WHI研究显示激素治疗可预防子宫内膜癌

阿姆斯特丹——欧洲多学科癌症会议上公布的女性健康倡议(WHI)随机安慰剂对照试验的扩展随访结果显示，持续使用雌激素和孕激素可预防绝经后女性发生子宫内膜癌。中位随访13.2年后，雌激素/孕激素联合激素治疗(HT)组的子宫内膜癌发生率比安慰剂组低35%[风险比(HR) 0.65；P = 0.007]。HT组和安慰剂组分别共有66例和95例女性发生子宫内膜癌，年发生率分别为0.06%和0.10%。


Rowan T. Chlebowski医生

1993~1998年，WHI激素治疗随机对照临床试验在美国40个临床中心入组了16,608例50~79岁的具有完整子宫的女性。由于该研究发现HT组的心血管疾病和乳腺癌发生率高于安慰剂组，因此被提前终止。然而，HT组子宫内膜癌风险降低17%，并且结直肠癌和髋部骨折风险也较低(JAMA 2002;288:321-33)。

洛杉矶生物医学研究所的Rowan T. Chlebowski医生及其同事与参与研究的女性重新订立合同，在12,788例(83%)提供知情同意的存活女性中研究HT对子宫内膜癌风险的影响。在这些女性中，6,545例接受马结合雌激素(0.625 mg/d)和醋酸甲羟孕酮(2.5 mg/d)持续口服治疗，其余6,243例接受安慰剂治疗。

此次公布的结果基于中位5.6年的治疗数据和8.2年的进一步随访数据。分析显示，重大差异在治疗停止后出现，HT组和安慰剂组的干预后子宫内膜癌例数分别为41例和65例(HR, 0.59; P = 0.008)。在出现的子宫内膜癌中，HT组低分化或间变性癌例数(HR, 0.51)和局部或远端癌例数(HR, 0.43)均少于安慰剂组。

亚组分析显示，雌激素/孕激素联合治疗对子宫内膜癌风险的影响与总体情况相似，甚至在校正体重指数(BMI)后仍然如此。BMI是子宫内膜癌的已知危险因素，体重越大，风险越高。

HT组和安慰剂组分别有5例和11例死亡，但该差异无统计学显著性(HR，0.42)。

大伦敦Mount Vernon癌症中心的内科肿瘤学家Marcia Hall医生在评论该研究时指出，联用雌激素和孕激素确实可预防子宫内膜癌，并且该研究结果与英国百万女性研究等观察性研究的结果一致 (Lancet 2007;369:1703-10)。一些女性仍可从HT治疗中获得明显益处，包括曾因其他疾病而进行子宫切除术、卵巢切除术或化学去势的绝经前女性；发生绝经症状的女性，以及骨病(如骨质疏松)风险较高和较早进入绝经期的女性。在这些女性中，在可能的最低剂量持续使用雌激素，安全性可以接受。 Hall医生建议低剂量雌激素可与不同的孕激素和给药方式组合，如通过宫内系统给药的左炔诺孕酮(曼月乐)。

Hall医生总结指出，最新的WHI结果将促使研究者进一步探索孕激素在子宫内膜癌和(可能)结直肠癌的预防中所起的作用。此外，研究结果将促使医生对高危合并症患者人群中的子宫内膜癌管理进行重新思考。

WHI由美国国立卫生研究院资助。Chlebowski医生是辉瑞、诺华和安进公司的顾问，并从诺华公司获得酬金。Hall医生声明无相关经济利益冲突。

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By: SARA FREEMAN, Internal Medicine News Digital Network

AMSTERDAM – The continuous use of estrogen and progestin protects against the development of endometrial cancer in postmenopausal women, according to extended follow-up findings from the seminal Women’s Health Initiative randomized, placebo-controlled trial.

After a median of 13.2 years’ follow-up, there were 35% fewer endometrial cancers among women given combined estrogen and progestin vs. placebo (hazard ratio, 0.65; P = .007). A total of 66 women treated with the hormone therapy (HT) and 95 given placebo had developed endometrial cancer, yielding annual incidences of 0.06% and 0.10%, respectively.

"We do not feel that this effect on endometrial cancer changes the overall balance of risk and benefit of estrogen plus progestin," Dr. Rowan T. Chlebowski stated at the multidisciplinary European cancer congresses.
 
Dr. Chlebowski of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, added that the original conclusion of the WHI study remains: "Estrogen plus progestin should not be used for chronic disease risk reduction."

Between 1993 and 1998, 16,608 women aged 50-79 years with intact uteri were enrolled into the Women’s Health Initiative randomized, controlled clinical trial of hormone therapy at 40 clinical centers in the United States. The study was halted early as it found an excess of cardiovascular diseases and breast cancer among women given the HT vs. placebo. However, there was a 17% decrease in the risk for endometrial cancer in women given HT, as well as reductions in colorectal cancer and hip fracture (JAMA 2002;288:321-33).

Women who had participated in the study were recontacted to obtain their consent to look at the impact of the HT on their risk of endometrial cancer, with 12,788 (83%) surviving women giving their consent. Of these women, 6,545 had received continuous oral treatment with conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day), and the remaining 6,243 had received placebo.

The findings now reported represented a median of 5.6 years of treatment data and a further 8.2 years of additional follow-up. Analysis revealed that the major difference emerged after the treatment was stopped, with 41 vs. 65 cases reported cases postintervention (HR, 0.59; P = .008).

Dr. Chlebowski reported that in the endometrial cancers that did occur, there were fewer poorly differentiated or anaplastic tumors (HR, 0.51) and fewer cases of regional or distant disease (HR, 0.43) in the HT than placebo group.

Subgroup analyses found that there was a similar effect of the estrogen plus progestin influence on endometrial cancer risk generally, even when body mass index was taken into account. BMI is a known risk factor for endometrial cancer, with risk increasing with increasing body weight.

There were 5 deaths from endometrial cancer in the HT group and 11 in the placebo group, but this difference was not statistically significant (HR, 0.42).

Dr. Marcia Hall, a consultant medical oncologist at the Mount Vernon Cancer Centre in greater London, provided independent comment on the results. "The combination of estrogen plus progestin does indeed protect against endometrial cancer," she said, noting that the results are in line with those of observational studies, such as the U.K.’s Million Women Study (Lancet 2007;369:1703-10).

There are women who may still benefit greatly from HT, Dr. Hall maintained. This includes premenopausal women who have had a hysterectomies, oophorectomies, or chemical castrations for other conditions; women experiencing menopausal symptoms, and those who may be at higher risk for bone diseases, such as osteoporosis and enter the menopause early. "Continuous estrogen, perhaps at the lowest dose possible, is a moderately safe drug in these conditions and situations," Dr. Hall said. She suggested that a low estrogen dose could perhaps be combined with a different progestin and mode of administration, such as levonorgestrel delivered by the intrauterine system (Mirena).

The latest WHI findings "should provoke further exploration of the role of progestins in the prevention of endometrial and possibly colorectal cancers," Dr. Hall concluded. "I hope it may also allow us to rethink the management of endometrial cancer in a population with high-risk comorbidities."

The U.S. National Institutes of Health sponsored the WHI. Dr. Chlebowski has acted as a consultant to Pfizer, Novartis, and Amgen, and has received honorarium from Novartis. Dr. Hall had no relevant conflicts of interest.