唑来膦酸每季度给药1次对乳腺癌患者或仍有效

芝加哥(EGMN)——意大利国家癌症研究所的Carla Ripamonti博士在美国临床肿瘤学会(ASCO)年会上报告称，ZOOM试验结果表明，乳腺癌骨转移患者在接受每月1次唑来膦酸标准治疗1年后，或可采取每季度给药1次的治疗方案，其疗效“非劣于”现行标准治疗。

在这项首个比较唑来膦酸两种给药方案的12个月的开放、多中心Ⅲ期试验中，分别有209例和216例女性患者随机接受4 mg/12周和4 mg/4周唑来膦酸治疗。所有患者在入组前均已接受9~12次输注治疗。试验结束时，分别有149例和142例患者完成治疗。意向治疗分析显示，两组患者骨骼发病率(主要终点指标)未见差异，平均年骨骼事件与试验时间之比分别为0.26和0.22。发生骨骼相关事件患者比例(次要终点指标)也相似，分别为14.8%和15.3%。此外，两种给药方案均具有良好耐受性，不良事件发生率也几乎没有差异。两组患者肾脏副作用发生率均为4%，每季度给药组和每月给药组分别有4例和3例患者发生颌骨坏死。

研究者指出，已知唑来膦酸(择泰)至少可在2年内预防该类患者发生骨骼相关事件，国际指南推荐患者应持续接受该药治疗直至身体状况出现实质性下降。基于上述试验结果，可考虑在患者接受1年标准治疗后，采用更为方便的每季度1次给药方案，将有助于改善患者依从性和安全性，降低治疗费用且保持药物疗效。约翰霍普金斯大学Sidney Kimmel癌症中心姑息医学部主任Thomas J. Smith博士在评论中强调了该问题的普遍性。他指出，在临床实践中曾遇到许多患者询问是否必须每月注射唑来膦酸，但答案不得而知。

但研究者表示，对基线和每3个月的Ⅰ型胶原N端肽(NT)中位水平的评估结果令人关注。每季度给药组在6个月时这种骨吸收标志物水平开始升高并维持较高水平，而标准治疗组未见升高，提示“应予以关注并进行更长时间随访，以评估新方案能否长期维持对骨骼相关事件的足够疗效”。

此外，研究者还强调，尽管得到了一般性阳性结果，但该试验是在一个国家完成的开放性研究，也未预先设定影像学检查频率，且随访时间仅为1年。为此，她极力建议临床医生应等待目前正在进行的双盲Ⅲ期优化-2试验结果。明年可望得到相关结果，届时肿瘤科医生将可决定如何改变其临床实践。Smith博士同意这一看法，他指出，依据NT水平作出判断尚为时过早，建议医生不要急于改变现行方案，应等待新数据和指南出台。他预计，一旦新方案可行，治疗费用将减少2/3。

Ripamonti博士报告无相关利益冲突；Smith博士报告接受了美国癌症学会研究经费资助。

CHICAGO (EGMN) – Women taking zoledronic acid monthly for metastatic breast cancer that has spread to the bone may be able to get by with quarterly injections after a year of standard treatment.

The first phase III trial to compare the two dosing schedules for the bisphosphonate found that less frequent therapy produced “noninferior” outcomes compared with the current standard of care, Dr. Carla Ripamonti reported at the annual meeting of the American Society of Clinical Oncology.

Zoledronic acid (Zometa) has been shown to reduce skeletal-related events for up to 2 years in such patients, and international guidelines recommend its use until they experience a substantial decrease in performance status, said Dr. Ripamonti of the National Cancer Institute in Milan, Italy. The thinking behind the current trial was that after a year of treatment, a more convenient regimen “might contribute to improved patient compliance and safety, and help reduce cost while maintaining the efficacy of the drug.”

Underscoring the universality of the issue, the invited discussant, Dr. Thomas J. Smith, director of palliative medicine at Johns Hopkins University’s Sidney Kimmel Cancer Center in Baltimore, introduced his comments with the observation, “I’m a breast cancer doctor, and so I see so many people who ask, ‘Do I have to come in every month for my zoledronic acid?’ And the answer is, ‘I don’t know.’ ”

Dr. Ripamonti and her coinvestigators randomized 209 women to 4 mg of zoledronic acid every 12 weeks and 216 women to 4 mg every 4 weeks in the 12-month, open-label, multicenter ZOOM trial. All participants had received 9-12 infusions prior to entering the prospective study.

At the trial’s end, 149 and 142 women, respectively, had completed treatment with no difference in the skeletal morbidity rate, the primary end point, in an intent-to-treat analysis. The mean of the ratio of skeletal events per year to time on trial was 0.26 with quarterly treatment and 0.22 with monthly dosing, she reported.

The proportion of patients with skeletal-related events, a secondary end point, also was similar at 14.8% in the quarterly group and 15.3% in the monthly group.

Both schedules were well tolerated, with little difference in adverse events, she reported. The rate of renal side effects was 4% in each arm; osteonecrosis of the jaw occurred in 4 patients on the quarterly schedule and 3 treated monthly.

An assessment of median NTx (N-telopeptides of type I collagen) levels at baseline and every 3 months on study raised some concern, in that the bone resorption marker was increased at 6 months and stayed elevated in the quarterly group, but it did not rise with standard care. This suggests that “caution is needed and longer follow-up is needed to assess whether zoledronic acid every 3 months can maintain adequate efficacy in skeletal-related events over time,” said Dr. Ripamonti.

Despite the generally positive results, she noted that the trial was conducted in just one country as an open-label study, it did not have a prespecified imaging frequency, and patients were followed for only 1 year. She urged clinicians to wait for data from the double-blind, phase III Optimize-2 trial, which compared the same dose schedules. Results will be available in the next year, and then oncologists “can decide how to change our clinical practice,” she said.

Dr. Smith agreed. It’s “too early” to use NTx levels, he said, recommending that clinicians wait for new data and guidelines. If quarterly dosing becomes possible, he predicted the “cost will be one-third of what it was before.”

“So don’t change your current approach, but stay tuned,” he told attendees.

Dr. Ripamonti said she had no relevant disclosures. Dr. Smith said he received research funds from the American Cancer Society.