Imaging oxygenation of human tumours

Abstract

Tumour hypoxia represents a significant challenge to the curability of human tumours leading to treatment resistance and enhanced tumour progression. Tumour hypoxia can be detected by non-invasive and invasive techniques but the inter-relationships between these remains largely undefined. (18)F-MISO and Cu-ATSM-PET, and BOLD-MRI are the lead contenders for human application based on their non-invasive nature, ease of use and robustness, measurement of hypoxia status, validity, ability to demonstrate heterogeneity and general availability, these techniques are the primary focus of this review. We discuss where developments are required for hypoxia imaging to become clinically useful and explore potential new uses for hypoxia imaging techniques including biological conformal radiotherapy.

Fig. 1

Stylised diagram showing how hypoxia leads to therapy resistance and the development of an aggressive tumour cell phenotype. Figure adapted from [4]

Fig. 2

The ¹⁸FDG-PET image (bottom left panel) shows increase uptake in both the oropharyngeal tumour (arrow) and in the left neck nodal metastasis (asterix). The ¹⁸F-MISO images (bottom right panel) were acquired in a dynamic mode and representative images after 1 minute, 30 minutes and 240 minutes are shown together with time-activity curves from the two regions of interest indicated in the FDG-PET image. The early distribution (1 minute) shows hyperperfusion in the region of the primary tumour and metastasis because of the high partition coefficient of ¹⁸F-MISO. After 2 hours, only the left neck nodal metastasis is shown to be hypoxic

Fig. 3

The structure of [¹⁸F]-fluoromisonidazole, ¹⁸F-MISO, and its mechanism of retention in hypoxic tissues. The partition coefficient of ¹⁸F-MISO is near unity so the molecule diffuses freely into all cells. Once ¹⁸F-MISO is in an environment where electron transport is occurring (viable tissues), the –NO₂ substituent (which has a high electron affinity) takes on an electron to form the radical anion reduction product. If O₂ is also present, that electron is rapidly transferred to oxygen and ¹⁸F-MISO changes back to its original structure and can leave the cell. However, if a second electron from cellular metabolism reacts with the nitroimidazole to form the 2-electron reduction product, the molecule reacts non-discriminately with peptides and RNA within the cell and becomes trapped. Thus, retention of FMISO is inversely related to the intracellular partial pressure of O₂ as shown in the lower left panel [45]. This mechanism is confirmed by the autoradiograph of a tumour spheroid (bottom right panel) with a radius of approximately 0.5 mm that shows no retention in the necrotic core or in the well-oxygenated outer sphere but intense uptake (white spots) in a donut like ring where cells are hypoxic

Fig. 4

Retention mechanism of Cu(II)ATSM in hypoxic tissues. (a) Cu(II)ATSM is bioreduced (Cu(II) to Cu(I)) once entering the cell. The reduced intermediate species (likely to be [Cu-ATSM]-) is trapped within the cell because of its charge. This transient complex can then go through one of two competing pathways: reoxidation to the uncharged Cu(II) species (which can escape by diffusion), or proton-induced dissociation (which releases copper to be irreversibly sequestered by intracellular proteins). [Cu-ATSM]- favours the reoxidation route because it is easily oxidised but chemically more resistant to protonation. Copper from Cu(II) ATSM is trapped reversibly as [Cu-ATSM]- (if oxygen is absent), with the possibility of irreversible trapping by dissociation over a longer period. Cu(II)ATSM is thus hypoxia-selective. (b) High quality axial ⁶⁰Cu-ATSM-PET image through the mid-upper thorax demonstrates heterogeneously increased uptake (arrow) within a known lung cancer in the aorto-pulmonary window and left suprahilar region. PET images representing summed data were obtained from 30 to 60 minutes after injection of ⁶⁰Cu-ATSM

Fig. 5

Data acquisition and quantification of BOLD-MRI in the prostate gland. Gradient recalled-echo MR images acquired at 1.5 T with a fixed repetition time and flip angle (TR ~100 msec; alpha 40 degrees) with lengthening echo-time (TE) are acquired through the prostate gland (bottom row of images). These images show increased susceptibility (T₂*) effects with increasing TE. The rate of signal intensity decay in the dorsal aspect of the prostate is dependent on intrinsic T₂* relaxation (local structure), deoxyhaemoglobin concentration [dHb] and local blood flow. Synthetic R₂* (=1/T₂*) images are created by plotting the natural logarithm of the signal intensity against the TE (top left panel). R₂* map (top right panel) reflects on the structure of tissues and local [dHb] but inflow effects are minimised; however, R₂* maps retain sensitivity to pO₂ changes caused by alterations in blood flow

Fig. 6

The re-oxygenation phenomenon. Tumours contain mixtures of aerated and hypoxic cells. Radiation is effective at eliminating well oxygenated cells because they are radiosensitive. Reoxygenation cause the preradiation pattern to return which can be eliminated by further radiation fractions but a progressive decrease in the tumour mass occurs after a series of fractions. Figure adapted from [15]

Fig. 7

Dose escalation map superimposed on CT with Planning Target Volume (red). Isodose lines show conformality to hypoxic lymph node with a maximum dose increase by 20%. This is the same patient illustrated in Fig. 2