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

Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, St. Louis, Missouri 63110, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 02/2008; 49(2):201-5. DOI: 10.2967/jnumed.107.048520
Source: PubMed


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 diacetyl-bis(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 = 0.006 and P = 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 < or = 3.5) was 71%, and that of patients with hypoxic tumors (T/M of > 3.5) was 28% (P = 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 = 0.9). Pretherapy (60)Cu-ATSM PET provides clinically relevant information about tumor oxygenation that is predictive of outcome in patients with cervical cancer.

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    • "Radiolabeled Cu-ATSM was originally developed as a positron emission tomography (PET) imaging agent for hypoxia [2], [4], [5], [6], [7]. Clinical PET studies with Cu-ATSM have been already performed, and the usefulness of this agent has been recognized; for example, Cu-ATSM uptake correlated with therapeutic resistance and metastatic potential in several tumors, including uterine cervical carcinoma and rectal carcinoma [4], [7], [8]. The mechanism of radiolabeled Cu-ATSM accumulation in hypoxic regions of tumor tissues has been well studied. "
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    ABSTRACT: (64)Cu-diacetyl-bis (N (4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with (64)Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during (64)Cu-ATSM IRT. Biodistribution was evaluated in HT-29 tumor-bearing mice injected with (64)Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between (64)Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after (64)Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic (64)Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses. Penicillamine reduced (64)Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after (64)Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic (64)Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine. We developed a novel strategy to reduce radiation exposure in critical organs during (64)Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other (64)Cu-labeled compounds.
    PLoS ONE 01/2014; 9(1):e86996. DOI:10.1371/journal.pone.0086996 · 3.23 Impact Factor
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    • "Varieties of metallic PET and single photon emission computed tomography (SPECT) radionuclides were incorporated into thiosemicarbazones chelates. Among these radionuclides , 67/68 Ga and copper-62/64 ( 62/64 Cu) have shown considerable success for targeting hypoxic and normoxic tumor xenografts in athymic mouse models [12] [13] [14] [15] [16] [17] [18] [19]. "
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    ABSTRACT: In an attempt to develop new tumor imaging radiotracers with favorable biochemical properties, we have synthesized new 68Ga-2-acetylpyridine semicarbazone (68Ga-[APSC]2) as a potential positron emission tomography (PET) tumor imaging agent using a straightforward and a one-step simple reaction. Radiochemical yield and purity were quantitative without HPLC purification. Biodistribution studies in nude mice model bearing human MDA-MB-231 cell line xenografts displayed significant tumor uptake of 68Ga-[APSC]2 radiotracer after 2 h postinjection (p.i.). The initial results demonstrate that 68Ga-[APSC]2 radiotracer may be useful probe for detecting and staging of hypoxic tumor using PET imaging modality.
    01/2014; 2014:1-6. DOI:10.1155/2014/616459
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    • "Several studies have linked FDG avidity or a high uptake of hypoxia tracers with poor outcome [9,26-28], and thereby confirmed the rationale for dose escalation protocols. Furthermore, a recent pattern of failure analysis in head and neck cancer patients compared FDG uptake before RT with local recurrence and revealed a higher recurrence density in FDG avid regions [29]. "
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    ABSTRACT: Glycolytic activity and hypoxia are associated with poor prognosis and radiation resistance. Including both the tumor uptake of 2-deoxy-2-[18 F]-fluorodeoxyglucose (FDG) and the proposed hypoxia tracer copper(II)diacetyl-bis(N4)-methylsemithio-carbazone (Cu-ATSM) in targeted therapy planning may therefore lead to improved tumor control. In this study we analyzed the overlap between sub-volumes of FDG and hypoxia assessed by the uptake of 64Cu-ATSM in canine solid tumors, and evaluated the possibilities for dose redistribution within the gross tumor volume (GTV).Materials and methods: Positron emission tomography/computed tomography (PET/CT) scans of five spontaneous canine solid tumors were included. FDG-PET/CT was obtained at day 1, 64Cu-ATSM at day 2 and 3 (3 and 24 h pi.). GTV was delineated and CT images were co-registered. Sub-volumes for 3 h and 24 h 64Cu-ATSM (Cu3 and Cu24) were defined by a threshold based method. FDG sub-volumes were delineated at 40% (FDG40) and 50% (FDG50) of SUVmax. The size of sub-volumes, intersection and biological target volume (BTV) were measured in a treatment planning software. By varying the average dose prescription to the tumor from 66 to 85 Gy, the possible dose boost (DB) was calculated for the three scenarios that the optimal target for the boost was one, the union or the intersection of the FDG and 64Cu-ATSM sub-volumes. The potential boost volumes represented a fairly large fraction of the total GTV: Cu3 49.8% (26.8-72.5%), Cu24 28.1% (2.4-54.3%), FDG40 45.2% (10.1-75.2%), and FDG50 32.5% (2.6-68.1%). A BTV including the union ([union]) of Cu3 and FDG would involve boosting to a larger fraction of the GTV, in the case of Cu3[union]FDG40 63.5% (51.8-83.8) and Cu3[union]FDG50 48.1% (43.7-80.8). The union allowed only a very limited DB whereas the intersection allowed a substantial dose escalation. FDG and 64Cu-ATSM sub-volumes were only partly overlapping, suggesting that the tracers offer complementing information on tumor physiology. Targeting the combined PET positive volume (BTV) for dose escalation within the GTV results in a limited DB. This suggests a more refined dose redistribution based on a weighted combination of the PET tracers in order to obtain an improved tumor control.
    Radiation Oncology 11/2013; 8(1):262. DOI:10.1186/1748-717X-8-262 · 2.55 Impact Factor
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