ORLANDO (EGMN) – The doublet of carboplatin plus pegylated liposomal doxorubicin extends progression-free survival as effectively as the standard treatment of carboplatin plus paclitaxel in women with platinum-sensitive recurrent epithelial ovarian cancer, and may even be superior, based on the results of the open-label phase III CALYPSO trial involving almost 1,000 women.

Median progression-free survival reached 11.3 months for women treated with carboplatin plus pegylated liposomal doxorubicin (PLD) and 9.4 months for women given carboplatin plus paclitaxel (Taxol) (hazard ratio, 0.82; P for noninferiority less than .001; P for superiority = .005), Dr. Eric Pujade-Lauraine reported on behalf of the Gynecologic Cancer Intergroup (GCIG) at the annual meeting of the American Society of Clinical Oncology. Median follow-up was 22 months.

“These results will change practice, as [carboplatin/PLD] offers an evidence-based option for patients with platinum-sensitive recurrent ovarian cancer,” he said.

It may be too soon to call carboplatin/PLD the superior treatment, cautioned Dr. Jonathan Ledermann, an oncologist at University College London, who was invited to discuss the study. “We can, without a doubt, say that noninferiority – which was the primary end point of this study – has been confirmed, but can one say that [carboplatin/PLD] is a superior treatment? There are differences in the duration of treatment [and] more early discontinuation and/or hypersensitivity reactions, and the differences in progression-free survival emerge after 6 months,” he said.

The study randomized 508 women with ovarian cancer in late relapse to receive carboplatin/paclitaxel and 466 women to receive carboplatin/PLD. They had to have had previous taxane exposure and disease progression more than 6 months after first- or second-line platinum-based therapy.

The control regimen consisted of carboplatin AUC (area under the curve) 5 plus 175 mg/m² intravenous paclitaxel on day 1 of a 21-day cycle, for six cycles. In the experimental arm, women received carboplatin AUC 5 plus 30 mg/m² intravenous PLD on day 1 of a 28-day cycle, for six cycles. Most patients (88% and 83% in the experimental and control arms, respectively) had received one previous line of chemotherapy.

Notably, median treatment duration was longer in the PLD arm (21 vs. 16 weeks). “This difference was not only due to the fact that the length of the cycle was different between the two arms, but also because a higher percentage of patients in the carboplatin/PLD arm [was able to achieve] the six planned cycles,” said Dr. Pujade-Lauraine of the Université Rene Descartes and the Hôpital Hôtel-Dieu, both in Paris. In all, 85% of patients in the PLD arm had at least six cycles vs. 78% of the control arm.

Among hematologic toxicities, grade 3/4 neutropenia was significantly more common in the control arm, and grade 3/4 thrombocytopenia in the PLD arm. “Overall, the clinical consequences of these hematologic toxicities were low in both arms,” he said.

Nonhematologic toxicities showed significant differences, mostly favoring PLD. Notably, grade 2 alopecia was much more common in the control arm (84% vs. 7%; P less than .001), as were grade 2 and grades 3-5 neuropathy and grade 2 arthralgia/myalgia. Grade 2 nausea/vomiting, hand-foot syndrome, and mucositis were significantly more common in the PLD arm.

“We were surprised to see that there was a lower rate of early treatment discontinuation due to toxicity in the carboplatin/PLD arm,” noted Dr. Pujade-Lauraine. In all, 27 patients in the experimental arm discontinued treatment early because of toxicity, compared with 73 in the control arm.

This appears to be related to an unexpected finding: Hypersensitivity to carboplatin occurred significantly more frequently when it was combined with paclitaxel than when it was combined with PLD. “This is an important finding with clinical implications for all of you who treat patients with ovarian cancer, and for women,” he said.

Dr. Ledermann urged attendees to keep in mind that the overall survival data are immature. “Should we be making decisions about changing to carboplatin/liposomal doxorubicin without any information at all on the survival data?” he asked.

