High Single Doses of Radiation May Induce Elevated Levels of Hypoxia in Early-Stage Non-Small Cell Lung Cancer Tumors

Abstract

Purpose: Tumor hypoxia correlates with treatment failure in patients undergoing conventional radiation therapy. However, no published studies have investigated tumor hypoxia in patients undergoing stereotactic body radiation therapy (SBRT). We aimed to noninvasively quantify the tumor hypoxic volume (HV) in non-small cell lung cancer (NSCLC) tumors to elucidate the potential role of tumor vascular response and reoxygenation at high single doses.

Methods and materials: Six SBRT-eligible patients with NSCLC tumors >1 cm were prospectively enrolled in an institutional review board-approved study. Dynamic positron emission tomography images were acquired at 0 to 120 minutes, 150 to 180 minutes, and 210 to 240 minutes after injection of ¹⁸F-fluoromisonidazole. Serial imaging was performed prior to delivery of 18 Gy and at approximately 48 hours and approximately 96 hours after SBRT. Tumor HVs were quantified using the tumor-to-blood ratio (>1.2) and rate of tracer influx (>0.0015 mL·min·cm^-3).

Results: An elevated and in some cases persistent level of tumor hypoxia was observed in 3 of 6 patients. Two patients exhibited no detectable baseline tumor hypoxia, and 1 patient with high baseline hypoxia only completed 1 imaging session. On the basis of the tumor-to-blood ratio, in the remaining 3 patients, tumor HVs increased on day 2 after 18 Gy and then showed variable responses on day 4. In the 3 of 6 patients with detectable hypoxia at baseline, baseline tumor HVs ranged between 17% and 24% (mean, 21%), and HVs on days 2 and 4 ranged between 33% and 45% (mean, 40%) and between 18% and 42% (mean, 28%), respectively.

Conclusions: High single doses of radiation delivered as part of SBRT may induce an elevated and in some cases persistent state of tumor hypoxia in NSCLC tumors. Hypoxia imaging with ¹⁸F-fluoromisonidazole positron emission tomography should be used in a larger cohort of NSCLC patients to determine whether elevated tumor hypoxia is predictive of treatment failure in SBRT.

Figure 1

PET/CT imaging protocol. A: Three dynamic ¹⁸F-FMISO PET scans were preformed from 0-120 min, 150-180 min, and 210-240 min post-injection, each preceded by a low-dose CT for attenuation correction. B: Serial imaging was performed around a single SBRT fraction. PET/CT was acquired immediately prior to the first fraction (day 0). Subsequent scans on days 2 and 4 were acquired ~48 hours and ~96 hours after the first fraction of SBRT, respectively. A 4DCT was acquired on day 4.

Figure 2

Representative axial images for patients with baseline tumor hypoxia (patient 2 (2A-C), patient 5 (5A-C), and patient 6 (6A-C)) show variation in the tumor HV (day 0 to 4). Red vertical line indicates SBRT fraction delivery (18 or 10 Gy) immediately after day 0 imaging. Rows (A) show CT images (scale bar in Hounsfield Units [HU]). Rows (B) and (C) show ungated and respiratory-corrected PET images. Arrows indicate the tumor or hypoxia. Scale bar in TBR (no units).

Figure 3

(A) Enlarged axial PET images of patients with detectable baseline tumor hypoxia (patients 2, 5, and 6) (B) Temporal variation in tumor hypoxic volume defined by TBR >1.2 (all patients) calculated on respiratory-corrected images.

Figure 4

Patlak (t^* = 40 min) tracer kinetic analysis of ¹⁸F-FMISO. Top panel: Axial K_i parametric maps (calculated on ungated images) of the rate of tracer influx K_i (mL·min· cm⁻³) for patients 2 (row A), 5 (row B), and 6 (row C) showing variation in the hypoxic volume across imaging days. Arrows indicate location of hypoxia. K_i indicates hypoxia as yellow/white. Bottom Panel: HV (%), calculated using K_i > 0.0015 mL·min·cm⁻³, mean and maximum K_i.