An aromatase inhibitor should be considered as adjuvant therapy for all postmenopausal women with hormone receptor–positive breast cancer, according to an updated American Society of Clinical Oncology clinical practice guideline published online July 12 in the Journal of Clinical Oncology.

The optimal timing and duration of aromatase inhibitor (AI) treatment are not yet resolved, but it appears to reduce the risk of recurrence when taken at some time during adjuvant therapy – either alone as monotherapy, as sequential therapy before tamoxifen therapy commences or after 2-3 years of tamoxifen treatment, or as extended therapy after 5 years of tamoxifen is completed, said Dr. Harold J. Burstein of the Dana-Farber Cancer Institute, Boston, and his associates on ASCO’s Endocrine Therapy for Breast Cancer Update Committee.

The last update on the adjuvant use of AIs for hormone receptor–positive breast cancer was published in 2004. “Our panel carefully reviewed the explosion of research that has emerged in the past 5 years on anti-estrogen drugs, and filled in gaps in our understanding of how best to use these newer treatments, and what the trade-offs and side effects of therapy would be,” Dr. Burstein noted in a press statement accompanying the new guideline.

Their review focused on 12 prospective randomized clinical trials gleaned from 484 articles or abstracts from the medical literature, presentations, or posters.

The data are somewhat limited. Most of the studies had relatively short follow-up times, and the longest median follow-up was only 8 years. Because of that and patients’ generally favorable prognoses, few breast cancer events occurred during follow-up.

In addition, the assessment of important subgroups of patients was limited by relatively small sample sizes, and the small samples also limited analysis of quality-of-life data, Dr. Burstein and his colleagues said (J. Clin. Oncol. 2010 [doi:10.1200/JCO.2009.26.3756]).

Among the committee’s major findings:

– Adding an AI to adjuvant therapy improves disease-free survival and reduces the risk of distant metastasis, locoregional recurrence, and contralateral breast cancer. The reduction is modest – typically less than 5% over several years – but these outcomes are clinically important to patients. Only a few trials demonstrated a statistically significant increase in overall survival.

– AI therapy should not extend beyond 5 years, as either initial or extended adjuvant treatment, because results on longer-term treatment are not yet available.

– The optimal length of time before switching from tamoxifen to an AI is not yet known. For sequential treatment, patients should receive an AI after 2-3 years of tamoxifen, for a total of 5 years of adjuvant endocrine therapy. Alternatively, patients who begin an AI but discontinue it before 5 years have elapsed can consider taking tamoxifen until a total of 5 years of endocrine therapy accrue. For extended therapy, patients can be offered an AI after they have taken 5 years of tamoxifen. The data on extended therapy, however, are not as extensive as with sequential therapy.

– As of now, no clinically important differences in effectiveness have been reported among the three commercially available AIs (anastrozole, letrozole, and exemestane).

– Research to date has not revealed a specific marker that identifies patients most likely to benefit from AI therapy, nor a clinical subset of patients most likely to benefit.

– AIs generally are well tolerated. The drugs have been linked to increased risk of hypercholesterolemia and hypertension, and possibly of cardiovascular disease, but longer follow-up is needed to determine potential CV toxicity.

AIs also often cause a mild to moderate musculoskeletal/arthralgia syndrome. They have been associated with a greater loss of bone mineral density and a 2%-4% increased risk of fracture, compared with tamoxifen, but the long-term impact of treatment on bone is not yet known.

AIs appear to have fewer gynecologic adverse effects than tamoxifen. An increased risk of uterine cancer, benign endometrial pathology, hysterectomy, and vaginal discharge has not yet been noted with AIs, as it has with tamoxifen. AIs may produce fewer hot flashes and less vaginal dryness than tamoxifen.

The committee stressed that the late effects of AI therapy, as well as the possible adverse effects of extended AI therapy, have not yet been fully characterized.

The committee also noted that there is no evidence yet for or against the usefulness of AI therapy in men with breast cancer.

To facilitate treatment adherence, the updated guideline emphasized that clinicians should alert patients to common adverse effects and potential toxicities of AIs. Research shows that up to 40% of patients discontinue tamoxifen within 3 years and half do so within 5 years, and the findings with AIs are similar. The clear majority of patients who stop treatment prematurely do so because of adverse effects.

In particular, the musculoskeletal effects of AIs prompted discontinuation in more than 10% of women in one study. “Information support for patients about anticipated adverse effects and management of those adverse effects may increase persistence,” according to the guideline.

Monetary constraints are another cause of nonadherence. In one study of tamoxifen, 60% of patients who discontinued treatment early said that the cost of the drug was a key factor. “It is likely that the out-of-pocket costs of AIs pose an even greater barrier to patients,” the committee said.

The complete clinical practice guideline is available at www.asco.org/guidelines/endocrinebreast. A corresponding patient guide is available on ASCO’s patient Web site, www.cancer.net.

