Reproducibility of Intratumor Distribution of ¹⁸F-Fluoromisonidazole in Head and Neck Cancer

Purpose

Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. ¹⁸F-fluoromisonidazole (¹⁸F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of ¹⁸F-FMISO intratumor distribution using two pretreatment PET scans.

Methods and Materials

We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an ¹⁸F-fluorodeoxyglucose study, followed by two ¹⁸F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio ≥1.2. The ¹⁸F-FMISO tracer distributions from the two ¹⁸F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the ¹⁸F-FMISO intensities of the corresponding spatial voxels was derived.

Results

A voxel-by-voxel analysis of the ¹⁸F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%.

Conclusion

Variability in spatial uptake can occur between repeat ¹⁸F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of ¹⁸F-FMISO—suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point ¹⁸F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.

Introduction

Most solid tumors show evidence of hypoxia, presumably as a consequence of tumor cell proliferation outpacing neoangiogenesis 1, 2, 3. To date, three methods have been used to assess hypoxia in human tumors. These include direct interstitial measurement of the partial oxygen pressure (pO₂) using a polarographic oxygen electrode (Eppendorf GMbH, Hamburg, Germany). In a study of 28 head and neck cancer patients, Brizel et al.(4) showed that the average pretreatment median pO₂ was 11.2 mm Hg (range, 0.4–60 mm Hg), with a lower median pO₂ correlating with shorter disease-free survival. A more recent study (5) of 397 head and neck cancer patients from seven centers showed that a hypoxic fraction defined by a pO₂ <2.5 mm Hg threshold was associated with poor overall survival (Kaplan-Meier analysis, p = 0.006).

Although often considered the benchmark standard, pO₂ probe measurements are associated with the following disadvantages: invasiveness; limitation in sampling, because they are restricted to accessible access sites; and an inability to distinguish between hypoxic and necrotic tissue.

The second approach is based on immunohistochemical analyses of either endogenous hypoxia-related proteins or exogenously administered hypoxic cell markers. Koukourakis et al.(6) studied the relationship between the intensity of hypoxia-inducible factor 2α and carbonic anhydrase 9 staining in head and neck cancer patients undergoing radiotherapy (RT) and observed a significant inverse association with poor locoregional control (p < 0.0001 and p = 0.0002, respectively) and poor survival (p = 0.0004 and 0.002, respectively). The predictive value of endogenous, as well as exogenous, hypoxia markers for treatment outcome has been reviewed by Bussink et al.(7).

The third approach is based on a noninvasive imaging technique. Previous positron emission tomography (PET) studies using fluorine-18 labeled misonidazole (¹⁸F-FMISO) (8) have demonstrated variable, but significant, levels of hypoxia in soft-tissue sarcomas 4, 9, 10, 11, breast cancer 12, 13, glioblastoma (14), and cancer of the uterine cervix 10, 15. In head and neck cancer, evidence of hypoxia was found in 40% of cases 16, 17.

Rajendran et al.(18) showed the feasibility of this approach using ¹⁸F-FMISO PET to detect tissue hypoxia (corresponding to pO₂ values of ≤3 mm Hg) in imaging studies and showed that ¹⁸F-FMISO uptake was directly related to tissue hypoxia (19). Different tumor/blood and tumor/muscle threshold ratios have been proposed as quantitative criteria for delineating hypoxic tumor volumes 19, 20, 21, 22, 23. To our knowledge, no standard PET criterion for defining hypoxia has yet been established. In the present study, we elected to adopt the criterion suggested by Rajendran et al.(19), using a tumor/blood ratio of ≥1.2 to define the hypoxic volumes, because our experience confirmed that in all patients <95% of the nontumor voxels were hypoxic using this criterion.

The effectiveness of local control in RT for head-and-neck cancer can be compromised by the presence of viable hypoxic cells in the target volume 11, 24. Previous studies have shown that threefold greater radiation doses are required to achieve the same level of cell kill of hypoxic vs. normoxic cells 25, 26, 27. One potential strategy to improve the effectiveness of RT is to selectively boost the hypoxic volume within the tumor using intensity-modulated RT (IMRT) 28, 29. In this approach, IMRT is used to increase the dose to the “hypoxic tumor volume,” a subvolume defined within the conventional gross tumor volume, as defined by the tumor hypoxia images (e.g., ¹⁸F-FMISO-PET). However, such a strategy is predicated on the time invariance of tumor hypoxia as detected by PET tracers. Thus, in this study, we investigated the reproducibility of the ¹⁸F-FMISO distribution in patients with head-and-neck tumors by performing two PET studies 3 days apart for each patient before RT. The degree of correlation between the distributions of ¹⁸F-FMISO hypoxic target volumes from the sequential ¹⁸F-FMISO studies was the principal focus of this work.

For simplicity, we have referred to ¹⁸F-FMISO as FMISO for the rest of this report.