Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) positron emission tomography: Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models

O’Donoghue, Joseph A.; Zanzonico, Pat; Pugachev, Andrei; Wen, Bixiu; Smith‐Jones, Peter; Cai, Sanjun; Burnazi, Eva; Finn, Ronald D.; Burgman, Paul; Ruan, Shutian; Lewis, Jason S.; Welch, Michael J.; Ling, C. Clifton; Humm, John L.

doi:10.1016/j.ijrobp.2004.12.057

Cited by 163 publications

(125 citation statements)

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“…O'Donoghue et al [19] compared early and late imaging of 64 Cu-ATSM with 18 Ffluoromisonidazole in rat tumor models. Although early imaging of 64 Cu-ATSM correlated with 18 F-fluoromisonidazole in the FaDu tumor model, 64 Cu-ATSM needed to be performed much later (16)(17)(18)(19)(20) hours) to achieve a distribution similar to 18 F-fluoromisonidazole in the R3327-AT tumor model. One hypothesis to explain these differences is that the distribution of Cu-ATSM may be limited in certain tumors by reduced delivery of the radiotracer because of poor perfusion.…”

Section: Discussionmentioning

confidence: 99%

PET of Hypoxia and Perfusion with ⁶²Cu-ATSM and ⁶²Cu-PTSM Using a ⁶²Zn/⁶²Cu Generator

Wong

Lacy

Petry

et al. 2008

American Journal of Roentgenology

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OBJECTIVE-Copper-diacetyl-bis(N 4 -methylthiosemicarbazone) (Cu-ATSM) and copperpyruvaldehyde-bis(N 4 -methylthiosemicarbazone) (Cu-PTSM) are being studied as potential markers of hypoxia and perfusion, respectively. The use of short-lived radionuclides (e.g., 62 Cu) has advantages for clinical PET, including a lower radiation dose than long-lived radionuclides and serial imaging capability. A 62 Zn/ 62 Cu microgenerator and rapid synthesis kits now provide a practical means of producing 62 Cu-PTSM and 62 Cu-ATSM on-site. Tumors can be characterized with 62 Cu-PTSM, 62 Cu-ATSM, and 18 F-FDG PET scans during one session. We present the initial clinical data in two patients with lung neoplasms.CONCLUSION-Hypoxia and perfusion are important parameters in tumor physiology and can have major implications in diagnosis, prognosis, treatment planning, and response to therapy. We have shown the feasibility of performing 62 Cu-ATSM and 62 Cu-PTSM PET together with FDG PET/ CT during a single imaging session to provide information on both perfusion and hypoxia and tumor anatomy and metabolism. Keywords granuloma; lung cancer; perfusion imaging; PET/CT; radionuclides; tumor hypoxia Tumor hypoxia is a critical factor in both the development and treatment of malignant disease. Hypoxia and altered angiogenesis are critical factors in carcinogenesis, and hypoxic tumors are more resistant to both radiation and chemotherapy than tumors that are not hypoxic. Tumor hypoxia has been shown to correlate with poorer prognosis in head and neck cancer and cervical cancer and may have similar negative prognostic implications in other malignancies. For these reasons, there is a compelling interest to develop techniques for imaging tumor hypoxia; these imaging techniques would increase the current understanding of tumor physiology and would have immediate applicability in guiding cytotoxic chemotherapy, radiation therapy, and the use of antiangiogenic agents. PET can provide quantitative information about positron-emitting Address correspondence to T. Z. Wong (wong0015@mc.duke.edu). J. L. Lacy is president of Proportional Technologies, Inc., Houston, TX. (Fig. 1) was scheduled for delivery on the day of PET scanning. NIH Public Access PatientsFor this preliminary clinical study, two patients with lung nodules (> 1 cm) suspicious for malignancy were enrolled. PET was performed to evaluate these lesions before surgical resection. The purpose of this research study was to determine the feasibility of imaging lung tumors using the 62 Zn/ 62 Cu generator and to compare the imaging findings with surgical pathology. The clinical protocol was approved by our institutional review board, and written informed consent was obtained from both patients. Regional PET images of the thorax were obtained using 62 Cu-ATSM and 62 Cu-PTSM. A routine clinical PET scan using FDG was also obtained in each patient for preoperative staging. PETImaging was performed using a PET/CT scanner (Discovery ST, GE Healthcare) with a 16-MDCT unit. CT-based attenuati...

