乳腺癌一线治疗 新药白蛋白结合型紫杉醇(nab-paclitaxel)和伊沙匹隆(ixabepilone)效果无优势

芝加哥(EGMN)——美国临床肿瘤学会(ASCO)年会上公布的一项纳入既往未接受过化疗的局部复发或转移性乳腺癌女性患者的Ⅲ期研究显示，白蛋白结合型紫杉醇(nab-paclitaxel)和伊沙匹隆(ixabepilone)这两种较新且昂贵的乳腺癌治疗药物的有效性和安全性并不高于紫杉醇这种老药。

在这项名为CALGB 40502/NCCTG N063H的研究中，加州大学旧金山分校海伦·迪勒家庭综合癌症中心乳腺癌和临床试验教育项目主任Hope S. Rugo博士及其同事将799例患者随机分入3个开放标记一线化疗组：紫杉醇组(90 mg/m2，每周1次，最常用的剂量方案)、白蛋白结合型紫杉醇组(150 mg/m2，每周1次)和伊沙匹隆组(16 mg/m2，每周1次)。所有3组均加用贝伐珠单抗(每2周1次)，均采用给药3周停药1周的方案。治疗6个周期后获得应答或疾病稳定的患者可停止化疗，仅继续接受贝伐珠单抗治疗。

中位随访12个月的结果显示，白蛋白结合型紫杉醇组[9.2个月；危险比(HR)=1.19；P=0.12]和伊沙匹隆组(7.6个月；HR=1.53；P＜0.0001)的无进展生存期均短于紫杉醇组(10.6个月)。紫杉醇组、白蛋白结合型紫杉醇组和伊沙匹隆组≥3级不良事件的总发生率分别为55%、79%和59%。白蛋白结合型紫杉醇组和伊沙匹隆组≥3级非血液学不良事件的发生率显著高于紫杉醇组。白蛋白结合型紫杉醇组和伊沙匹隆组周围神经病变发生率也高于紫杉醇组。白蛋白结合型紫杉醇组≥3级血液学事件的发生率显著高于紫杉醇组，而伊沙匹隆组该发生率则显著低于紫杉醇组。

研究者表示，虽然该研究未设无贝伐珠单抗的对照组，但紫杉醇对照组的无进展生存结果与比较紫杉醇单药治疗与紫杉醇/贝伐珠单抗联合治疗的ECOG 2100研究结果基本相同。因此，即使在不使用贝伐珠单抗的情况下重新进行整个研究，所得出的结果也不会与目前的研究结果有很大出入。研究结果表明白蛋白结合型紫杉醇并不优于紫杉醇，但可作为替代性药物用于不适合使用紫杉醇的患者，比如对cremophor(紫杉醇溶剂)过敏的患者或不能耐受激素预处理的糖尿病患者。此外，白蛋白结合型紫杉醇还能有效治疗晚期转移性乳腺癌或经其他紫杉烷类药物治疗后出现进展的癌症患者。最后，在缺乏紫杉醇的情况下，白蛋白结合型紫杉醇无疑也可作为替代药物。然而，需指出的是，有资料表明，在100 mg/m2这样的低剂量水平(比本研究所用剂量低1/3)使用白蛋白结合型紫杉醇，毒性较小。因此，在使用白蛋白结合型紫杉醇治疗患者时，应使用100 mg/m2剂量。

该研究获美国国立癌症研究所资助。Rugo博士声明从Abraxis BioScience、百时美施贵宝和罗氏/基因泰克公司获得研究资金。


CHICAGO (EGMN) – Two fairly new and expensive drugs for breast cancer were no more effective or safer than a drug that has been used for this disease for over a decade, finds a phase III cooperative group trial among nearly 800 women with chemotherapy-naive locally recurrent or metastatic disease.

The trial pitted the newer nab-paclitaxel and ixabepilone against the older paclitaxel as a control, each given weekly, along with bevacizumab given every 2 weeks, as first-line therapy.

Trial results reported at the annual meeting of the American Society of Clinical Oncology showed that progression-free survival was not superior with nab-paclitaxel and was in fact inferior with ixabepilone, translating to a 53% higher risk of progression or death relative to paclitaxel, first author Dr. Hope S. Rugo reported in a press briefing.

Moreover, rates of grade 3 or worse adverse events were higher with both of the newer agents than with the old stand-by.

