Oxygen-Guided Radiation Therapy

Abstract

Purpose: It has been known for over 100 years that tumor hypoxia, a near-universal characteristic of solid tumors, decreases the curative effectiveness of radiation therapy. However, to date, there are no reports that demonstrate an improvement in radiation effectiveness in a mammalian tumor on the basis of tumor hypoxia localization and local hypoxia treatment.

Methods and materials: For radiation targeting of hypoxic subregions in mouse fibrosarcoma, we used oxygen images obtained using pulse electron paramagnetic resonance pO₂ imaging combined with 3D-printed radiation blocks. This achieved conformal radiation delivery to all hypoxic areas in FSa fibrosarcomas in mice.

Results: We demonstrate that treatment delivering a radiation boost to hypoxic volumes has a significant (P = .04) doubling of tumor control relative to boosts to well-oxygenated volumes. Additional dose to well-oxygenated tumor regions minimally increases tumor control beyond the 15% control dose to the entire tumor. If we can identify portions of the tumor that are more resistant to radiation, it might be possible to reduce the dose to more sensitive tumor volumes without significant compromise in tumor control.

Conclusions: This work demonstrates in a single, intact mammalian tumor type that tumor hypoxia is a local tumor phenomenon whose treatment can be enhanced by local radiation. Despite enormous clinical effort to overcome hypoxic radiation resistance, to our knowledge this is the first such demonstration, even in preclinical models, of targeting additional radiation to hypoxic tumor to improve the therapeutic ratio.

Fig. 1.

Radiation treatment plans and delivery scheme. (A) EPR pO₂ image slice orthogonal to the radiation beam showing hypoxia boost treatment plan. (B) The same EPR pO₂ image slice showing hypoxia avoidance boost. Magenta contour: MRI-defined tumor margin. Red contour: projection of all in-tumor hypoxic volumes onto the EPR image plane. Black contours - radiation treatment beam shape including additional setup uncertainty margins. The area of the hypoxia avoiding boost equals the area of the hypoxia boost. Note in both (A) and (B). the islands of hypoxia out of the plane derived from the DRR of the whole tumor volume as well as the margin about the hypoxia, 1.2 mm for the hypoxia boost and 0.6 mm for the hypoxia avoiding boost. Upper Left corners of (A) and (B): Black shapes of hypoxic boost (A) and well oxygenated boost (B) apertures. (C) Illustration of opposed field radiation boost treatment with XRAD225Cx gantry-mounted X-ray machine. Each field was treated with half of the total boost dose.

Fig. 2.

Kaplan-Meier survival plot comparing conformal hypoxia boost with hypoxia avoidance boost. The two treatments differ significantly (P = .04) demonstrating the therapeutic efficacy of hypoxia guided radiation.