早期淋巴结阳性乳腺癌患者加用伊班膦酸钠无益

根据8月26日在线发表于《临床肿瘤学杂志》上的一项针对德国早期淋巴结阳性乳腺癌患者的研究结果，在剂量密集化疗后进行2年的伊班膦酸钠辅助治疗并未改善预后。

已有研究显示双膦酸盐能够预防转移性乳腺癌患者发生骨骼相关事件，但其疗效尚未在早期乳腺癌患者中得到证实。为此，德国乳腺组的Gunter von Minckwitz医生联合德国乳腺组/妇科肿瘤工作组/东北部德国妇科肿瘤协会研究组的同事进行了这项名为GAIN（German Adjuvant Intergroup Node-Positive）的研究。该研究是一项Ⅲ期开放性随机对照试验（NCT00196872），在本研究中，逾3,000例淋巴结阳性的早期乳腺癌患者在手术后4周内被随机分配接受两种不同的剂量密集化疗方案，并在末次化疗用药后的4周内按照2:1的比例被分配接受伊班膦酸钠50 mg/d口服用药、持续2年（2,015例患者）或单纯接受观察（1,008例）。

随机分配接受的化疗方案包括3个疗程的表柔比星150 mg/m2治疗，序贯3个疗程的225 mg/m2紫杉醇治疗，随后接受3个疗程的2,500 mg/m2环磷酰胺治疗（在招募大约1,200例患者后减至2,000 mg/m2），均间隔2周用药（iddETC方案），或是接受112.5 mg/m2表柔比星+600 mg/m2环磷酰胺治疗、持续4个疗程（2周为1个疗程），序贯10个疗程的67.5 mg/m2紫杉醇治疗、每周用药1次，在每3周的第1~14天给予2,000mg/m2卡培他滨治疗（EC-TX方案）。根据AGO指南，这些患者适宜采取放疗、内分泌治疗以及曲妥珠单抗治疗，并且在化疗结束后，如何合适的话，与伊班膦酸钠治疗平行用药。所有进行保乳手术的患者都接受了针对患侧乳腺的放疗。内分泌治疗敏感型乳腺癌患者接受了5年内分泌治疗，方案为芳香化酶抑制剂单药治疗，如若处于绝经后，则在此基础上序贯他莫昔芬治疗。如果患者在化疗结束后处于绝经前期，则单用他莫昔芬治疗5年配伍一种促性腺激素释放激素（LHRH）类似物治疗。人类表皮生长因子受体-2过表达的肿瘤患者接受1年的曲妥珠单抗辅助治疗。在最初2年的治疗期间，每12周对患者评价1次，随后改为每6个月评价1次。

总共有1,421例患者（78.2%）按计划完成了伊班膦酸钠治疗，5.8%因为进展或死亡而停止治疗，还有16%因各种原因停止治疗。在中位38.7个月的随访期（范围：0~73个月）内共发生405例事件，其中包括186例死亡，总共有76.8%的患者完成随访。

分析结果显示， 2年伊班膦酸钠治疗组与观察组患者在无病生存率（HR，0.945；95% CI，0.768~1.161；P=0.589）或总体生存率（HR，1.040；95% CI，0.763~ 1.419；P=0.803）上无差异，分别有31% 和38%的患者发生了骨转移。对研究数据进行Post hoc亚组分析提示，双膦酸盐辅助治疗的收益仅限于雌激素水平低的患者，这要么归因于药物性卵巢去势，要么归因于明确的停经。今后对个体患者的数据进行meta分析或可阐明可能受益于辅助性双膦酸盐治疗的早期高危乳腺癌亚组患者。

本研究由德国安进、德国施贵宝以及德国罗氏资助，罗氏还为本研究提供了药品。von Minckwitz医生报告与罗氏有联系，其同事表示与多家药企有联系。

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By: MARY JO M. DALES, Internal Medicine News Digital Network

Two years of adjuvant treatment with ibandronate after dose-dense chemotherapy did not improve survival in a study of more than 3,000 German patients with early stage, node-positive breast cancer.

