International Journal of Radiation Oncology*Biology*Physics
Clinical investigation: cervixAssessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: Relationship to therapeutic response—a preliminary report☆
Introduction
Tumor hypoxia in several solid cancers, notably those of lung, head and neck, and uterine cervix, has been recognized for many years to be important in determining response to radiotherapy, because tumor cells become radioresistant at low oxygen tensions 1, 2. In addition, tumor hypoxia is associated with resistance to chemotherapy and with increased tumor aggressiveness, manifested as a higher rate of recurrence and metastasis 3, 4, 5, 6, 7. Therefore, considerable effort has been focused on methods to improve the oxygen content of hypoxic tumors. However, trials of most therapeutic strategies known to improve tumor oxygenation have not demonstrated clear improvement in patient outcome. Accordingly, the clinical relevance of tumor hypoxia remains controversial.
Direct measurement of oxygen tension in human tumors can be performed with polarographic oxygen electrodes (Eppendorf GmbH, Hamburg, Germany). The pretreatment oxygen tension assessed with this method has been shown to predict response to radiation therapy and survival in patients with cervical cancer 4, 8, 9, 10. However, this method is invasive and technically demanding and thus has not been widely used in clinical practice. Accordingly, there has been substantial interest in the development of noninvasive imaging methods for assessing tumor hypoxia. The most widely studied method involves the use of positron emission tomography (PET) with the radiolabeled nitroimidazole derivative, 18F-fluoromisonidazole (FMISO) (11). This compound is reduced enzymatically and trapped within hypoxic cells. However, because of relatively low relative uptake of FMISO in hypoxic tissues, its clinical application has had limited success.
Recently, Fujibayashi and colleagues have developed copper-labeled diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), which appears to be more optimal for imaging hypoxic tissues (12). Cu-ATSM, as with FMISO, is reduced and retained in hypoxic tissues, but its uptake occurs more rapidly and the hypoxic/normoxic tissue activity ratio is greater, likely reflecting the greater membrane permeability of Cu-ATSM and its more rapid blood clearance (13). We thus undertook a pilot study to determine whether there is a relationship between tumor uptake of 60Cu-ATSM assessed by PET and response to therapy in patients with locally advanced cervical cancer.
Section snippets
Patients
We prospectively studied 14 patients (ages 23–84 years) with biopsy-proved cervical cancer who underwent PET with 60Cu-ATSM before initiation of therapy. This investigation was approved by the Human Studies Committee and the Radioactive Drug Research Committee of Washington University School of Medicine. Each patient gave written informed consent before participating in the study.
All patients were initially evaluated before treatment with a history (smoking history was not recorded) and
Results
All patients had locally advanced cervical cancer with primary lesions >2.0 cm in diameter (FIGO clinical Stage IB1 in 1, Stage IB2 in 1, Stage IIB in 8, and Stage IIIB in 4). The tumor histology was squamous cell carcinoma in 13 and adenosquamous carcinoma in 1. A summary of the pertinent clinical data and study results for these patients is shown in Table 1.
The clinical FDG-PET studies demonstrated markedly increased FDG uptake in the primary cervical tumors of all 14 patients. The mean SUV
Discussion
Hypoxia is a common feature of solid tumors and has an important role in determining response to therapy and tumor progression (2). Therefore, several therapeutic strategies, including blood transfusions, hyperbaric oxygenation, split-course irradiation, neutron irradiation, and hypoxic cell sensitizers, have been used in attempts to overcome hypoxia in a variety of tumors. However, none of these therapeutic strategies currently has been proven to have an important impact on patient outcome (22)
References (33)
- et al.
Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix
Radiother Oncol
(1993) - et al.
Tumor size and oxygenation are independent predictors of nodal disease in patients with cervix cancer
Int J Radiat Oncol Biol Phys
(2001) - et al.
High purity production and potential applications of copper-60 and copper-61
Nucl Med Biol
(1999) - et al.
Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers
Semin Radiat Oncol
(1996) - et al.
Cervix cancer oxygenation measured following external radiation therapy
Int J Radiat Oncol Biol Phys
(1998) - et al.
Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole
Int J Radiat Oncol Biol Phys
(1992) - et al.
Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazoleA pretherapy study of 37 patients
Int J Radiat Oncol Biol Phys
(1996) - et al.
Efficient production of high specific activity 64Cu using a biomedical cyclotron
Nucl Med Biol
(1997) - et al.
The unique physiology of solid tumorsOpportunities (and problems) for cancer therapy
Cancer Res
(1998) The hypoxic cellA target for selective cancer therapy. Eighteenth Bruce F. Cain Memorial Award Lecture
Cancer Res
(1999)
Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas
Cancer Res
Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix
Cancer Res
Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis
Br J Cancer
Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis
Nature
Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumors
Nature
Tumor hypoxia in pelvic recurrences of cervical cancer
Int J Cancer
Cited by (0)
- ☆
Supported by NIH Grant CA81525 and DOE Grant DE-FG02-87.