Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial.
早期乳腺癌的辅助denosumab (D-CARE): 一项国际、多中心、随机、对照、 3 期试验。
- 作者列表："Coleman R","Finkelstein DM","Barrios C","Martin M","Iwata H","Hegg R","Glaspy J","Periañez AM","Tonkin K","Deleu I","Sohn J","Crown J","Delaloge S","Dai T","Zhou Y","Jandial D","Chan A
BACKGROUND:Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer. METHOD:In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154. FINDINGS:Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. INTERPRETATION:Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer. FUNDING:Amgen.
背景: Denosumab是一种完全人源的单克隆抗体，结合并抑制RANKL (TNFSF11) 的受体激活剂，并可能影响乳腺癌生物学，如临床前证据所示。我们的目的是评估denosumab联合标准护理辅助或新辅助全身治疗和局部治疗是否会增加乳腺癌女性患者的无骨转移生存率。 方法: 在这项国际、双盲、随机、安慰剂对照、 3 期研究 (D-CARE) 中，从 39 个国家的 389 个中心招募患者。我们招募了组织学确诊的II期或III期乳腺癌且东部肿瘤协作组表现状态为 0 或 1 的女性 (年龄 ≥ 18 岁)。在资格确认后，每个地点的调查人员打电话给一个交互式语音应答系统，集中随机分配患者 (1:1)基于固定分层置换区组随机列表 (区组大小 4)，每 3-4 周皮下接受denosumab (120 mg) 或匹配安慰剂，开始新辅助或辅助化疗，大约 6 个月，然后每 12 周，总持续时间为 5 年。分层因素为乳腺癌治疗、淋巴结状态、激素受体和HER2 状态、年龄和地理区域。主要终点是无骨转移生存期的复合终点。该试验注册于ClinicalTrials.gov，nct01077154。 结果: 在 2010 年 6 月 2 日至 20 12 年 8 月 24 日期间，4509 名女性被随机分配接受denosumab (n = 2256) 或安慰剂 (n = 2253) 并纳入意向治疗分析。研究的主要分析是在所有患者都有机会完成 5 年随访时完成的，分析数据截止日期为 2017 年 8 月 31 日。两组间无骨转移生存期的主要终点无显著差异 (两组均未达到中位数; 风险比 0 · 97，95% CI 0 · 82-1 · 14; p = 0 · 70)。最常见的 3 级或更严重的治疗突发不良事件，在至少服用一剂试验产品的患者中报告 (2241 例denosumab患者vs 2218 例安慰剂患者)，为中性粒细胞减少症 (340 [15%] vs 328 [15%])，发热性中性粒细胞减少症 (112 [5%] vs 142 [6%])，白细胞减少 (62 [3%] vs 61 [3%])。在接受denosumab治疗的 122 例患者中，5% 例 (2241) 发生了正性的颌骨坏死，而在接受安慰剂治疗的 1% 例患者中，有 4 例 (<2218) 发生了颌骨坏死; 治疗紧急低钙血症发生率为 152 (7%) 比 82 (4%)。安慰剂组因急性髓系白血病和意识水平低下发生两例治疗相关死亡。 解释: 尽管临床前证据表明抑制RANKL可能延缓早期乳腺癌患者的骨转移或疾病复发，但在这项研究中，denosumab没有改善高危早期乳腺癌女性的疾病相关结局。 资助: 安进。
METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.
METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.
METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.