Some of the update committee members reported ties to Pfizer, Novartis, and AstraZeneca.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据7月12日在线发表于《临床肿瘤学杂志》上的美国临床肿瘤学会(ASCO)最新临床实践指南，对激素受体阳性的所有绝经后乳腺癌患者均应考虑将芳香化酶抑制剂作为辅助治疗。

 

波士顿达纳法伯癌症研究所(Dana-Farber Cancer Institute)的Harold J. Burstein博士及合作者在ASCO的乳腺癌内分泌治疗进展委员会(Endocrine Therapy for Breast Cancer Update Committee)上指出，目前尚未确定芳香化酶抑制剂(AI)治疗的最佳时机和疗程，但在辅助治疗期间——作为单药治疗，他莫昔芬治疗开始前或治疗后2~3年的序贯治疗，抑或作为完成5年他莫昔芬治疗后的强化治疗——AI似乎可以减少复发风险。

 

2004年发表的对激素受体阳性乳腺癌应用AI辅助治疗是距离现在最近的一次疗法更新。Burstein博士在与新指南一起发布的新闻稿中指出：“我们的专家组认真审查了过去5年中大量涌现的有关抗雌激素药物的探讨性研究，并填补了我们对如何更好地使用这些较新疗法以及对治疗的利弊关系和副作用理解上的空白。”

 

他们重点审查了12项前瞻性随机临床试验，这些试验由源自医学文献、发言稿或壁报中的484篇文章或摘要中收集得到。

 

这些数据具有一定的局限性。大多数研究随访时间相对较短，最长的中位随访时间仅为8年。由于随访时间短加之患者整体预后较优，故随访期间发生的乳腺癌事件极少。

 

Burstein博士及其同事说，由于样本量相对较小，小样本也使生命质量数据的分析受到限制，故对重要亚组患者的评估具有局限性 (J. Clin. Oncol. 2010 [doi:10.1200/JCO.2009.26.3756])。

 

委员会的重大发现包括：

 

–辅助治疗中添加AI可改善无病生存，并可减少发生远处转移、局部区域复发及对侧乳腺癌的风险。减少程度适中­——在数年中通常不足5%——但上述预后对患者具有很重要的临床意义。仅几项试验证实AI治疗组总生存时间的延长有统计学意义。

 

– AI治疗不应超过5年，无论是初始辅助治疗抑或强化辅助治疗，原因为目前尚未获得长期治疗结果。

 

–由他莫昔芬换成AI治疗前的最佳时长尚不清楚。对于序贯治疗而言，患者应在接受2~3年他莫昔芬治疗后接受AI治疗，辅助内分泌治疗的总疗程为5年。若非如此，开始AI治疗但于5年治疗期满之前停药的患者也可以考虑服用他莫昔芬，直至内分泌疗程满5年。但有关强化治疗的数据不及序贯治疗全面。

 

–迄今，尚无报道指出目前市售的3种AI(阿那曲唑、来曲唑及依西美坦)之间在临床疗效上具有重要差异。

 

–截止目前，尚无研究发现可识别受益于AI治疗可能性最大的患者或临床亚组患者的特异性标志物。

 

–总体而言，AI的耐受性良好。该药与高胆固醇血症和高血压、还可能与心血管疾病的发病风险增加有关联，但其潜在的心血管毒性尚有待于通过较长时间的随访得以明确。

 

AI也常常引起轻度至中度的骨骼肌或关节痛综合征。与他莫昔芬相比，AI可导致骨矿物质密度大大减少，使骨折风险增加2%~4%，但AI治疗对骨的长期影响尚不清楚。

 

AI的妇产科不良反应可能少于他莫昔芬。他莫昔芬治疗可增加子宫癌、良性子宫内膜病变、子宫切除术及阴道分泌物的发生风险，但在AI治疗中尚未观察到出现上述情况。AI所致的潮热和阴道干燥症少于他莫昔芬。

 

委员会强调AI治疗的迟发效应以及强化AI治疗的可能不良反应尚未得到充分定性。

 

委员会还指出，对于男性乳腺癌患者尚无证据显示支持抑或反对应用AI治疗。

 

为提高治疗遵从性，最新指南强调指出，医生应提醒患者AI的常见不良反应及潜在毒性。研究显示，多达40%的患者在 3年内停用他莫昔芬，50%的患者在5年内做出此举，AI治疗的研究结果相近。因不良反应而提前停止治疗的患者明显占大多数。

 

尤为值得一提的是，在一项研究中，AI对骨骼肌的作用促使逾10%的妇女停用该药。据该指南，“在所预料的不良反应和相应的不良反应处置方面为患者提供信息支持，可以提高治疗的遵从性。”

 

金钱的限制是不遵从治疗的另一原因。在对他莫昔芬进行的一项研究中，提前停止治疗的患者中有60%称药物的费用是一个关键因素。“超出支付能力应用AI很可能会给患者造成更大的阻碍，”委员会说道。

 

完整的临床实践指南可登录www.asco.org/guidelines/endocrinebreast查阅。登录ASCO的患者网站www.cancer.net可获取相应的患者指导。

 

最新的委员会成员中有一部分报告称与辉瑞、诺华和阿斯利康有关联。

 

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