Abstract：
BACKGROUND: Optimizing functional outcomes and securing long-term remissions are key goals in managing patients with locally advanced rectal cancer. In this proof-of-concept study, we set out to further optimize neoadjuvant therapy by integrating the radiosensitizer trifluridine/tipiracil and explore the potential of cell free tumor DNA (ctDNA) to monitor residual disease.
METHODS: About 10 patients were enrolled in the phase I dose finding part which followed a 3 + 3 dose escalation design. Tipiracil/trifluridine was administered concomitantly to radiotherapy. ctDNA monitoring was performed before and after chemoradiation with patient-individualized digital droplet PCRs.
RESULTS: No dose-limiting toxicities were observed at the maximum tolerated dose level of 2 × 35 mg/m² trifluridine/tipiracil. There were 9 grade 3 adverse events, of which 8 were hematologic with anemia and leukopenia. Chemoradiation yielded a pathological complete response in 1 out of 8 assessable patients, downstaging in nearly all patients, and 1 clinical complete response referred for watchful waiting. Three of 4 assessable patients with residual tumor cells at pathological assessment remained liquid biopsy positive after chemoradiation, but 1 turned negative.
CONCLUSIONS: In this exploratory phase I trial, the novel combination of neoadjuvant trifluridine/tipiracil and radiotherapy proved to be feasible, tolerable, and effective. However, the application of liquid biopsy as a potential marker for therapeutic de-escalation in the neoadjuvant setting requires additional research and prospective validation. The trial was registered at ClinicalTrials.gov: NCT04177602.
METHODS: About 10 patients were enrolled in the phase I dose finding part which followed a 3 + 3 dose escalation design. Tipiracil/trifluridine was administered concomitantly to radiotherapy. ctDNA monitoring was performed before and after chemoradiation with patient-individualized digital droplet PCRs.
RESULTS: No dose-limiting toxicities were observed at the maximum tolerated dose level of 2 × 35 mg/m² trifluridine/tipiracil. There were 9 grade 3 adverse events, of which 8 were hematologic with anemia and leukopenia. Chemoradiation yielded a pathological complete response in 1 out of 8 assessable patients, downstaging in nearly all patients, and 1 clinical complete response referred for watchful waiting. Three of 4 assessable patients with residual tumor cells at pathological assessment remained liquid biopsy positive after chemoradiation, but 1 turned negative.
CONCLUSIONS: In this exploratory phase I trial, the novel combination of neoadjuvant trifluridine/tipiracil and radiotherapy proved to be feasible, tolerable, and effective. However, the application of liquid biopsy as a potential marker for therapeutic de-escalation in the neoadjuvant setting requires additional research and prospective validation. The trial was registered at ClinicalTrials.gov: NCT04177602.
摘要：
背景：优化功能结局和确保长期缓解是治疗局部晚期直肠癌患者的关键目标。在这个概念验证研究中,我们着手通过整合放射增敏剂氟尿苷/替吡嘧啶来进一步优化新辅助治疗,并探索无细胞肿瘤DNA(ctDNA)监测残留疾病的潜力.
方法：约10名患者被纳入I期剂量发现部分，遵循3+3剂量递增设计。放疗时同时给予替吡拉嘧啶/氟尿苷。在患者个体化数字液滴PCR放化疗前后进行ctDNA监测。
结果：在2×35mg/m²的最大耐受剂量水平下未观察到剂量限制性毒性。有9个3级不良事件，其中8例为血液学伴贫血和白细胞减少症。在8个可评估的患者中，有1个出现了病理完全缓解，几乎所有的病人都降期，和1个临床完全缓解，用于观察等待。4名可评估的患者中有3名在病理评估时残留的肿瘤细胞在放化疗后保持液体活检阳性，但1变成了负值。
结论：在这项探索性I期试验中，新辅助三氟尿苷/替吡草定与放疗的新型组合被证明是可行的，可容忍,而且有效。然而,在新辅助治疗中,液体活检作为潜在的治疗降阶梯标志物的应用需要更多的研究和前瞻性验证.该试验在ClinicalTrials.gov:NCT04177602注册。
方法：约10名患者被纳入I期剂量发现部分，遵循3+3剂量递增设计。放疗时同时给予替吡拉嘧啶/氟尿苷。在患者个体化数字液滴PCR放化疗前后进行ctDNA监测。
结果：在2×35mg/m²的最大耐受剂量水平下未观察到剂量限制性毒性。有9个3级不良事件，其中8例为血液学伴贫血和白细胞减少症。在8个可评估的患者中，有1个出现了病理完全缓解，几乎所有的病人都降期，和1个临床完全缓解，用于观察等待。4名可评估的患者中有3名在病理评估时残留的肿瘤细胞在放化疗后保持液体活检阳性，但1变成了负值。
结论：在这项探索性I期试验中，新辅助三氟尿苷/替吡草定与放疗的新型组合被证明是可行的，可容忍,而且有效。然而,在新辅助治疗中,液体活检作为潜在的治疗降阶梯标志物的应用需要更多的研究和前瞻性验证.该试验在ClinicalTrials.gov:NCT04177602注册。
