Does PET Hypoxia Imaging Detect Hypoxia and Regions of Radiation Resistance in Human Cancers

There are ample data from preclinical studies to suggest that PET-based hypoxia imaging does measure hypoxia in solid tumors, and these data have been reviewed in detail previously [17, 19]. With regard to actual human tumors, the data are less clear. In an initial study of 16 patients with cervical nodal metastases from head and neck carcinoma (HNC), comparison of the FMISO tumor-to-muscle uptake ratio (TMR) at 2 h post-injection and tumor PO2, as measured by the Eppendorf PO2 microelectrode, showed high correlation [20]. However, in an updated report of 38 HNC patients, the same group found that the correlation between the two parameters had dropped to either slight or moderate, due to the failure of hypoxia imaging to detect hypoxia in small nodes and the overestimation of hypoxia in necrotic nodes by the electrode [21]. Another study in 13 patients with soft-tissue sarcomas (STS) did not show a significant correlation between FMISO imaging and tumor PO2 [22]. The authors, therefore, concluded that FMISO PET imaging would not be feasible for assessing hypoxia in STS.

With regard to the correlation between hypoxia PET imaging tracers and other approaches for hypoxia assessment, such as the expression of intrinsic tissue hypoxia markers (i.e., tumor expression of hypoxia-regulated proteins or genes), the published data for human tumors are even more meager.. Grigsby et al. [23] compared 64Cu-ATSM-PET to several hypoxia-related biomarkers, including vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX2), epithelial growth factor receptor (EGFR), carbonic anhydrase IX (CAIX), and the apoptotic index in 15 patients with cervical cancer. They found that the only significant correlation was with tumoral CAIX and the apoptosis level, at P < 0.05. Hu et al. [24] reported that the maximum intratumoral standardized uptake value (SUVmax) of pretreatment 18FETNIM in 19 patients with non-small cell lung cancer (NSCLC)

correlated significantly with the intratumoral expression of hypoxia inducible fac-tor-1a (HIF-1a), glucose transporter-1 (Glut-1), and VEGF. However, 18FETNIM SUVmax also correlated with tumor volume. In contrast, Cherk et al. [25] found no significant correlation between FMISO uptake and tumoral Glut-1 expression in another group of patients with NSCLC.

Regardless of the correlation between PET-based hypoxia imaging and other approaches for hypoxia detection, the most important question is whether hypoxia imaging can detect regions of radiation resistance in human cancers for radiation targeting or treatment modification. Because it is impossible, in most situations, to determine the exact focus of recurrence within the tumor at the time of relapse, most studies use local relapse, locoregional relapse, or progression-free survival as surrogate endpoints. A recent critical review of FMISO-PET provides a useful clinical summary of the prognostic role of this tracer in more than 300 patients imaged throughout the world [26]. The largest published study to date, correlating treatment outcomes with hypoxia imaging, is that of Rajendran et al. [27], who performed pretreatment FMISO-PET in 73 HNC patients treated in a nonuniform manner. The investigators found that the FMISO tumor-to-blood ratio (T/BR) was an independent prognostic factor for survival; however, no locoregional relapse data were reported, and there was no control for treatment approach. Another study of 12 HNC patients found that pretreatment FMISO uptake was a prognostic indicator of RT response [28]. The most convincing data came from the Rischin and Hicks group ([Hicks et al. [29] and Rischin et al. [30]), who showed, in a phase II randomized study, that failure to achieve a complete metabolic response on serial FMISO imaging studies before and during hypoxia-targeted therapy (chemoradio-therapy plus tirapazamine [TPZ], a hypoxic cell cytotoxin) was a predictor for early relapse and that pretreatment FMISO signal intensity could be used to identify patients who would benefit from TPZ. In patients with malignant gliomas, preop-erative FMISO scans showed uptake in all high-grade tumors and was prognostic for treatment outcomes [31]. In a group of 14 patients with NSCLC, a high TMR and tumor/mediastinum ratio on pretreatment FMISO was associated with a higher risk of relapse [32]. However, more recently, the group at Memorial Sloan Kettering Cancer Center imaged 20 HNC patients (of whom 90% had oropharyngeal primaries) with serial FMISO scans, pre- and mid-radiation treatment [33]. All patients were treated with fractionated RT to 70 Gy and concurrent high-dose cisplatin. Only 2 patients had persistent FMISO uptake on the mid-treatment scans. At a median follow up of 3 years for surviving patients, there was no local failure and neither of the 2 patients with persistent FMISO uptake at mid-treatment had relapsed. These excellent outcomes are much better than previously noted for tobacco-related HNC and are more compatible with those reported for human papilloma virus (HPV)-related oropharyngeal carcinomas, raising the question about the prognostic role of hypoxia in these more recently emerging HPV-induced tumors.

Outside of FMISO, prognostic data for other hypoxia PET-tracers are limited. Cu-ATSM imaging has been shown to predict response in 14 patients with NSCLC treated with either RT alone or RT and chemotherapy [34]; Cu-ATSM imaging was an independent prognostic factor for clinical outcomes as measured by overall survival and relapse-free survival in 15 cervical cancer patients treated with combined chemoradiation [23], and it correlated with survival and progression-free survival in 17 colorectal cancer patients treated with neoadjuvant chemoradio-therapy followed by surgical resection [35]. Although labeled 18F-labeled EF5 has just recently been employed as an imaging agent, with minimal outcome data [36], unlabeled or "cold" EF5 has been shown to be a prognostic factor in several solid tumors, using an immunohistochemistry (IHC) approach. In a small study of 16 patients with soft tissue sarcoma, severe hypoxia, defined as EF5 binding of 20% or more in the primary tumors, correlated with increased risk of distant metastasis [37]. In 18 patients with supratentorial gliomas, increasing EF5 binding was associated with higher tumor grade and shorter time to recurrence [38]. Similarly, in 22 HNC patients, those whose tumors had an EF5 level corresponding to severe hypoxia (<0.1% O2) had shorter event-free survival than those with less binding [39].

In summary, published data to date suggest that PET-based hypoxia imaging most likely reflects hypoxia in solid tumors and, more importantly, can help to identify patients who may benefit from future hypoxia targeting strategies.

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