Gravis Gwenaelle, Boher Jean-Marie, Chen Yu-Hui, Liu Glenn, Fizazi Karim, Carducci Michael A, Oudard Stephane, Joly Florence, Jarrard David M, Soulie Michel, Eisenberger Mario J, Habibian Muriel, Dreicer Robert, Garcia Jorge A, Hussain Maha H M, Kohli Manish, Vogelzang Nicholas J, Picus Joel, DiPaola Robert, Sweeney Christopher
Centre de Recherche en Cancerologie de Marseille (CRCM), Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
Biostatistic, Institut Paoli-Calmettes, Aix-Marseille Universite, Marseille, France.
Eur Urol. 2018 Jun;73(6):847-855. doi: 10.1016/j.eururo.2018.02.001. Epub 2018 Feb 21.
Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D.
To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]).
DESIGN, SETTING, AND PARTICIPANTS: Data were accessed from two independent phase III trials of ADT alone or ADT+D-GETUG-AFU15 (N=385) and CHAARTED (N=790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized.
The primary end point was OS.
Meta-analysis results of the aggregate data showed significant heterogeneity in ADT+D versus ADT effect sizes between HV and LV subgroups (p=0.017), and failed to detect heterogeneity in ADT+D versus ADT effect sizes between upfront and PRLT subgroups (p=0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT+D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p<0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT+D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials.
There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients.
Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits.
多西他赛（D）在转移性去势敏感性前列腺癌开始雄激素剥夺治疗（ADT）时，对高负荷（HV）疾病患者显示出明显的生存获益。尚不清楚低负荷（LV）疾病患者是否能从早期使用D中获益。
通过转移性负担（HV和LV）以及转移发生时间（诊断时或先前局部治疗[PRLT]后）来定义CHAARTED和GETUG-AFU15研究中患者亚组的汇总数据的总生存期（OS）。
设计、设置和参与者：数据来自两项独立的III期试验，单独使用ADT或ADT + D——GETUG-AFU15（N = 385）和CHAARTED（N = 790），幸存者的中位随访时间分别为83.2个月和48.2个月。HV和LV疾病的定义进行了统一。
主要终点为OS。
汇总数据的荟萃分析结果显示，HV和LV亚组之间ADT + D与ADT效应大小存在显著异质性（p = 0.017），且未检测到 upfront和PRLT亚组之间ADT + D与ADT效应大小的异质性（p = 0.4）。在HV疾病患者中添加D对改善中位OS有一致的效果（CHAARTED和GETUG-AFU15中，HV-ADT分别为34.4个月和35.1个月，HV-ADT + D分别为51.2个月和39.8个月；合并平均风险比或HR（95%置信区间[CI]）0.68（[95% CI 0.56；0.82]，p < 0.001）。LV疾病患者的OS长得多，没有证据表明D能改善OS（CHAARTED和GETUG-AFU15中，LV-ADT分别为未达到[NR]和83.4个月，LV-ADT + D分别为63.5个月和NR；合并HR（95% CI）1.03（95% CI 0.77；1.38）。汇总数据显示，无论患者是否接受PRLT，LV和HV亚组中早期使用D均无异质性证据。事后亚组分析基于两项独立的III期随机试验的汇总数据。
在CHAARTED和GETUG-AFU15研究中，D对LV患者没有明显的生存获益。在两项研究中，早期使用D对HV患者显示出一致的效果并改善了OS。
开始雄激素剥夺治疗（ADT）的转移性前列腺癌负担较高的患者预后较差，更有可能从早期多西他赛中获益。低负荷患者单独使用ADT时总生存期更长，多西他赛的毒性可能超过其益处。
