Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer

Abstract

Purpose

The outcome of locally advanced head-and-neck cancer often is poor. An important determinant of treatment failure is tumor hypoxia arising from an inappropriate blood supply. Quantitation of the hypoxic fraction and blood flow in vivo may provide prognostic information and a means to target specifically tumor cells resistant to conventional treatment.

Methods and materials

Twenty-one patients with head-and-neck cancer underwent multitracer positron emission tomography (PET) before the start of preoperative or definitive radiotherapy (RT). Tumor blood flow was measured using the [¹⁵O]H₂O autoradiographic technique followed by evaluation of oxygenation status using [¹⁸F]fluoroerythronitroimidazole ([¹⁸F]FETNIM). [¹⁸F]fluorodeoxyglucose PET was performed on a separate day to calculate the metabolically active tumor volume. The definition of the fractional hypoxic volume (FHV) in the tumor was determined by multiple voxel-wise measurements of the uptake of [¹⁸F]FETNIM in well-oxygenated tissues and tumor. PET findings were then correlated with the RT outcome and survival.

Results

High blood flow was associated with poor local control after RT (p = 0.021) and with poor survival (p = 0.018). Patients with a FHV greater or equal to the median had significantly worse survival than those with a FHV less than the median (p = 0.036). The relationship between tumor hypoxia and FHV was supported in 3 patients who underwent invasive measurement of the tissue O₂ partial pressure.

Conclusion

High tumor blood flow predicted for a poor response to RT in head-and-neck cancer. The use of [¹⁸F]FETNIM for assessment of radiobiologic hypoxia requires a study with greater statistical power. PET with [¹⁵O]H₂O or [¹⁸F]FETNIM may become useful in clinical trials in which novel therapeutic agents targeting tumor vasculature or hypoxia are evaluated.

Introduction

Locally advanced head-and-neck cancer is a challenge for the clinical oncologist. Standard treatment consists of surgery and radiotherapy (RT) (1) and recently, concurrent chemoradiotherapy has gained acceptance for physically fit patients 2, 3. Local control is the primary goal of treatment because recurrences are usually fatal. However, treatment often results in debilitating side effects, and it is of utmost importance to select patients likely to benefit from more elaborate treatment efforts (4).

Hypoxia stands out as an important explanation for the failure of traditional treatment modalities in head-and-neck cancer. Hypoxic squamous carcinoma cells are resistant to RT, cytostatic drugs, and, potentially, also to conventional surgery 5, 6. To overcome this notorious feature, hypoxia-selective chemotherapeutic agents and chemical and physical modifiers of tumor oxygenation have recently been introduced in the clinical setting (7). However, for the optimal use of these modifiers and selective drugs, it is crucial to determine the hypoxic fraction individually. This is clearly not possible with the standard tools used in the diagnosis and staging of head-and-neck cancer.

Another significant feature coupled with hypoxia and with potential clinical impact is blood flow. High blood flow has consistently been found in experimental and human solid tumors 8, 9. However, the impact of high blood flow on the sensitivity to oncologic therapy has been quite controversial. It has been proposed that with high tumor blood flow, plenty of oxygen is available in situ (10), which should render tumor cells more susceptible to both RT and chemotherapy. However, hypoxia is a strong stimulus for angiogenesis (11). Thus, high flow might result as a consequence of the neovascularization elicited by angiogenic factors secreted by hypoxic tumor cells (12). At the cellular level, it is quite possible that hypoxia and high perfusion exist together. In tumors, the vascularity is far from normal. Despite a high apparent flow, oxygen might not be available to a considerable fraction of individual cells because of the high amount of nonnutritive flow, pertaining to flow containing only plasma and lacking blood cells carrying oxygen (12). The quantification of various aspects of tumor vasculature might provide an indication of the angiogenic activity, and, perhaps, oxygenation 13, 14.

Positron emission tomography (PET) is a quantitative imaging modality that can assess biologic characters of the tissue, including metabolism, proliferation, and blood flow. Recently, there has been clinical interest in developing hypoxia-avid PET tracers for defining the proportion of hypoxic cells in vivo (15). The most used compound among this group has been fluorine-18–labeled fluoromisonidazole ([¹⁸F]FMISO) 16, 17. [¹⁸F]FMISO and other related nitroimidazole compounds undergo a series of reductions intracellularly and become trapped in the cells with low oxygen content (18). [¹⁸F]FMISO is rather lipophilic, which may contribute to the finding that hypoxia-specific accumulation is rather slow. Therefore, a continuous attempt to develop more feasible compounds for clinical use is in progress. One such candidate is fluorine-18–labeled fluoroerythronitroimidazole ([¹⁸F]FETNIM), which is a more hydrophilic nitroimidazole compound and shows rapid elimination of nontarget tissues via excretion through the urinary pathway 19, 20, 21.

Our initial experience with [¹⁸F]FETNIM PET indicated a highly variable uptake in untreated head-and-neck cancer (22). We assumed this diverse [¹⁸F]FETNIM uptake to reflect different hypoxic fractions in individual tumors. To test this hypothesis further, we studied the association of [¹⁸F]FETNIM uptake in tumor with response to standard multimodality treatment in patients with head-and-neck cancer. All patients underwent multitracer PET imaging with [¹⁸F]FETNIM, oxygen-15–labeled water ([¹⁵O]H₂O), and fluorine-18–labeled fluorodeoxyglucose ([¹⁸F]FDG). Three patients also underwent invasive measurement of tumor hypoxia using polarographic needle electrodes. Our aim was to compare the perfusion and hypoxia, as measured with PET, with outcome to validate the use of functional imaging in the pretherapeutic evaluation of patients at high risk of failure after locoregional treatment.