Assessing Tumor Hypoxia in Cervical Cancer by PET with ⁶⁰Cu-Labeled Diacetyl-Bis(N⁴-Methylthiosemicarbazone)

Abstract

Tumor hypoxia indicates a poor prognosis. This study was undertaken to confirm our prior pilot results showing that pretreatment tumor hypoxia demonstrated by PET with 60 Cu-labeled diacetylbis(N 4 -methylthiosemicarbazone) ( 60 Cu-ATSM) is a biomarker of poor prognosis in patients with cervical cancer. Thirty-eight women with biopsy-proved cervical cancer underwent 60 Cu-ATSM PET before the initiation of radiotherapy and chemotherapy. 60 Cu-ATSM uptake was evaluated semiquantitatively as the tumor-to-muscle activity ratio (T/M). A log-rank test was used to determine the cutoff uptake value that was strongly predictive of prognosis. All patients also underwent clinical PET with 18 F-FDG before the institution of therapy. The PET results were correlated with clinical follow-up. Tumor 60 Cu-ATSM uptake was inversely related to progression-free survival and cause-specific survival (P 5 0.006 and P 5 0.04, respectively, as determined by the log-rank test). We found that a T/M threshold of 3.5 best discriminated patients likely to develop a recurrence from those unlikely to develop a recurrence; the 3-y progression-free survival of patients with normoxic tumors (as defined by T/M of #3.5) was 71%, and that of patients with hypoxic tumors (T/M of .3.5) was 28% (P 5 0.01). Tumor 18 F-FDG uptake did not correlate with 60 Cu-ATSM uptake, and there was no significant difference in tumor 18 F-FDG uptake between patients with hypoxic tumors and those with normoxic tumors (P 5 0.9). Pretherapy 60 Cu-ATSM PET provides clinically relevant information about tumor oxygenation that is predictive of outcome in patients with cervical cancer. Tumorhypoxi a has been shown to be important in determining the response to therapy in solid tumors, including cervical cancer. Hypoxic cells are more resistant to killing by ionizing radiation and chemotherapy, more likely to be locally invasive and to metastasize, more resistant to apoptosis, and more genetically unstable (1,2). Thus, because of the importance of tumor hypoxia, considerable research has focused on developing methods to measure hypoxia reliably as well as on strategies for improving tumor oxygenation or ameliorating the effects of hypoxia. Considering the new therapeutic agents that target hypoxia, identifying a practical method for detecting hypoxia becomes highly important. In general, a method suitable for routine clinical application needs to be practical, readily available, and reliable. Polarographic oxygen electrodes (Eppendorf GmbH) made it possible to measure tumor oxygenation, which produced clinically relevant information. Early clinical studies with oxygen electrodes were very promising and demonstrated that hypoxic tumors, including cervical tumors, respond poorly to radiation therapy (3-10). However, the oxygen electrode method is invasive, technically demanding, useful only for studying tumors accessible to electrode placement, and subject to sampling errors. Thus, this method is not considered clinically practical.Recently, noninvasive imaging methods, particu...

PET imaging of cardiac hypoxia: Opportunities and challenges

“…While it has since been extensively investigated for characterizing hypoxic tumors [83][84][85][86][87] [88], relatively few studies have addressed its potential application for imaging ischemic or hypoxic myocardium [89][90]. Fujibayashi et al were the first group to report selective trapping of 62 Cu-ATSM in isolated perfused rat hearts.…”

Positron emission tomography to assess hypoxia and perfusion in lung cancer

“…The short-lived radionuclides can be used for sequential measurements, whereas radionuclides with longer half lives do Table 2 for full names. Lewis et al [133] , Yuan et al [134] , Kersemans et al [135] , Matsumoto et al [136] Ballegeer et al [137] , Bowen et al [138] , Lewis et al [133] , Myerson et al [139] , O'Donoghue et al [72] Ballegeer et al [137] , Hansen et al [140] , Matsumoto et al [136] , McCall et al [66] , O'Donoghue et al [72] , Oh et al [74] , Yuan et al [134] Grigsby et al [141] , Tateishi et al [142] , Valtorta et al [143] , Weeks et al [144] Dence et al [145] , Kersemans et al [135] , Lewis et al [146] , Matsumoto et al [136] , O'Donoghue et al [72] Dehdashti et al [86] , Lohith et al [67] , Wong et al [80] , Zhang et al [81] Chao et al [147] , Dehdashti et al [148] , Dehdashti et al [149] , Dietz et al [150] , Grassi et al [151] , Grigsby et al [141] , Kositwattanarerk et al [152] , Laforest et al [153] , Lewis et al [154] , Minagawa et al [155] , Nyflot et al [156] [ Mahy et al [158] , Mahy et al …”

64Cu-ATSM Reflects pO2 Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with 64CuCl2

“…64 Cu-ATSM has a high tumor-to-background ratio and has shown promising results in small clinical studies, in which the tumor-to-muscle ratio was able to predict treatment outcome (11)(12)(13). However, the robustness of 64 Cu-ATSM as a marker of hypoxia has been questioned, because preclinical studies have reported temporal changes in tumor uptake and cell-type-specific differences in hypoxia selectivity (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”