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Section: Discussionmentioning

confidence: 99%

PET of Hypoxia and Perfusion with ⁶²Cu-ATSM and ⁶²Cu-PTSM Using a ⁶²Zn/⁶²Cu Generator

Wong

Lacy

Petry

et al. 2008

American Journal of Roentgenology

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“…Furthermore, its use requires a skilled operator, and it is invasive, subject to sampling errors, and unable to exclude low readings obtained from nonviable necrotic tissue (2,4,(12)(13)(14)(15)(16)(17). Other methods have claimed equivalent accuracy (e.g., the Comet assay) (18).…”

Section: Introductionmentioning

confidence: 99%

Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study

Lee

Mechalakos

Nehmeh

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTV h ) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTV h increases the tumor control probability. This study examined the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ( 18 F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients.Methods and Materials-18 F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and 18 F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated 18 F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate 18 F-FMISO PET/CT-guided IMRT plans.Results-The heterogeneous distribution of 18 F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing 18 F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTV h and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTV h for 2 patients and were successful in 1, with normal tissue sparing. Conclusion-It was feasible to dose escalate the GTV h to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.

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“…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). Table 1 provides an overview of major studies using 64 Cu-ATSM in small-animal tumor xenograft models.…”

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

Jørgensen

Forman

et al. 2015

J Nucl Med

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The hypoxia PET tracer 64 Cu-diacetyl-bis(N 4 -methylthiosemicarbazonate) ( 64 Cu-ATSM) has shown promising results in clinical studies. However, concerns have been raised with regard to the possible effect of copper metabolism and free copper on tumor uptake and thereby the robustness of 64 Cu-ATSM as a hypoxia marker. In this study, accumulation and distribution of 64 Cu-ATSM and 64 CuCl 2 in tumor tissue were compared with partial pressure of oxygen (pO 2 ) probe measurements. Methods: One-hour dynamic PET scans were performed on nude mice bearing subcutaneous human head and neck tumors (FaDu) and human colorectal tumors (HT29) after administration of either 64 Cu-ATSM or 64 CuCl 2 . Subsequently, tracks were generated and track markers were positioned in tumors to allow for registration of their exact location on the high-resolution CT scan. After completion of the CT scan, pO 2 probe measurements were performed along each track. PET and CT images were coregistered and ROIs drawn on the basis of the location of track markers and pO 2 probe measurement depth. A linear mixed model for repeated measures was applied for the comparison of PET tracer uptake to corresponding pO 2 values. Results: Comparable uptake of 64 Cu-ATSM and 64 CuCl 2 was found in the kidney, muscle, and liver of all animals, but 64 CuCl 2 showed a higher uptake 10-60 min after injection in both tumor models. Significant differences were also found for both tumor-to-muscle and tumor-to-liver ratios. The intratumoral distribution of 64 Cu-ATSM, but not 64 CuCl 2 , showed a significant negative relationship with pO 2 measurements in FaDu tumors. However, this relationship was not found in HT29 tumors. Conclusion: 64 Cu-ATSM and 64 CuCl 2 displayed different uptake in tumors. In human head and neck xenografts, 64 Cu-ATSM but not 64 CuCl 2 reflected pO 2 measurements, indicating that 64 Cu-ATSM is a hypoxia-specific marker in this tumor type. However, data from colorectal cancer xenografts indicated that 64 Cu-ATSM may not be a hypoxia marker in all tumor types.

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Cited by 163 publications

References 26 publications

PET of Hypoxia and Perfusion with ⁶²Cu-ATSM and ⁶²Cu-PTSM Using a ⁶²Zn/⁶²Cu Generator

PET of Hypoxia and Perfusion with ⁶²Cu-ATSM and ⁶²Cu-PTSM Using a ⁶²Zn/⁶²Cu Generator

Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study

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

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Cited by 163 publications

References 26 publications

PET of Hypoxia and Perfusion with 62Cu-ATSM and 62Cu-PTSM Using a 62Zn/62Cu Generator

PET of Hypoxia and Perfusion with 62Cu-ATSM and 62Cu-PTSM Using a 62Zn/62Cu Generator

Fluorine-18-Labeled Fluoromisonidazole Positron Emission and Computed Tomography-Guided Intensity-Modulated Radiotherapy for Head and Neck Cancer: A Feasibility Study

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

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PET of Hypoxia and Perfusion with ⁶²Cu-ATSM and ⁶²Cu-PTSM Using a ⁶²Zn/⁶²Cu Generator

PET of Hypoxia and Perfusion with ⁶²Cu-ATSM and ⁶²Cu-PTSM Using a ⁶²Zn/⁶²Cu Generator

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