Sestak Ivana, Cuzick Jack, Sapunar Francisco, Eastell Richard, Forbes John F, Bianco Angelo R, Buzdar Aman U
Cancer Research UK, Centre for Epidemiology, Mathematics, and Statistics, Wolfson Institute of Preventive Medicine, London, UK.
Lancet Oncol. 2008 Sep;9(9):866-72. doi: 10.1016/S1470-2045(08)70182-7. Epub 2008 Aug 12.
Joint symptoms (eg, arthralgia and arthritis) are a well-known side-effect of aromatase inhibitors. Low oestrogen concentrations and postmenopausal status are associated with the development of these symptoms. Chemotherapy can also induce joint symptoms, but tamoxifen seems to have little effect on their incidence. The aim of this study was to assess the relative importance of different risk factors for treatment-emergent joint symptoms in patients assigned to anastrozole or tamoxifen as adjuvant treatment for postmenopausal breast cancer.
The Arimidex Tamoxifen Alone or in Combination (ATAC) trial randomly assigned 9366 postmenopausal women to anastrozole (1 mg/day), to tamoxifen (20 mg/day), or to a combination of both. Our analyses were based on data from case reports of 5433 women who were randomly assigned to anastrozole or tamoxifen, who started with their allocated treatment, and who did not have joint symptoms at entry (anastrozole group: n=2698; tamoxifen group: n=2735). The analysis was restricted to the occurrence of joint symptoms at any time during active treatment or within 14 days of its discontinuation. Joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder on a case-report form. Joint disorders were defined as reports of cervical spondylosis, osteoarthritis, and disc herniation. The date of occurrence was recorded, along with a severity score (ie, mild, moderate, or severe). Our analyses were done by use of logistic regression. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230.
777 of 1914 women (40.6%) who used hormone replacement therapy (HRT) before trial entry developed joint symptoms compared with 1001 of 3519 women (28.4%) without previous HRT use (odds ratio [OR] 1.72 [95% CI 1.53-1.93]). Women with hormone-receptor-negative breast cancer developed significantly fewer joint symptoms compared with those with hormone-receptor-positive tumours (124 of 461 [26.9%] vs 1556 of 4548 [34.2%]; OR 0.71 [0.57-0.88]). Women for whom chemotherapy was part of their initial treatment developed significantly more joint symptoms than those who did not receive it (461 of 1219 women [37.8%] vs 1317 of 4214 women [31.3%]; OR 1.34 [1.17-1.53]). Obese women (body-mass index [BMI] >30 kg/m(2)) reported more joint symptoms than women with a BMI of 25-30 kg/m(2) or those with a BMI <25 kg/m(2) (504 of 1354 women [37.2%] vs 502 of 1926 women [31.3%; OR 1.01 (0.88-1.16)] vs 592 of 1908 women [31.0%; OR 1.32 (1.14-1.53)]) and women on anastrozole reported more joint symptoms compared with those on tamoxifen (949 of 2698 women [35.2%] vs 829 of 2735 women [30.3%]; OR 1.25 [1.11-1.40]). All significant risk factors from the univariate analysis were included in a multivariate analysis and remained significant with little change.
In this trial, the major risk factors for developing joint symptoms were previous HRT, hormone-receptor positivity, previous chemotherapy, obesity, and treatment with anastrozole. Discussion of identified risk factors is appropriate when counselling women before initiation of adjuvant hormonal treatment.
关节症状（如关节痛和关节炎）是芳香化酶抑制剂众所周知的副作用。低雌激素浓度和绝经后状态与这些症状的发生有关。化疗也可诱发关节症状，但他莫昔芬似乎对其发生率影响不大。本研究的目的是评估在接受阿那曲唑或他莫昔芬作为绝经后乳腺癌辅助治疗的患者中，不同危险因素对治疗中出现的关节症状的相对重要性。
阿那曲唑他莫昔芬单药或联合应用（ATAC）试验将9366名绝经后女性随机分为阿那曲唑（1毫克/天）组、他莫昔芬（20毫克/天）组或两者联合组。我们的分析基于5433名女性的病例报告数据，这些女性被随机分配至阿那曲唑或他莫昔芬组，开始接受分配的治疗，且入组时无关节症状（阿那曲唑组：n = 2698；他莫昔芬组：n = 2735）。分析仅限于在积极治疗期间或停药后14天内任何时间出现的关节症状。关节症状定义为病例报告表上有关节痛、关节病、关节炎或关节疾病的任何报告。关节疾病定义为有关颈椎病、骨关节炎和椎间盘突出症的报告。记录发生日期以及严重程度评分（即轻度、中度或重度）。我们的分析采用逻辑回归进行。ATAC试验已注册为国际标准随机对照试验，编号为ISRCTN18233230。
在试验入组前使用激素替代疗法（HRT）的1914名女性中有777名（40.6%）出现关节症状，而未使用过HRT的3519名女性中有1001名（28.4%）出现关节症状（比值比[OR]为1.72[95%置信区间1.53 - 1.93]）。激素受体阴性乳腺癌女性出现的关节症状明显少于激素受体阳性肿瘤女性（461名中的124名[26.9%]对4548名中的1556名[34.2%]；OR为0.71[0.57 - 0.88]）。初始治疗包含化疗的女性比未接受化疗的女性出现的关节症状明显更多（1219名女性中的461名[37.8%]对4214名女性中的1317名[31.3%]；OR为1.34[1.17 - 1.53]）。肥胖女性（体重指数[BMI]＞30kg/m²）报告的关节症状多于BMI为25 - 30kg/m²或BMI＜25kg/m²的女性（1354名女性中的504名[37.2%]对1926名女性中的502名[31.3%；OR为1.01(0.88 - 1.16)]对1908名女性中的592名[31.0%；OR为1.32(1.14 - 1.53)]），且接受阿那曲唑治疗的女性比接受他莫昔芬治疗的女性报告的关节症状更多（2698名女性中的949名[35.2%]对2735名女性中的829名[30.3%]；OR为1.25[1.11 - 1.40]）。单变量分析中所有显著的危险因素都纳入了多变量分析，且仍然显著，变化不大。
在本试验中，出现关节症状的主要危险因素是既往HRT、激素受体阳性、既往化疗、肥胖以及阿那曲唑治疗。在开始辅助激素治疗前为女性提供咨询时，对已确定的危险因素进行讨论是恰当的。