“These data suggest that similar patients could be appropriately treated with weekly paclitaxel,” said Dr. Rugo, professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco.

“Interestingly, ixabepilone is an epothilone where preclinical and some clinical data suggest an ability to reverse resistance to the microtubule inhibitors like paclitaxel, and nab-paclitaxel has similar data,” she added. “However, in this chemotherapy-naive population, these results showed equivalency or inferiority.”

“These are all good drugs, these are all major-league baseball players. I want them all on my team,” asserted press briefing moderator Dr. Nicholas Vogelzang, chair and medical director, Developmental Therapeutics Committee, US Oncology, Comprehensive Cancer Centers of Nevada. “And when they are used to treat breast cancer, a patient should be considered for all of them, perhaps in different sequences for different patients.”

The trial’s findings do not preclude use of at least nab-paclitaxel in selected patients similar to those studied or in other treatment settings, according to Dr. Rugo.

“Based on our data, it’s very unlikely that [nab-paclitaxel] is superior to paclitaxel, but it could be used as an alternative in patients who had a reason not to receive paclitaxel,” such as an allergy to cremophor (paclitaxel’s solvent), or diabetes making it hard to tolerate the steroids needed as premedication, she said. Also, the drug is effective in patients with later-stage metastatic breast cancer or with cancers that have progressed on other taxanes.

Finally, nab-paclitaxel is a useful alternative in the context of drug shortages. “In the setting where paclitaxel is not readily available, nab-paclitaxel could clearly be used in its place,” she said.

Of note, however, data have shown that nab-paclitaxel given at a lower dose of 100 mg/m2 – one-third lower than the dose used in the trial – is less toxic. Therefore, “in patients in whom nab-paclitaxel is chosen ... we should be using the 100 mg/m2 dose,” Dr. Rugo recommended.

The trial, formally known as CALGB 40502/NCCTG N063H and sponsored by the U.S. National Cancer Institute, randomized 799 patients to open-label treatment with one of the three chemotherapies – paclitaxel (90 mg/m2 weekly, the most commonly used dosage schedule), nab-paclitaxel (150 mg/m2 weekly), or ixabepilone (16 mg/m2 weekly) – plus bevacizumab every 2 weeks.

All chemotherapy was given on a 3-weeks-on, 1-week-off schedule. Patients who had a response or stable disease after six cycles could stop chemotherapy and continue with the bevacizumab alone.

With a median follow-up of 12 months, analyses showed that progression-free survival was no better with nab-paclitaxel (9.2 months; hazard ratio, 1.19; P = .12) and was actually worse with ixabepilone (7.6 months; hazard ratio, 1.53; P less than .0001) than with paclitaxel (10.6 months), Dr. Rugo reported.
The overall rate of grade 3 or worse adverse events was 55% with paclitaxel, compared with 79% with nab-paclitaxel and 59% with ixabepilone.

The rate of grade 3 or worse nonhematologic adverse events was significantly higher with the newer agents than with the older one. “We saw increased peripheral neuropathy in the experimental arms as compared with the control arms as well,” Dr. Rugo noted. The rate of grade 3 or worse hematologic events was significantly higher with nab-paclitaxel and significantly lower with ixabepilone.

The findings are likely to remain relevant despite the U.S. Food and Drug Administration’s withdrawal of approval for bevacizumab, according to Dr. Rugo. “Interestingly, in our study, we obviously don’t have a control arm without bevacizumab, but the progression-free survival in the control arm was almost identical to ECOG 2100,” which compared paclitaxel with and without bevacizumab. “And I think for that reason, it’s unlikely that there would be a big difference if you redid the whole study without bevacizumab,” she said.

Dr. Rugo said she receives research funding from Abraxis BioScience, Bristol-Myers Squibb, and Roche/Genentech. Dr. Vogelzang said he is a consultant to Amgen, AVEO, Bayer, Celgene(U), Dendreon, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, Johnson & Johnson, Keryx, Medscape, Novartis, Oncogenex, Pfizer, and Wilex; he receives honoraria from Amgen, Bayer, Clinical Care Options, Genentech, Imedex, Lilly, Lippincott, Williams, and Wilkins, Medscape, Novartis, Onyx, Pfizer, and Veridex; and he receives research funding from Algeta, Pfizer, Progenics, and Tokai Pharmaceuticals.