Conformal Avoidance of Normal Organs at Risk by Perfusion-Modulated Dose Sculpting in Tumor Single-Dose Radiation Therapy.

Abstract

Although 24 Gy single-dose radiation therapy (SDRT) renders >90% 5-year local relapse-free survival in human solid tumor lesions, SDRT delivery is not feasible in ∼50% of oligometastatic lesions owing to interference by dose/volume constraints of a serial organ at risk (OAR). Conformal OAR avoidance is based on a hypothetical model positing that the recently described SDRT biology specifically permits volumetric subdivision of the SDRT dose, such that high-intensity vascular drivers of SDRT lethality, generated within a major tumor subvolume exposed to a high 24 Gy dose (high-dose planning target volume [PTV_HD]), would equilibrate SDRT signaling intensity throughout the tumor interstitial space, rendering bystander radiosensitization of a minor subvolume (perfusion-modulated dose sculpting PTV [PTV_PMDS]), dose-sculpted to meet a serial OAR dose/volume constraint. An engineered PTV_PMDS may thus yield tumor ablation despite PMDS dose reduction and conformally avoiding OAR exposure to a toxic dose. Dose fall-off within the PTV_PMDS penumbra of oligometastatic lesions was planned and delivered by intensity modulated inverse dose painting. SDRT- and SDRT-PMDS-treated lesions were followed with periodic positron emission tomography/computed tomography imaging to assess local tumor control. Cumulative baseline 5-year local relapse rates of oligometastases treated with 24 Gy SDRT alone (8% relapses, n = 292) were similar in moderate PTV_PMDS dose-sculpted (23-18 Gy, n = 76, 11% relapses, P = .36) and extreme dose-sculpted (<18 Gy, n = 61, 14% relapses, P = .29) lesions, provided the major 24 Gy PTV_HD constituted ≥60% of the total PTV. In contrast, 28% of local relapses occurred in 26 extreme dose-sculpted PTV_PMDS lesions when PTV_HD constituted <60% of the total PTV (P = .004), suggesting a threshold for the PTV_PMDS bystander effect. The study provides compelling clinical support for the bystander radiosensitization hypothesis, rendering local cure of tumor lesions despite a ≥25% PTV_PMDS dose reduction of the 24 Gy PTV_HD dose, adapted to conformally meet OAR dose/volume constraints. The SDRT-PMDS approach thus provides a therapeutic resolution to otherwise radioablation-intractable oligometastatic disease.