Imaging tumor hypoxia to advance radiation oncology

Abstract

Significance: Most solid tumors contain regions of low oxygenation or hypoxia. Tumor hypoxia has been associated with a poor clinical outcome and plays a critical role in tumor radioresistance.

Recent advances: Two main types of hypoxia exist in the tumor microenvironment: chronic and cycling hypoxia. Chronic hypoxia results from the limited diffusion distance of oxygen, and cycling hypoxia primarily results from the variation in microvessel red blood cell flux and temporary disturbances in perfusion. Chronic hypoxia may cause either tumor progression or regressive effects depending on the tumor model. However, there is a general trend toward the development of a more aggressive phenotype after cycling hypoxia. With advanced hypoxia imaging techniques, spatiotemporal characteristics of tumor hypoxia and the changes to the tumor microenvironment can be analyzed.

Critical issues: In this review, we focus on the biological and clinical consequences of chronic and cycling hypoxia on radiation treatment. We also discuss the advanced non-invasive imaging techniques that have been developed to detect and monitor tumor hypoxia in preclinical and clinical studies.

Future directions: A better understanding of the mechanisms of tumor hypoxia with non-invasive imaging will provide a basis for improved radiation therapeutic practices.

FIG. 1.

Serial hemoglobin saturation and redox images from a tumor grown in the window chamber. (a) Hbsat and (b) redox images obtained over a 36-h time course. Longitudinal oxygen gradients (a) are apparent at all of the time points. This is depicted by groups of vessels with varied Hbsat in the upper right quadrant of tumor compared with the lower right quadrant. However, the extent of difference between the more hypoxic and less hypoxic regions varies between different time points. Note at 30 h, the upper right quadrant is more hypoxic than the same quadrant imaged at 24 or 36 h. In (b), the redox ratio, which reflects the relative extent of oxidative metabolism within the tumor, is higher in areas with more oxygenated vessels (3). Reproduced from Skala et al. (202) with permission from the authors and SPIE. Hbsat, hemoglobin saturation. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Time to local failure (Kaplan–Meier plot) by treatment arm and hypoxia in the primary tumor. Censored times are indicated as tick marks on the curves. Cis, cisplatin; FU, fluoroucil; TPZ, tirapazamine. Reproduced from Rischin 2006 with permission from the authors and the American Society of Clinical Oncology (180). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Hypoxia imaging with FMISO-PET in head and neck cancer patients. In (a–c) hypoxia imaging with FMISO-PET guided hypoxia-advanced radiation treatment planning with IMRT. Isodose display on axial slices for simultaneous integrated boost IMRT plan showing conformal 70 Gy dose around primary planning target volume (red) and 60 Gy dose around affected nodes (pink and blue). Hypoxic gross target volume (green) is covered by 80 Gy isodose. Parotid glands (orange and lilac) are avoided by high isodose lines. In (A–B), IMRT dose distributions in color-wash display are shown of a patient for whom the sequential hypoxia images were dissimilar. (A) Both sub-volumes of the first hypoxic sub-volume (the red contours) were prescribed 84 Gy. (B) When the same treatment plan was applied to the second hypoxic sub-volume (the green contour), a part of the hypoxic volume would not receive the intended boost dose. Reproduced from Hendrickson et al. (93) (a–c) and Lin et al. (138) (A–B) with permission from the authors and from Elsevier. FMISO, ¹⁸F-fluoromisonidazole; IMRT, intensity modulated radiation therapy; PET, positron-emission tomography. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Mapping onto prostate gland outlines, grid arrays, and areas of high R₂* and low relative blood volume. (a, b) Hematoxylin-eosin (H&E)- and pimonidazole-stained whole-mount pathologic slides from adjacent slices. The sites of the tumor are outlined in the H&E image. These images were used to map onto the prostate gland outlines of areas of tumor (pink) and hypoxia (brown) staining, as shown in (c) with the anatomic T₂-weighted image. (d) The R₂* map (8 mm; scale 0–25 s⁻¹) at the same slice location. The arrow shows the location of the obturator internus muscle with a high R₂* value. It should be noted that the center of the gland has intermediate R₂* values. (e) The relative blood volume image (8 mm; scale, 0–1700 AU) with the arrow showing the position of ischiorectal fat. The images were used to define areas of high R₂* and low blood volume. (f) The corresponding T₂-weighted image with the 5×5-mm grid overlay created with Adobe Photoshop. Arrowheads point to the dark line of the prostatic outline, the pink and brown color represents the position of tumor and pimonidazole staining, and the green is the area of high R₂* values. The long arrows show the regions in which pimonidazole and tumor staining coincide with a high R₂*. Reproduced from Hoskin 2007 with permission from the authors and Elsevier (103). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Three-dimensional-EPR oxygen images of chronic and cycling hypoxia before and at 1 day after radiation. EPR oxygen images were obtained pre RT and at 1 day after 3 Gy irradiation in a mouse implanted with an HT29 tumor. Two ROIs were selected in the tumor (1 and 2), and pO₂ was assessed in the ROIs every 3 min over 30 min. ROI 1 represents a cycling hypoxic region (median pO₂>10 mmHg, minimum pO₂<10 mmHg, and maximum pO₂>10 mmHg during 30 min). ROI 2 indicates a chronically hypoxic region (median pO₂<10 mmHg during 30 min). Two representative images acquired at 9 and 27 min in pre RT and at 15 and 24 min in 1 day after radiation are shown (Krishna et al., unpublished data). EPR, electron paramagnetic resonance; pO₂, pressure of O₂; ROI, region of interest. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Baseline tumor oxygen saturation. Baseline tumor oxygen saturation as measured by diffuse optical spectroscopic imaging correlates with a pCR in breast cancer patients undergoing neoadjuvant chemotherapy. Box-and-whisker plots showing the difference in tumor oxygen saturation (stO₂) levels between pCR and non-pCR tumors (left; median, 77.8% vs. 72.3%; p=0.01, Wilcoxon) and the lack of difference in stO₂ levels between contralateral normal tissues (right; median, 77.7% vs. 78.1%; p=0.98, Wilcoxon). Reproduced from Ueda 2012 with permission from the authors and the American Association for Cancer Research (220). pCR, pathologic complete response.