Hoskin P J, Malhi Aman, Reczko Krystyna, Hackshaw Allan
Mount Vernon Cancer Centre, Northwood, UK.
Division of Cancer Sciences, University of Manchester, UK.
J Bone Oncol. 2024 Jul 18;47:100624. doi: 10.1016/j.jbo.2024.100624. eCollection 2024 Aug.
The Radiotherapy IBandronate (RIB) trial compared single dose radiotherapy and a single infusion of ibandronate in 470 bisphosphonate naïve patients with metastatic bone pain from prostate cancer randomised into a non-inferiority two arm study. Results for the primary endpoint of pain score response at 4 weeks showed that the ibandronate arm was non-inferior to single dose radiotherapy.
In addition to pain assessments including analgesic use made at baseline, 4, 8, 12, 26 and 52 weeks, urine was collected at baseline, 4 and 12 weeks. It was subsequently analysed for urinary N-telopeptide (NTx) and cystatin C. Linear regression models were used to compare the continuous outcome measures for urinary markers within treatment arms and baseline measurements were included as covariates. Interaction terms were fitted to allow for cross-treatment group comparisons.
The primary endpoint of the RIB trial was worst pain response at 4 weeks and there was no treatment difference seen. Urine samples and paired pain scores at 4 weeks were available for 273 patients (radiotherapy 168; ibandronate 159)The baseline samples measured for the RIB trial had an average concentration of 193 nM BCE/mM creatinine (range of 7.3-1871) compared to the quoted normal range of 33 nM BCE/mM creatinine (3 to 63). In contrast the average value of Cystatin C was 66 ng/ml (ranges ND - 1120 ng/ml) compared to the quoted normal range of 62.9 ng/ml (ranges 12.6-188 ng/ml). A statistically significant reduction in NTx concentrations between baseline and 4 weeks was seen in the ibandronate arm but not in the radiotherapy arm. No correlation between pain response and urinary marker concentration was seen in either the ibandronate or radiotherapy cohort at any time point.
NTx was significantly raised compared to the normal range consistent with a role as a biomarker for bone metastases from prostate cancer. A significant reduction in NTx 4 weeks after ibandronate is consistent with its action in osteoclast inhibition which was not seen after radiotherapy implying a different mode of action for radiation. There was no correlation between bone biomarker levels and pain response.
放疗联合伊班膦酸钠（RIB）试验将470例未使用过双膦酸盐的前列腺癌骨转移疼痛患者随机分为两组，进行非劣效性双臂研究，比较单次放疗与单次输注伊班膦酸钠的疗效。4周时疼痛评分反应这一主要终点的结果显示，伊班膦酸钠组不劣于单次放疗组。
除了在基线、4周、8周、12周、26周和52周进行包括镇痛药使用情况的疼痛评估外，还在基线、4周和12周收集尿液。随后对尿液进行N-端肽（NTx）和胱抑素C分析。使用线性回归模型比较各治疗组内尿液标志物的连续测量结果，并将基线测量值作为协变量纳入。拟合交互项以进行跨治疗组比较。
RIB试验的主要终点是4周时最严重的疼痛反应，未观察到治疗差异。273例患者（放疗组168例；伊班膦酸钠组159例）有4周时的尿液样本和配对疼痛评分。RIB试验测量的基线样本平均浓度为193 nM BCE/mmol肌酐（范围7.3 - 1871），而引用的正常范围为33 nM BCE/mmol肌酐（3至63）。相比之下，胱抑素C的平均值为66 ng/ml（范围未检出 - 1120 ng/ml），而引用的正常范围为62.9 ng/ml（范围12.6 - 188 ng/ml）。伊班膦酸钠组在基线和4周之间NTx浓度有统计学显著降低，而放疗组未出现。在伊班膦酸钠组或放疗组的任何时间点，均未观察到疼痛反应与尿液标志物浓度之间的相关性。
与正常范围相比，NTx显著升高，这与其作为前列腺癌骨转移生物标志物的作用一致。伊班膦酸钠治疗4周后NTx显著降低，与其抑制破骨细胞的作用一致，而放疗后未观察到这种情况，这意味着放疗的作用模式不同。骨生物标志物水平与疼痛反应之间无相关性。
