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

Abstract

Purpose: 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 [PTVHD]), would equilibrate SDRT signaling intensity throughout the tumor interstitial space, rendering bystander radiosensitization of a minor subvolume (perfusion-modulated dose sculpting PTV [PTVPMDS]), dose-sculpted to meet a serial OAR dose/volume constraint. An engineered PTVPMDS may thus yield tumor ablation despite PMDS dose reduction and conformally avoiding OAR exposure to a toxic dose.

Methods and materials: Dose fall-off within the PTVPMDS 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.

Results: Cumulative baseline 5-year local relapse rates of oligometastases treated with 24 Gy SDRT alone (8% relapses, n = 292) were similar in moderate PTVPMDS 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 PTVHD constituted ≥60% of the total PTV. In contrast, 28% of local relapses occurred in 26 extreme dose-sculpted PTVPMDS lesions when PTVHD constituted <60% of the total PTV (P = .004), suggesting a threshold for the PTVPMDS bystander effect.

Conclusion: The study provides compelling clinical support for the bystander radiosensitization hypothesis, rendering local cure of tumor lesions despite a ≥25% PTVPMDS dose reduction of the 24 Gy PTVHD dose, adapted to conformally meet OAR dose/volume constraints. The SDRT-PMDS approach thus provides a therapeutic resolution to otherwise radioablation-intractable oligometastatic disease.

Trial registration: ClinicalTrials.gov NCT03543696.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Fig. 1.

Color-wash dose distribution of treatment plans to treat an fluorodeoxyglucose-avid left pelvic lymph node metastasis from a primary colorectal cancer interacting with the sigmoid colon. The positron emission tomography/computed tomography–derived gross tumor volume was expanded into planned target volume (PTV) by an isotropic 3-mm margin. (A) A clinically infeasible plan with 95% of the PTV of 24.0 Gy (D50% 24.5 Gy; D2% 25.5 Gy; D98 24.2 Gy), as the outer penumbra dose interacts with the sigmoid colon at a near-maximum dose (D2%) of 19.2 Gy, exceeding the permissible 14.5 Gy dose/volume constraint. (B) An alternative single-dose radiation therapy-PMDS treatment plan created to comply with the organ at risk (OAR) constraint. The overlap between the PTV and the sigmoid colon was used to generate the PTVPMDS subvolume dose sculpted to meet the 14.5 Gy colonic tolerance restriction. Dose fall-off across the PTVPMDS was engineered by volumetric modulated arc therapy inverse dose-painting, rendering a dose gradient of 42% within the distal 4 mm of the PTVPMDS penumbra interacting with the contour of the OAR. The high-dose PTV has a D95 of 24.3 Gy (D50% 24.9 Gy; D2 25.6 Gy; D98 24.2 Gy). The PTVPMDS shows a pronounced inhomogeneity (D50% 19.8 Gy; D2% 24.5 Gy; D98% 14.5 Gy), with the outer isodose interacting with the OAR fulfilling the sigmoid colon Dmax constraint of 14.5 Gy, thereby attenuating the radiation dose to the colonic wall to a nontoxic dose level.

Fig. 2.

Cumulative 5-year actuarial incidence of in-field local failure of oligometastatic lesions treated with ablative radiation therapy. Single-dose radiation therapy (SDRT) designates lesions with a prescribed single dose of 24 Gy covering the whole planned target volume (PTV) (PTV D99 ≥24 Gy). Perfusion-modulated dose sculpting (PMDS) indicates SDRT-PMDS treated lesions reducing the dose coverage in the PTVPMDS to comply with the organ at risk constraints. When the PMDS plan failed to meet the organ-at-risk tolerance criteria, a hypofractionated 3 × 9 Gy stereotactic body radiation therapy scheme was used, designated here as single-dose radiation therapy. Actuarial analysis was used to calculate cumulative incidence of local failure, and statistical significance of treatment outcomes by treatment mode was calculated using the log-rank test.

Fig. 3.

Dosimetric characterization by local control and local failure of oligometastatic lesions treated with single-dose radiation therapy (SDRT) alone or with SDRT–perfusion-modulated dose sculpting (PMDS). No PMDS designates treatment with 24 Gy SDRT (D99) to the whole planned target volume (PTV). Moderate PMDS designates lesions dose sculpted to generate a PTVPMDS D99 fall-off to within the range of 23 to 18 Gy, and extreme PMSD designates PTVPMDS dose sculpted to <18 Gy. (A) Scatter plots of local control and local relapse by treatment modality. Each dot represents a treated lesion. (B) Cumulative 5-year actuarial incidence of local relapse by treatment modality. The log rank analysis indicates moderate PMDS local failure does not differ significantly from no PMDS (P = .36), and for extreme PMDS the analysis indicates P = .02.

Fig. 4.

Volumetric characterization by local control and local failure (LF) of the oligometastatic lesions treated with single-dose radiation therapy (SDRT) alone or with SDRT-PMDS. The volumetric unit VHD designates the ratio of planned target volume (PTV) covering the major tumor subvolume with the 24 Gy dose (PTVHD) as a percentage of total tumor PTV (PTVHD + PTVPMDS). (A) Scatter plots of local control and local relapse by VHD. Each dot represents a treated lesion. (B) Cumulative 5-year actuarial incidence of local relapse by VHD. Log rank analysis indicates that incidence of LF for extreme PMDS with VHD ≥60% LF did not differ significantly from no PMDS (P = .29), and it was significant for extreme PMDS with VHD <60% (P = .004).