Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom.
Division of Cancer Sciences, The University of Manchester, Manchester, United Kingdom; Division of Pharmacy, The University of Manchester, Manchester, United Kingdom.
Int J Radiat Oncol Biol Phys. 2021 Aug 1;110(5):1407-1415. doi: 10.1016/j.ijrobp.2021.03.001. Epub 2021 Mar 6.
Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes.
Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis.
We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08).
Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification.
许多肌肉浸润性膀胱癌存在缺氧，这限制了放射治疗的疗效。在一项名为 Bladder Carbogen Nicotinamide 的 3 期试验中，已经测试了使用碳化氧和烟酰胺来改变缺氧状态。我们报告了成熟的随访数据，并预测了生物标志物的结果。
Bladder Carbogen Nicotinamide 是一项前瞻性、3 期、多中心、随机、2 臂、非盲临床试验。参与者被随机分配接受根治性放射治疗（RT；对照组）或加用碳化氧（98% O2；2% CO2）和烟酰胺（CON）。纳入了肌肉浸润性或高级非肌肉浸润性膀胱癌患者。在入组时采集肿瘤组织，并分析肿瘤坏死、缺氧（24 基因特征）以及基底和腔面肿瘤分子亚型。使用多变量 Cox 回归和对数秩分析分析总生存（OS）、无病生存和与生物标志物状态结果的关系。
我们分析了 333 例患者，中位随访时间为 10.3 年。RT+CON 组的 10 年 OS 率为 30%（95%置信区间 [CI]，0.23-0.39），RT 组为 24%（95% CI，0.18-0.33）（风险比 [HR]，0.80；95% CI，0.61-1.04；P =.08）。CON 最大的获益见于有肿瘤坏死的患者（n = 79；5 年 OS，53% vs. 无肿瘤坏死的患者 33%；HR，0.59；95% CI，0.36-0.99；P =.04）。高缺氧基因评分病例（n = 75）的 5 年 OS 率为 51%，而低评分病例为 34%（HR，0.64；95% CI，0.38-1.08；P =.09）；基底分子亚型病例（n = 70）的 5 年 OS 率为 58%，而腔面亚型病例为 38%（HR，0.58；95% CI，0.32-1.06；P =.08）。
尽管整个人群的长期 OS 改善没有统计学意义，但通过坏死和高缺氧基因评分选择的患者从缺氧状态改变中获益。
