镭223可延长转移性前列腺癌患者生存

《新英格兰医学杂志》7月17日在线发表的ALSYMPCA国际Ⅲ期临床研究结果显示，镭223可使去势难治性骨转移前列腺癌患者的总生存延长近4个月并使死亡风险降低30%(N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755])。


Christopher Parker医生

在这项研究中，英国萨顿皇家马斯登医院的Christopher Parker医生及其同事从19个国家的136个研究中心纳入921例具有≥2处症状性骨转移且无内脏转移的进行性去势难治性前列腺癌男性患者。所有患者均需接受常规镇痛药物或其他治疗来缓解癌症相关骨痛。

根据是否曾接受多西紫杉醇或二磷酸盐治疗及根据基线碱性磷酸酶水平对患者进行分层，然后随机分组，镭223组614例，匹配安慰剂组307例，每月静脉注射1次，共注射6次。所有患者在各自治疗中心同时接受现有最佳标准治疗，包括局部外束放射治疗、糖皮质激素、抗雄激素、酮康唑或雌激素。因此，研究结果应可外推至常规临床实践。

结果显示，镭223组的中位总生存(主要终点)为14.9个月，显著长于安慰剂组的11.3个月。意向治疗人群中共有528例患者死亡；镭223组和安慰剂组的死亡率分别为54%和64%。镭223组任何原因所致死亡率比安慰剂组低30%。这些总生存差异在所有亚组患者中一致，不论基线碱性磷酸酶水平、当前二膦酸盐应用、既往多西紫杉醇治疗、任何阿片类应用及基础癌症程度如何。

与安慰剂组相比，镭223可显著延长至首发症状性骨骼事件的时间(15.6个月vs. 9.8个月)。此外，镭223还可延长至总碱性磷酸酶水平和PSA水平增高的时间。FACT-P评分结果显示，镭223组生活质量获得有意义的改善的患者比例显著高于安慰剂组(25% vs. 16%)。

镭223组不良事件、严重不良事件、3级或4级不良事件及血液学不良事件的总发生率均低于安慰剂组。镭223组停药患者数量少于安慰剂组。镭223的这一良好安全性可归因于其高度靶向作用，即其既可最大程度地减少骨髓抑制，同时对正常组织的影响又小。

该研究包含一个重要的患者亚组，即被拒绝或不适合接受多西紫杉醇治疗的患者。目前，许多去势难治性骨转移前列腺癌患者不接受多西紫杉醇治疗，因为其体质虚弱、存在禁用该药的合并症、或拒绝化疗。因此，该研究满足了此类未接受现有治疗的患者人群的重要需求。

研究者表示，自该研究开始后，前列腺癌治疗就不断发展，目前已积累了有关卡巴他赛、阿比特龙和enzalutamide的新数据。未来研究应评估镭223是否适合与这些药物序贯应用或合并应用。

Algeta和拜耳保健医药公司资助并与研究者共同设计和开展ALSYMPCA研究。Parker 医生及其同事声明与安进等多家公司存在联系。

随刊述评：耐受性非常高的治疗

费城宾夕法尼亚大学放射肿瘤学科的Neha Vapiwala博士和Eli Glatstein博士表示，该研究表明镭223具有明显的生存优势，促进了对α发射体的应用研究。鉴于镭223对现有治疗既有补充性也有竞争性，因此可能需重新探讨紫杉烷类在转移性去势难治性前列腺癌中的一线作用，并且也需要探索α粒子在药物中的生存力(N. Engl. J. Med. 2013 July 18 [doi:10.1056/NEJMe1304041])。

Vapiwala博士和Glatstein博士均声明无相关经济利益冲突。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.

Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).

The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.

The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.

These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).

All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.

The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).

A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.

These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.

Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.

In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.

The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.

This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.

The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.

The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.

A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.

The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

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Remarkably tolerable therapy

This study demonstrates a clear survival advantage with a compound that has "remarkable tolerability," imparting "some long-awaited momentum to research on the use of alpha emitters," said Dr. Neha Vapiwala and Dr. Eli Glatstein.

Given radium-223’s ability to both complement and contend with existing treatments, "the first-line role of taxanes in metastatic castration-resistant prostate cancer may be reexamined, and the viability of alpha particles in medicine may be newly explored," they noted.

Dr. Vapiwala and Dr. Glatstein are in the department of radiation oncology at the University of Pennsylvania, Philadelphia. They reported no relevant financial conflicts of interest. These remarks were taken from their editorial accompanying Dr. Parker’s report (N. Engl. J. Med. 2013 July 18 [doi:10.1056/NEJMe1304041]).