Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY, USA; The Netherlands Cancer Institute, Amsterdam, Department of Radiation Oncology, the Netherlands.
Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY, USA.
Radiother Oncol. 2024 Jan;190:110006. doi: 10.1016/j.radonc.2023.110006. Epub 2023 Nov 14.
Radiotherapy is traditionally given in equally spaced weekday fractions. We hypothesize that heterogeneous interfraction intervals can increase radiosensitivity via reoxygenation. Through modeling, we investigate whether this minimizes local failures and toxicity for early-stage non-small cell lung cancer (NSCLC).
Previously, a tumor dose-response model based on resource competition and cell-cycle-dependent radiosensitivity accurately predicted local failure rates for early-stage NSCLC cohorts. Here, the model mathematically determined non-uniform inter-fraction intervals minimizing local failures at similar normal tissue toxicity risk, i.e., iso-BED3 (iso-NTCP) for fractionation schemes 18Gyx3, 12Gyx4, 10Gyx5, 7.5Gyx8, 5Gyx12, 4Gyx15. Next, we used these optimized schedules to reduce toxicity risk (BED3) while maintaining stable local failures (TCP).
Optimal schedules consistently favored a "primer shot" fraction followed by a 2-week break, allowing tumor reoxygenation. Increasing or decreasing the assumed baseline hypoxia extended or shortened this optimal break by up to one week. Fraction sizes of 7.5 Gy and up required a single primer shot, while smaller fractions needed one or two extra fractions for full reoxygenation. The optimized schedules, versus consecutive weekday fractionation, predicted absolute LF reductions of 4.6%-7.4%, except for the already optimal LF rate seen for 18Gyx3. Primer shot schedules could also reduce BED3 at iso-TCP with the biggest improvements for the shortest schedules (94.6Gy reduction for 18Gyx3).
A validated simulation model clearly supports non-standard "primer shot" fractionation, reducing the impact of hypoxia-induced radioresistance. A limitation of this study is that primer-shot fractionation is outside prior clinical experience and therefore will require clinical studies for definitive testing.
放射治疗传统上是以均等间隔的工作日分次进行。我们假设不均匀的分次间隔可以通过再氧合增加放射敏感性。通过建模，我们研究了这种方法是否可以最大限度地减少早期非小细胞肺癌（NSCLC）的局部失败和毒性。
此前，一种基于资源竞争和细胞周期依赖性放射敏感性的肿瘤剂量反应模型准确预测了早期 NSCLC 队列的局部失败率。在这里，该模型通过数学方法确定了非均匀的分次间隔，以在相似的正常组织毒性风险下最小化局部失败，即 18Gyx3、12Gyx4、10Gyx5、7.5Gyx8、5Gyx12、4Gyx15 分割方案的 iso-BED3（iso-NTCP）。接下来，我们使用这些优化方案来降低毒性风险（BED3），同时保持稳定的局部失败（TCP）。
优化方案始终倾向于“ Primer 射击”分数，然后休息两周，以允许肿瘤再氧合。增加或减少假设的基线缺氧会将此最佳休息时间延长或缩短一周。7.5 Gy 及以上的分次大小需要一次 Primer 射击，而较小的分次大小需要一次或两次额外的分次才能完全再氧合。与连续的工作日分次相比，优化方案预测绝对 LF 减少了 4.6%-7.4%，但对于已经看到的最佳 LF 率（18Gyx3）除外。Primer 射击方案还可以在保持 TCP 不变的情况下降低 BED3，对于最短的方案（18Gyx3 的 94.6Gy 降低），改进最大。
一个经过验证的模拟模型清楚地支持非标准的“ Primer 射击”分次，减少了缺氧诱导的放射抵抗的影响。本研究的一个局限性是 Primer 射击分次不在先前的临床经验范围内，因此需要进行临床研究以进行明确的测试。