Schering-Plough Corp., which sponsors PLD as Caelyx outside the United States, was among the trial’s many sponsors and collaborators. The study authors reported no relevant financial relationships. Dr. Ledermann disclosed that he is on ad hoc advisory boards for Schering-Plough and four other drug companies.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

奥兰多(EGMN)——根据纳入大约1,000例女性患者的开放性III 期CALYPSO试验的结果，卡铂加聚乙二醇脂质体阿霉素(PLD)的联合方案，在延长铂类敏感性复发性卵巢上皮癌患者的无进展生存期方面，等效于甚至可能优于卡铂加紫杉醇标准疗法。

 

Eric Pujade-Lauraine博士在美国临床肿瘤学会年会上代表妇产科恶性肿瘤国际小组(GCIG)报道，接受卡铂加PLD治疗的患者，其中位无进展生存期达11.3个月，而接受卡铂加紫杉醇(Taxol) 治疗的患者中位无进展生存期为9.4个月(危险比，0.82；非劣效性P <0.001，优效性P =0.005)。中位随访期为22个月。

 

他说，“由于卡铂+PLD为铂类敏感性复发性卵巢癌患者提供了一个以循证的治疗选择，故这些结果将改变临床实践。”

 

受邀讨论该研究的Jonathan Ledermann博士告诫，称卡铂+PLD为优势疗法可能尚为时过早。Jonathan Ledermann博士是伦敦大学学院的一位肿瘤科医生。他说，“毫无疑问，我们可以说非劣效性——该研究的主要终点——已被证实，但可以说卡铂+PLD是优势疗法吗？在治疗持续时间和过早停止治疗和/或过敏反应方面尚存在差异，而且6个月后出现无进展生存方面的差异。”

 

该研究将508例晚期复发的卵巢癌患者随机分配接受卡铂+紫杉醇治疗，466例接受卡铂+PLD治疗。这些患者既往必须使用过紫杉烷类，而且在以铂类为基础一线或二线治疗后6个多月出现疾病进展。

 

对照组方案包括卡铂AUC(曲线下面积) 5+175mg/m²，第一天静脉注射紫杉醇，21天为一个治疗周期，共 6个周期。试验组患者接受卡铂AUC 5+30mg/m²，第一天静脉注射PLD，28天为一个治疗周期，共 6个周期。大多数患者（试验组和对照组分别为88%和83%）既往接受过一种化疗方案。

 

值得注意的是，PLD组中位治疗时间较长(21周对16周)。巴黎勒内笛卡尔大学和Hôtel-Dieu医院的Pujade-Lauraine 博士说，“造成这一差异的原因不仅是因为两组治疗周期的长度不同，还源于卡铂+PLD组有较高比例的患者能够完成6个计划周期。”总之，PLD组有85%的患者完成至少6个周期的治疗，而对照组则只有78%的患者。

 

在血液学毒性方面，对照组3/4级中性粒细胞减少明显更常见，PLD组3/4级血小板减少更常见。他说，“整体而言，这些血液学毒性的临床后果较轻。”

 

非血液学毒性存在显著差异，主要支持PLD组。值得注意的是，对照组2级脱发更为常见(84%对7%；P <0.001)，对照组2级和3~5级神经病以及2级关节痛/肌痛也较常见。PLD组2级恶心/呕吐、手足综合征和黏膜炎明显较常见。

 

Pujade-Lauraine博士指出，“我们惊讶地发现，卡铂+PLD组因毒性而早期停止治疗的患者比例较低。”总之，试验组有27例患者因毒性而早期停止治疗，而对照组有73例患者。

 

这似乎是一个出乎意料的发现：与卡铂和PLD联合相比，当卡铂和紫杉醇联合时，患者更见频繁地发生铂类过敏现象。他说，“对所有治疗卵巢癌患者的医生以及女性而言，这是一个具有临床意义的重大发现。”

 

Ledermann博士敦促参会者们记住，总体存活数据尚不成熟。“在没有任何存活数据的情况下，我们应决定采用卡铂+PLD治疗吗?”他反问。

 

在美国以外以商品名Caelyx生产PLD的先灵葆雅公司是该试验的赞助者和合作者之一。该研究的作者们报道无相关财务关系。Ledermann博士披露，他是先灵葆雅公司以及其他4个制药公司特设咨询委员会的成员。