George Angela, Kristeleit Rebecca, Rafii Saeed, Michie Caroline O, Bowen Rebecca, Michalarea Vasiliki, van Hagen Tom, Wong Mabel, Rallis Grigorios, Molife L Rhoda, Lopez Juanita, Banerji Udai, Banerjee Susana N, Gore Martin E, de Bono Johann S, Kaye Stan B, Yap Timothy A
Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK.
Royal Marsden NHS Foundation Trust, Downs Road, London SM2 5PT, UK; The Institute of Cancer Research, Cotswold Road, London SM2 5NG, UK.
Eur J Cancer. 2017 May;76:52-59. doi: 10.1016/j.ejca.2017.01.020. Epub 2017 Mar 6.
Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1-8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine.
晚期卵巢癌（AOC）患者对传统抗癌疗法产生耐药几乎不可避免，这限制了他们可用的治疗选择。在专门的药物研发部门开展的新型I期试验疗法可能是一种可行的替代方案；然而，目前几乎没有此类患者的预后证据。为了解决这一问题，我们对1998年6月至2010年10月期间在皇家马斯登医院（RMH）药物研发部门分配到I期试验的AOC患者进行了回顾性研究。共有200例疾病进展的AOC患者每人被分配到≥1项试验，共进行了281次分配。其中，135例（68%）患者开始了≥1项试验（平均1.4 [1 - 8]项），共进行了216次分配试验；65例（32%）患者因疾病快速进展导致病情恶化（63例患者）或患者选择（2例患者）而未开始试验。在开始试验的患者中，43例（20%）观察到实体瘤疗效评价标准（RECIST）的完全/部分缓解（CR/PR），包括接受聚（ADP - 核糖）聚合酶（PARP）抑制剂治疗的患者（18/79 [23%]）、抗血管生成药物治疗的患者（9/65 [14%]）和化疗联合治疗的患者（14/43 [33%]）。与CR/PR相关的因素包括：既往治疗次数较少、铂敏感疾病、既往治疗有CR/PR、（美国）东部肿瘤协作组（ECOG）体能状态评分、转移部位较少、白蛋白和血红蛋白水平较高、白细胞计数较低以及基线CA125水平、胚系BRCA1/2突变和较好的RMH预后评分。达到CR/PR的患者平均生存期为32个月。治疗耐受性一般良好。大多数AOC患者（134/200 [67%]）在I期试验后接受了≥1线后续治疗。我们的数据表明，在AOC治疗过程中，尤其是在精准医学时代有前景的新型药物出现的情况下，应在疾病快速进展之前更早地考虑将患者转诊至I期试验。