The results were published online Aug. 26 in the Journal of Clinical Oncology.

Bisphosphonates have been shown to prevent skeletal-related events in patients with metastatic breast cancer, but their effectiveness has not been demonstrated in early breast cancer.

No differences in disease-free survival or overall survival were noted in the GAIN (German Adjuvant Intergroup Node-Positive) study, an open-label, randomized, controlled phase III trial (NCT00196872), reported Dr. Gunter von Minckwitz of the German Breast Group, along with his colleagues in the German Breast Group/Gynecologic Oncology Working Group/North-Eastern Germany Society of Gynecologic Oncology study groups.

In patients randomly assigned to 2 years of ibandronate or observation, there was no difference in disease-free survival (HR, 0.945; 95% CI, 0.768 to 1.161; P equals .589) or in overall survival (HR, 1.040; 95% CI, 0.763 to 1.419; P equals .803). Metastasis to the bone was documented in 31% in the ibandronate arm and in 38% in the observation arm.

Post hoc subgroup analyses of the study data imply that the benefit of adjuvant bisphosphonates was restricted to patients with low estrogen levels, either because of medical ovarian suppression or definite menopause. Future meta-analyses on an individual patient data level may reliably reveal subgroups of early-stage, high-risk breast cancer patients who might benefit from adjuvant bisphosphonates, the researchers noted (J. Clin. Oncol. 2013 Aug. 26 [doi:10.1200/JCO.2012.47.2167]).

In GAIN, patients with node-positive early breast cancer were randomly assigned within 4 weeks after surgery to two different dose-dense chemotherapy regimens and then in 2:1 fashion to ibandronate 50 mg per day orally starting within 4 weeks after last administration of chemotherapy and continuing for 2 years (2,015 patients) or to observation (1,008 patients).

Randomly assigned chemotherapy consisted of three courses of epirubicin 150 mg/m2 followed by three courses of paclitaxel 225 mg/m2 followed by three courses of cyclophosphamide 2,500 mg/m2 (reduced to 2,000 mg/m2 after recruitment of approximately 1,200 patients), all given at 2-week intervals (iddETC regimen) or epirubicin 112.5 mg/m2 and cyclophosphamide 600 mg/m2 for four 2-week courses followed by 10 courses of paclitaxel 67.5 mg/m2 given once per week with capecitabine 2,000 mg/m2 given days 1-14 every 3 weeks (EC-TX regimen).

Radiotherapy, endocrine treatment, and trastuzumab were indicated according to AGO guidelines and, if appropriate, were given in parallel with ibandronate after the end of chemotherapy. All patients received radiotherapy to the affected breast if breast-conserving surgery was performed, the researchers wrote.

Patients with endocrine-sensitive disease received endocrine treatment for 5 years with an aromatase inhibitor either alone or in sequence with tamoxifen if they were postmenopausal. Tamoxifen alone was given for 5 years in some patients together with a luteinizing hormone-releasing hormone (LHRH) analog if they were premenopausal after the end of chemotherapy. Patients with human epidermal growth factor receptor 2–overexpressing tumors received 1 year of adjuvant trastuzumab treatment.

Patients were evaluated every 12 weeks during the first 2 years of treatment and then every 6 months.

A total of 1,421 patients (78.2%) completed ibandronate treatment as planned, 5.8% discontinued treatment due to progression or death, and 16% discontinued treatment for various reasons. There were 405 events, including 186 deaths, after a median of 38.7 months (range, 0-73 months) with a completeness of follow-up of 76.8%.

The study was supported by Amgen, Germany; Bristol-Myers Squibb, Germany; and Roche, Germany, which also provided drugs for the study. Dr. von Minckwitz reported ties with Roche. His colleagues noted ties with numerous drug companies.