Characterization of hypoxia in malignant pleural mesothelioma with FMISO PET-CT
Introduction
Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. The median survival following diagnosis is 9–12 months. Most patients present with advanced disease, and current standard of care is systemic palliative chemotherapy with a combination of a platinum and pemetrexed. Nevertheless, fewer than 50% of patients show a complete or partial response with combination chemotherapy [1]. A proportion of patients also receive palliative radiation therapy to symptomatic tumor masses, with a symptomatic benefit of around 40–50% [2], [3]. Strategies to identify patients who will benefit from treatment, and to improve outcomes in patients with resistant tumors, are urgently needed.
Solid tumors may exist in well-oxygenated or hypoxic conditions. Tumor hypoxia is clinically relevant as it is associated with chemotherapy and radiation resistance [4]. The presence of hypoxia or its intensity in solid tumors may be a prognostic indicator [5] and determinant of malignant progression, metastatic development and treatment resistance [6], [7]. Hypoxia modulation has been shown to have the potential to significantly improve treatment efficacy [8].
[F-18] fluoromisonidazole (FMISO) is a nitroimidazole PET tracer that localizes to areas of tumor hypoxia; thereby the presence and distribution of hypoxia in solid tumors can be non-invasively imaged [9]. FMISO enters cells by passive diffusion, and is then reduced by intracellular nitroreductase enzymes. When oxygen is abundant in normally oxygenated cells, the parent compound is quickly regenerated by re-oxidation and metabolites do not accumulate. However, in hypoxic cells, the low oxygen partial pressure prevents re-oxidation of FMISO metabolites, resulting in tracer accumulation [9]. Importantly, because FMISO only accumulates in hypoxic cells with functional nitroreductase enzymes, it accumulates in viable cells, and cannot accumulate in necrotic cells.
The distribution of FMISO has been shown to correlate with autoradiographic and histologic markers of hypoxia [10], although correlation with pO2 electrode measurements in vivo has been more variable [11], [12]. PET imaging using nitroimidazole tracers in solid tumors has been shown to identify areas of hypoxia, and to guide treatment [13]. The most experience with hypoxia PET imaging has been in head and neck cancer and, in this patient group, the prognostic significance of tumor hypoxia identified on FMISO PET imaging is becoming increasingly apparent [14].
Whilst the role of FDG PET-CT is well described in MPM, hypoxia imaging has not previously been examined in this disease [15], [16], [17]. We report the results of the first prospective pilot study of hypoxia imaging with FMISO PET-CT in MPM.
Section snippets
Methods
Patients with histologically or cytologically confirmed pleural mesothelioma were prospectively recruited. There were no selection criteria specifying tumor morphology or bulk. Patients were ineligible if receiving active treatment with chemotherapy, immunotherapy or radiation therapy currently or in the previous 6 weeks. Following study enrolment, each patient received a FMISO PET-CT and FDG PET-CT study. The two PET studies were performed within 2 weeks of each other. Patients were treated as
Patient characteristics
20 patients were recruited to the study, including 19 males and 1 female. Baseline characteristics are shown in Table 1. Most patients had epithelioid histology, with only two patients with the sarcomatoid subtype of MPM. Five patients had previous talc pleurodesis and 2 patients had previous VATS pleurectomy. 55% of patients had previously received chemotherapy.
FDG and FMISO PET-CT results
FDG and FMISO PET scans were performed a median of 3 days apart (range 1–12 days). 19 of 20 patients were visually assessed as having
Discussion
This pilot study represents the first published clinical data on hypoxia imaging with FMISO PET-CT in malignant pleural mesothelioma. The study provides evidence that mesothelioma is a tumor with significant areas of hypoxia, with 17 of 20 patients having tumor hypoxia detectable visually with FMISO PET imaging. This finding is important both in understanding therapy resistance in MPM and in planning future treatment strategies.
Semi-quantitative techniques have been used to measure hypoxia with
Conclusion
This study demonstrates the feasibility of hypoxia imaging in mesothelioma, and likely a distinct role from FDG-PET imaging in demonstrating differential hypoxia within tumor areas. Further studies of FMISO PET-CT are warranted to gain a greater understanding of the role of hypoxia in prognosis and treatment response in this challenging tumor type, with exploration of the relationship between hypoxia and radiotherapy response in bulky symptomatic lesions in MPM being the highest priority.
Conflict of interest
None.
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