Aromatase 抑制剂的关节症状与其他副作用

　　December 22, 2006 (圣安东尼奥) —在圣安东尼奥乳癌(SABC)研讨会中，有数篇壁报发表了有关aromatase 抑制剂(AIs)更详细的副作用资料，让医师们更深地了解和此类新药有关的副作用；最近几年有三种此类药物上市— anastrozole (Arimidex, AstraZeneca)、exemestane (Aromasin, Pfizer)与letrozole (Femara, Novartis) — 用于荷尔蒙受体阳性乳癌之停经后妇女的辅助治疗，他们的作用是阻断雌激素合成，提供了选择性雌激素受体调节剂(SERM) tamoxifen之标准疗程外的另一种选择。
　　
　　这些发表的壁报之一所提出的结论是，AIs的关节症状比之前在临床试验中所描述的更多且更严重；哥伦比亚大学Herbert Irving综合癌症中心的Katherine Drew医师与同事指出，大型的辅助治疗试验报告了2002-2004年间的肌肉骨骼异常发生率在20%- 30%，且将近 5%的病患因为毒性反应而停止治疗 。
　　
　　不过，哥伦比亚大学对200位病患的横断式学术研究资料发现，有47%有AI相关的关节痛，44%有AI相关的关节僵硬。
　　
　　有关节症状的病患中，约有三分之二病患的症状是中度到严重，最常见的发作部位是在膝盖和手，这之中有半数以上是妇女 (52%)，服用口服药物以缓解症状，包括服用非类固醇类消炎药(NSAIDs) 和acetaminophen (paracetamol)，约有46% 使用非药物方式治疗 (主要是运动)。
　　
　　这些样本中，关节症状的风险与年纪和AI使用多久无关，有关的因素包括过重、曾用tamoxifen治疗、曾使用 taxanes这个强烈引起AI相关关节症状的药物；服用taxanes的病患发生关节痛与僵硬的比率是服用AIs者的四倍。
　　
　　Drew医师与同事结论认为，因为AI 治疗的成功与否在于病患遵守治疗建议的程度，需要进一步的进行可以缓解这些症状与改善生活品质的介入研究；在旁边的海报中，该团队报告了以针灸缓解这些关节症状的成功案例，21位妇女的单组前驱式研究显示可以改善疼痛与僵硬现象，且降低止痛药之使用。
　　
　　另一篇壁报发表的研究发现是来自美国乳癌行动(BCA)团体对病患的线上调查，该调查在2005年8月进行，列出38项与aromatase 抑制剂有关之副作用(依据FDA所核准的产品标签所示)，也询问是否有发生过这几项之外的其他副作用。
　　
　　共有612位妇女回覆，将近全部 (96%) 有一种或多种副作用，约有30%的妇女表示因而中止治疗，这之中的大多数(87%)是因为无法耐受副作用，而有47%是因为关节相关问题所致；超过一半的人表示有中风、咳嗽、手臂和脚肿胀、类似感冒症状与焦虑现象发生；其他还包括阴道病变和干燥、胆固醇值升高、全身性疼痛；这些完整的报告与建议可在线上浏览。
　　
　　主要作者Marilyn Zivian医师建议，在调查中显然可以发现有些妇女的确为此所苦，BCA执行主任Barbara Brenner指出，病患比医师更早知道药物所发生的副作用— 病患们是第一手经验者。
　　
　　【3种产品的直接比较】
　　第一期研究针对健康停经妇女进行关于这三种Ais之效果与脂质数值的直接比较，一个来自英国Sheffield大学的研究团队与AstraZeneca共同发表了“Letrozole, Exemestane,与 Anastrozole 药物动力学(LEAP)研究”。
　　
　　这三种Ais与中度增加血清骨质翻转标记有关，也与治疗24周之后中度增加骨质密度 (BMD)有关，各种药物之间没有显著不同；研究者指出，长期服用Ais已知和停经后乳癌病患降低BMD 与增加骨折风险和骨质疏松有关。
　　
　　Exemestane是自然界中的类固醇物质 (另外两种产品则是非类固醇)，之前此药被认为可以保护骨质避免流失；研究者表示，本研究并未发现类似这种效果的证据，但有提出一不同之处，仅有 exemestane与降低副甲状腺素(PTH) 值有关，这意味着可能增加骨质流失。
　　
　　这三种药物在脂质数据上显示不同的结果，相较于anastrozole，letrozole 和exemestane 会对这些健康志愿者产生脂质数据之潜在的不良结果；以letrozole治疗导致在第12周时显著的增加三酸甘油脂，在该研究的第36周时，提高的程度相当多变，因此所观察到的这种增加现象可能和临床变化有关而不是和治疗有关；Exemestane和增加高密度脂蛋白胆固醇有关，也与增加低密度和高密度脂蛋白胆固醇比值有关，此外，也和增加载体蛋白apoB 与apoA-1比值有关，研究者认为这些都可能会导致动脉粥样化的效果。

Joint Symptoms and Other Adverse Effects of Aromatase Inhibitors

By Zosia Chustecka
Medscape Medical News

December 22, 2006 (San Antonio) — New details about adverse effects associated with aromatase inhibitors (AIs) were reported in several poster presentations during the San Antonio Breast Cancer (SABC) Symposium and were poured over by clinicians eager to learn more about these relatively new products. Three of these drugs have been launched in recent years — anastrozole (Arimidex, AstraZeneca), exemestane (Aromasin, Pfizer) and letrozole (Femara, Novartis) — for use as adjuvant therapy in postmenopausal women with hormone-receptor–positive breast cancer. With their action of blocking estrogen synthesis, they offer an alternative to what has been the standard therapy, the selective estrogen-receptor modifier (SERM) tamoxifen.

