PO.CT01.05 · 临床试验
高剂量静脉注射抗坏血酸联合化疗作为顺铂不耐受的肌层浸润性膀胱癌患者的新辅助化疗（NAC）
High dose intravenous ascorbate with chemotherapy as NAC for muscle invasive cisplatin ineligible bladder cancer patients
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：新辅助顺铂类化疗（NAC）被认为是肌层浸润性膀胱癌（MIBC）患者的标准治疗（SOC）。然而，约50%的患者顺铂不耐受（CI），常常直接接受手术。其他方案如吉西他滨联合卡铂在此情况下疗效有限。高剂量静脉注射抗坏血酸（IVC）在临床前和临床研究中已显示出抗癌疗效，并在其他癌症模型中提高了卡铂和吉西他滨类治疗的疗效。在此，我们启动了一项Ib/IIa期试验，评估IVC联合吉西他滨/卡铂（Gem/Carbo）作为CI-MIBC患者NAC的疗效（NCT04046094）。患者与方法：新诊断的CI-MIBC患者接受单周期Gem（1000 mg/m² D1、8）/Carbo（AUC 5 第1天）和IVC（25-125g，滴定至血药浓度350-400 mg/dL，然后每周2次，持续21天），随后接受根治性膀胱切除术。主要结局为膀胱切除术时的病理降期（<ypT2N0Mx）。通过FACT-BI在入组时、治疗结束时以及膀胱切除术后6周评估患者报告的生活质量（QOL）。结果：共入组16名受试者，其中12名完成方案；平均年龄76岁。4例（33%）出现病理降期，其中3/4例患者达到病理完全缓解（pCR，ypT0N0Mx），1例仅残留ypTisN0Mx。值得注意的是，1例CR见于一名局部晚期浆细胞样变异型患者。治疗耐受性良好，治疗相关AE/SAEs极少。在平均随访32.3个月（SD 18.9，范围6.6-63.8）时，4例无缓解患者复发并死于该病，3例有缓解患者复发，其中1例死于该病。QOL FACT-Bl显示从基线到治疗结束（EOT）再到膀胱切除术后6周无下降。结论：新辅助单周期Gem/Carbo+IVC耐受性良好，在难治性CI-MIBC人群中具有显著活性，为原本顺铂不耐受、可能无法从NAC获益的患者提供了一种替代方案。在此早期临床试验中，缓解率（RR）与SOC相当。有必要开展更大规模试验以证实这些发现并确定缓解的生物标志物。
查看英文原文 English abstract
Purpose: Neoadjuvant cisplatin-based chemotherapy (NAC) is considered the standard of care (SOC) for patients with muscle-invasive bladder cancer (MIBC). However, ~50% of patients are cisplatin ineligible (CI) and often proceed directly to surgery. Other regimen such as gemcitabine and carboplatin has limited success in this setting. High-dose intravenous ascorbate (IVC) has been shown to have anti-cancer efficacy in pre-clinical and clinical studies, and to improve efficacy of carboplatin and gemcitabine-based therapy in other cancer models. Here we initiated a phase Ib/IIa trial to evaluate IVC with gemcitabine/carboplatin (Gem/Carbo) as NAC in CI-MIBC patients (NCT04046094). Patients and Methods: Patients with newly diagnosed CI-MIBC received single cycle Gem (1000 mg/m2 D1, 8) / Carbo (AUC 5 day 1) and IVC (25-125g titrated to 350-400 mg/dL blood concentrations, and then 2x per week for 21 days) followed by definitive cystectomy. The primary outcome was pathological downstaging (<ypT2N0Mx) at cystectomy. Patient-reported quality of life (QOL) was assessed by FACT-BI at enrollment, end of treatment, and 6 weeks after cystectomy. Results: Sixteen participants were enrolled, with 12 completing the protocol; mean age was 76. Pathological downstaging was present in 4 (33%), with 3/4 patients having a pathologic complete response (pCR, ypT0N0Mx), and 1 with residual ypTisN0Mx only. Of note, 1 CR was seen in a patient with locally advanced plasmacytoid variant. Treatment was well tolerated with minimal treatment related AE/SAEs. At a mean follow-up of 32.3 months (SD 18.9, range 6.6 - 63.8), 4 patients without response recurred and died of disease, 3 with response have recurred with one passing from disease. QOL FACT-Bl showed no decline from baseline to end of treatment (EOT) to 6 weeks post cystectomy. Conclusions: Neoadjuvant, single cycle Gem/Carbo + IVC was well tolerated and had significant activity in a difficult to treat population of CI-MIBC, offering an alternative for patients who otherwise are cisplatin-ineligible and may not realize the benefit of NAC. Response rate (RR) is comparable to SOC in this early Phase trial. Larger trials are warranted to confirm these findings and identify biomarkers of response.
利益披露 Disclosure
Q. Chen, None..
J. Taylor, None..
R. Parikh, None..
B. Woolbright, None..
J. Drisko, None.