Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial.
Cabozantinib治疗晚期尤文肉瘤或骨肉瘤患者 (CABONE): 一项多中心、单组、 2 期试验。
- 作者列表："Italiano A","Mir O","Mathoulin-Pelissier S","Penel N","Piperno-Neumann S","Bompas E","Chevreau C","Duffaud F","Entz-Werlé N","Saada E","Ray-Coquard I","Lervat C","Gaspar N","Marec-Berard P","Pacquement H","Wright J","Toulmonde M","Bessede A","Crombe A","Kind M","Bellera C","Blay JY
BACKGROUND:Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS:We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS:Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION:Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING:Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.
背景: 尤文肉瘤或骨肉瘤患者确诊后的中位总生存期不到 12 个月，标准治疗策略尚未确立。药理学抑制MET信号和异常血管生成在尤文肉瘤和骨肉瘤的几种临床前模型中显示出有希望的结果。我们旨在研究MET和VEGFR2 抑制剂cabozantinib在晚期尤文肉瘤和骨肉瘤患者中的活性。 方法: 我们在法国肉瘤组 10 个中心招募的晚期尤文肉瘤或骨肉瘤患者中进行了一项多中心、单臂、两阶段、 2 期试验。关键合格标准为年龄在 12 岁或以上，东部肿瘤协作组表现状态为 0-1，并记录了疾病进展 (根据实体瘤 1.1 版的反应评价标准) 在进入研究之前。以前的治疗线的数量不受限制。患者接受cabozantinib (成人 60 mg，儿童 [<16 岁] 40 mg/m2) 口服，每日一次，28 天周期，直至疾病进展，不可接受的毒性，研究者决定停止，或参与者退出。尤文肉瘤的主要终点是治疗开始后 6 个月内的最佳客观缓解; 对于骨肉瘤，评估了 6 个月客观缓解和 6 个月无进展的双主要终点。所有接受至少一剂卡博替尼治疗的入组患者纳入安全性分析，所有接受至少一个完整或两个不完整治疗周期的参与者纳入疗效人群。本研究注册于ClinicalTrials.gov，编号为nct02243605。 研究结果: 在 2015 年 4 月 16 日至 20 18 年 7 月 12 日期间，90 例患者 (45 例尤文肉瘤 45 例合并骨肉瘤) 被纳入研究。尤文肉瘤患者中位随访时间为 31 · 3 个月 (95% CI 12 · 4-35 · 4)，31 · 1 个月 (24 · 4-31 · 7) 对于骨肉瘤患者。经组织学和影像学检查，39 例 (87%) 尤文肉瘤患者和 42 例 (93%) 骨肉瘤患者可评估疗效。在尤文肉瘤患者中，39 例患者中有 10 例 (26%; 95% CI 13-42) 在 6 个月时客观缓解 (全部部分缓解); 在骨肉瘤患者中，42 例患者中有 5 例 (12%; 4-26) 有客观反应 (所有部分反应)，14 例 (33%; 20-50)6 个月无进展。最常见的 3 级或 4 级不良事件为低磷酸盐血症 (尤文肉瘤为 5 [11%]，骨肉瘤为 3 [7%])，天冬氨酸氨基转移酶升高 (尤文肉瘤为 2 [4%]，骨肉瘤三 [7%])，掌跖综合征 (尤文肉瘤三 [7%]，二[4%] 为骨肉瘤) 、气胸 (尤文肉瘤 1 例 [2%]，骨肉瘤 4 例 [9%]) 、中性粒细胞减少症 (尤文肉瘤 2 例 [4%]，四 [9%] 为骨肉瘤)。90 例患者中 61 例 (68%) 报告了至少 1 例严重不良事件。无患者死于药物相关的毒性作用。 解释: 卡博替尼对晚期尤文肉瘤和骨肉瘤患者具有抗肿瘤活性，一般耐受性良好。Cabozantinib可能代表了这种情况下的一种新的治疗选择，值得进一步研究。 资助: bergoni é 研究所; 法国国家癌症研究所; Repola Recherche contre le Cancer协会。
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.