One of the presentations concluded that joint symptoms with AIs are more prevalent and more severe than what has previously been described in clinical trials. Katherine Drew, MD, and colleagues from the Herbert Irving Comprehensive Cancer Center at Columbia University, in New York, noted that large adjuvant trials reported in 2002–2004 found the incidence of musculoskeletal disorders was 20% to 30% and that nearly 5% of patients discontinued therapy because of toxic effects.

However, in a cross-sectional study of 200 patients attending the academic practice at Columbia University, they found that 47% reported AI-related joint pain and 44% reported AI-related joint stiffness.

About two thirds of the patients who reported joint symptoms said the symptoms were moderate to severe, with the most common sites affected being knees and hands. Just over half of these women (52%) took oral medications for symptom relief, including nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol), while 46% used nonpharmacological interventions (mainly exercise).

Within this sample, the risk of joint symptoms was independent of age and which AI was used or for how long, the researchers commented. It was, however, inversely associated with being overweight and prior tamoxifen therapy, and previous exposure to taxanes was the strongest predictor of AI-related joint symptoms. Patients who had received taxanes were 4 times more likely than others to develop joint pain and stiffness while taking AIs.

"Because the success of AI therapy depends on patients' ability to adhere to treatment recommendations, further studies of interventions that may alleviate these symptoms and improve quality of life are needed," Dr. Crew and colleagues concluded. In a neighboring poster, the same team reported some success with acupuncture for these joint symptoms. A single-group pilot study in 21 women showed improvements in pain and stiffness and a decrease in analgesic use.

Another poster presented findings from an online patient survey carried out by the US advocacy group Breast Cancer Action (BCA). The survey, launched in August 2005, listed 38 adverse events associated with aromatase inhibitors (compiled from FDA-approved product labeling) and also asked whether respondents experienced any other unlisted adverse effects.

Of 612 women who responded, nearly all (96%) reported 1 or more adverse effects. About 30% of women reported discontinuing therapy, most of them (87%) because of intolerable adverse events and 47% because of joint-related problems. More than half of the respondents reported stroke, cough, swelling of arms and legs, flulike symptoms, and anxiety. Other effects included vaginal atrophy and dryness, a rise in cholesterol levels, and general pain. The full report and comments from respondents are available online.

"It's very apparent that some women who responded to the survey are really suffering," commented lead author Marilyn Zivian, PhD, in a statement. "Patients know about side effects before their doctors do — they experience them first-hand," added Barbara Brenner, executive director of BCA. Both women are breast cancer survivors.

Direct Comparison of 3 Products

A direct comparison of the 3 AIs in a phase 1 study in healthy postmenopausal women revealed differences between the drugs, particularly in the effects of these agents on lipid profiles. The Letrozole, Exemestane, and Anastrozole Pharmacodynamics (LEAP) study was reported by a team from the University of Sheffield, in the United Kingdom, in collaboration with researchers from AstraZeneca.

All 3 AIs were associated with modest increases in serum markers of bone turnover and with modest decreases in bone-mineral density (BMD) after 24 weeks of treatment, with no significant differences between agents. The researchers note that long-term administration of AIs has already been associated with a decrease in BMD and an increase in fracture risk and osteoporosis in postmenopausal breast cancer patients.

As exemestane is steroidal in nature (whereas the other 2 products are nonsteroidal), it has previously been suggested that this drug may protect against bone loss. "No evidence of such an effect was detected in this study," the researchers commented. One difference did emerge, however — only exemestane was associated with a decrease in parathyroid hormone (PTH) levels, which may indicate increased bone resorption, they suggested.

The 3 drugs showed differential effects on lipid profiles. Compared with anastrozole, treatment with letrozole and exemestane produced potentially unfavorable changes in lipid profiles of these healthy volunteers, the researchers commented. Treatment with letrozole resulted in a significant increase in triglycerides at 12 weeks, although levels were highly variable during the 36-week course of this study, and so this observed increase may have been due to clinical fluctuations and not related to the treatment, they said. Exemestane was associated with an increase in high-density lipoprotein cholesterol and also increases in the ratio of low- to high-density lipoprotein cholesterol and the ratio of apolipoprotein apoB to apoA-1, all of which suggest a possible atherogenic effect, the group commented.


SABC Symposium: Abstracts 2092, 3131, 5068, and 507. Presented December 15 and 16, 2006.