  WHI研究是一个在美国40个中心进行的随机、双盲、安慰剂控制试验,因为发现HRT对于健康的风险超过利益而提早停止。根据计算机化分类块状排列演算,16,608名年纪50至79岁、有完整子宫的妇女,被随机指派接受每天1锭、0.625-mg的共轭马黄体素以及2.5-mg的medroxyprogesterone acetate (n = 8506人)或相对的安慰剂(n=8102人)。根据治疗期和后介入追踪期的资料,采用治疗意向分析,确认所有肺癌、小细胞肺癌以及非小细胞肺癌的发生率和死亡率;平均治疗期间为5.6 ± 1.3年,平均额外追踪期间为2.4 ± 0·4年。
  
  并用两种荷尔蒙治疗这一组有109名妇女诊断出肺癌,安慰剂组有85人(每年发生率分别是0.16% vs 0.13%;风险比[HR],1.23;95% CI,0.92 - 1.63;P= .16)。HRT组有96名妇女诊断有非小细胞肺癌,安慰剂组有72人(0.14% vs 0.11%;HR,1.28;95% CI,0.94 - 1.73;P = .12)。并用两种荷尔蒙治疗这一组的肺癌死亡率大于安慰剂组(死亡数为73 vs 40;死亡率0.11% vs 0.06%;HR,1.71;95% CI,1.16 - 2.52;P = .01)。
  
  HRT组死亡率较高,主要是有较多因非小细胞肺癌而死亡者(死亡数为62 vs 31;0.09% vs 0.05%; HR, 1.87; 95% CI, 1.22 - 2.88; P = .004);两组的小细胞肺癌发生率和死亡率相似。
  
  研究作者写道,虽然停经后妇女使用雌激素加黄体素治疗并未增加肺癌发生率,但是增加了因肺癌死亡的人数,特别是死于非小细胞肺癌者。这些发现应整合到并用两种荷尔蒙之妇女的风险与利益讨论中,特别是那些有肺癌风险高者。
  
  研究限制包括,采用事后分析、肺癌与小细胞肺癌病患数少、缺乏诊断后的治疗信息。此外,结果无法外推到其它口服或外用荷尔蒙治疗或其它治疗期间。
  
  研究作者结论表示,并用两种荷尔蒙组的确比安慰剂组有更多的分化不佳的癌症以及转移癌症。这些以及非小细胞肺癌诊断后死亡率增加的发现,认为并用两种荷尔蒙治疗主要会刺激已有的非小细胞肺癌成长。
  
  内布拉斯加大学医学中心的Apar Kishor Ganti医师,在评论中讨论这些发现对于考虑使用HRT治疗停经期间症状之妇女的临床影响。
  
  Ganti医师写道,因为荷尔蒙替代治疗在肺癌存活这方面的适当安全期间还不清楚,有发生肺癌高风险的妇女,特别是有抽菸史者,或许应避免此类治疗。这些结果以及之前对于冠心症没有保护力的发现,严重质疑了荷尔蒙替代治疗在今日医疗的角色。难以假设规律使用这类治疗对于停经症候群的利益会大于死亡率增加的风险,特别是生活质量也未能改善。
  
  国家心肺与血液研究中心、国家健康研究中心资助本研究。有些研究作者与AstraZeneca、Novartis、Lilly、Amgen、Pfizer、国家健康研究中心、加拿大国家癌症研究中心和/或Wyeth药厂有各种财务关系。Ganti医师宣告没有相关资金上的往来。
  
  Lancet.在线发表于2009年9月20日。
  

Hormone Replacement Therapy Linked to Risk for Death From Lung Cancer

By Laurie Barclay, MD
Medscape Medical News

September 29, 2009 — Hormone replacement therapy (HRT) using estrogen and progestin is associated with an increased risk for death from lung cancer, according to the results of an analysis of data from the Women's Health Initiative (WHI) trial reported in the September 20 Online First issue of The Lancet. These results were initially presented at the American Society of Clinical Oncology 45th Annual Meeting as reported by Medscape Oncology.

"In the post-intervention period of the...WHI trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo," write Rowan T. Chlebowski, from Los Angeles Biomedical Research Institute at Harbour-University of California, Los Angeles, Medical Center, Torrance, California, and colleagues from the WHI Investigators. "Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period."

The WHI study, which was a randomized, double-blind, placebo-controlled trial performed at 40 US centers, was stopped early when health risks of HRT were found to exceed benefits. With use of a computerized, stratified, permuted block algorithm, 16,608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive a once-daily tablet of 0.625-mg conjugated equine estrogen plus 2.5-mg medroxyprogesterone acetate (n = 8506) or matching placebo (n = 8102). Data from treatment and postintervention follow-up periods allowed determination of incidence and mortality rates for all lung cancer, small-cell lung cancer, and non–small-cell lung cancer, with analysis by intent-to-treat. Mean treatment duration was 5.6 ± 1.3 years, and mean additional follow-up duration was 2.4 ± 0·4 years.

Lung cancer was diagnosed in 109 women in the combined hormone therapy group vs 85 in the placebo group (incidence per year, 0.16% vs 0.13%; hazard ratio [HR], 1.23; 95% CI, 0.92 - 1.63; P = .16). Non–small-cell lung cancer was diagnosed in 96 women in the HRT group vs 72 in the placebo group (0.14% vs 0.11%; HR, 1.28; 95% CI, 0.94 - 1.73; P = .12).

Mortality rate from lung cancer was greater in the combined hormone therapy group vs the placebo group (73 vs 40 deaths; 0.11% vs 0.06%; HR, 1.71; 95% CI, 1.16 - 2.52; P = .01). This excess mortality rate in the HRT group was primarily attributed to more deaths from non–small-cell lung cancer (62 vs 31 deaths; 0.09% vs 0.05%; HR, 1.87; 95% CI, 1.22 - 2.88; P = .004). Both groups had similar incidence and mortality rates of small-cell lung cancer.

"Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer," the study authors write. "These findings should be incorporated into risk–benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer."

Limitations of this study include post hoc analysis, small number of lung cancers and small-cell lung cancers, and absence of information on treatment after diagnosis. In addition, the results cannot be extrapolated to other oral or topical hormone treatments or other treatment durations.

"There were significantly more poorly differentiated cancers and cancers with metastatic spread in the combined hormone therapy group than in the placebo group," the study authors conclude. "These findings, together with the substantial increase in mortality after a diagnosis of non-small-cell lung cancer, suggest that the main effect of combined hormone therapy might be on stimulating growth of already established non-small-cell lung cancers."

In an accompanying comment, Apar Kishor Ganti, MD, from the University of Nebraska Medical Center in Omaha, discusses the clinical implications of these findings for women considering use of HRT for perimenopausal symptoms.

"Because the optimum safe duration of hormone-replacement therapy in terms of lung-cancer survival is unclear, such therapy should probably be avoided in women at a high risk of developing lung cancer, especially those with a history of smoking," Dr. Ganti writes. "These results, along with the findings showing no protection against coronary heart disease, seriously question whether hormone-replacement therapy has any role in medicine today. It is difficult to presume that the benefits of routine use of such therapy for menopausal symptoms outweigh the increased risks of mortality, especially in the absence of improvement in the quality of life."

The National Heart, Lung and Blood Institute, National Institutes of Health, funded this study. Some of the study authors have disclosed various financial relationships with AstraZeneca, Novartis, Lilly, Amgen, Pfizer, the National Institutes of Health, the National Cancer Institute of Canada, and/or Wyeth. Dr. Ganti has disclosed no relevant financial relationships.

Lancet. Published online September 20, 2009.

    
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