Feasibility and repeatability of PET with the hypoxia tracer [18F]HX4 in oesophageal and pancreatic cancer

Klaassen, Remy; Bennink, Roelof J.; Tienhoven, Geertjan van; Bijlsma, Maarten F.; Besselink, Marc G.; Henegouwen, Mark I. van Berge; Wilmink, Johanna W.; Nederveen, Aart J.; Windhorst, Albert D.; Hulshof, Maarten C.C.M.; Laarhoven, Hanneke W. M. van

doi:10.1016/j.radonc.2015.05.009

Cited by 44 publications

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“…The tumor uptake of 18 F-FAZA varied considerably between patients, with 15 of 20 showing detectable hypoxia ranging from less than 5% to greater than 50% HF, similar to the recent report by Klaassen et al using the tracer 18 F-HX4 (21). The pattern is similar to that seen in our study of primary pancreatic cancer xenografts, in which high levels of hypoxia were associated with increased metastatic potential (12).…”

Section: Discussionsupporting

confidence: 89%

“…In experimental models, tracer uptake measured by PET correlates with the extent of hypoxia measured by invasive techniques. However, there are several challenges to applying this approach to cancer patients, including the optimization of pharmacologic properties to facilitate tracer uptake in poorly vascularized tissue and the relatively low signal generated compared with other PET tracers.We used 18 F-fluoroazomycin arabinoside ( 18 F-1-a-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [ 18 F-FAZA]), which, similar to the recently introduced tracer 18 F-HX4, has lower lipophilicity and more rapid clearance from the circulation, relative to earlier tracers (18)(19)(20)(21)(22). In keeping with these pharmacodynamic differences, preclinical studies have demonstrated higher tumor-to-background ratios than earlier tracers, making 18 F-FAZA and 18 F-HX4 attractive for clinical deployment.…”

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confidence: 99%

“…We used 18 F-fluoroazomycin arabinoside ( 18 F-1-a-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [ 18 F-FAZA]), which, similar to the recently introduced tracer 18 F-HX4, has lower lipophilicity and more rapid clearance from the circulation, relative to earlier tracers (18)(19)(20)(21)(22). In keeping with these pharmacodynamic differences, preclinical studies have demonstrated higher tumor-to-background ratios than earlier tracers, making 18 F-FAZA and 18 F-HX4 attractive for clinical deployment.…”

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confidence: 99%

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Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on ¹⁸F-Fluoroazomyin Arabinoside Uptake

et al. 2016

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Pancreatic cancers are thought to be unusually hypoxic, which might sensitize them to drugs that are activated under hypoxic conditions. In order to develop this idea in the clinic, a minimally invasive technique for measuring the oxygenation status of pancreatic cancers is needed. Methods: We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer 18 F-fluoroazomycin arabinoside (or 18 F-1-α-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [ 18 F-FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. Results: Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia; nor did we see an association between tumor volume and hypoxia. Conclusion: Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents. Pancr eatic cancers are commonly believed to be unusually hypoxic, perhaps explaining in part their aggressive biology and poor response to standard treatments (1-7) and providing a rationale for treatment protocols incorporating hypoxia-targeted agents (8). However, direct evidence rests largely on inferences drawn from their poor perfusion by radiologic contrast agents (9,10), from histologic staining for surrogate hypoxia markers (2,3), and from animal models (11). The most compelling direct evidence comes from intraoperative pO 2 measurements made using the Eppendorf polarographic probe (4).We observed a wide range in the levels of hypoxia in a series of 16 primary pancreatic cancer xenografts, with strong associations between high levels of hypoxia, rapid growth, and spontaneous metastasis formation (12), and similar heterogeneity of hypoxia in a series of patients given the 2-nitroimidazole tracer pimonidazole before pancreatectomy (13). This heterogeneity highlights the need for a minimally invasive technique to assess hypoxia in pancreatic cancer patients, enabling stratification toward the use of hypoxia-targeted agents.Small-molecule tracers containing a 2-nitroimidazole undergo single electron reduction to form reactive radicals (14,15), and significant accumulation occurs under hypoxic conditions. They provide a versatile group of hypoxia probes that can be labeled with a radioisotope for noninvasive imaging (16)(17)(18). ...

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

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confidence: 99%

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Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on ¹⁸F-Fluoroazomyin Arabinoside Uptake

et al. 2016

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“…4,5). Two prominent characteristics of pancreatic cancer, hypoperfusion and desmoplasia, play important roles in forming the hypoxic microenvironment (6).…”

Section: Introductionmentioning

confidence: 99%

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Zhou

Guo

Chen

et al. 2018

Molecular Cancer Research

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Hypoxia contributes to pancreatic cancer progression and promotes its growth and invasion. Previous research principally focused on hypoxia-inducible factor-1 alpha (HIF-1a) and HIF2a (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3a (HIF3A) has not been investigated. Therefore, HIF-1a, HIF-2a, and HIF-3a expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3a expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3a expression on cell invasion and migration was investigated in vitro and in vivo, as well as the underlying mechanisms. Under hypoxic conditions, HIF-3a expression was stimulated in pancreatic cancer cells to a greater degree than HIF-1a and HIF-2a expression. HIF-3a protein levels were also elevated in pancreatic cancer tissues and correlated with reduced survival and greater local invasion and distant metastasis, whereas knockdown of HIF-3a, under hypoxic conditions, suppressed pancreatic cancer cell invasion and migration. Under normoxia, HIF-3a overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3a promotes pancreatic cancer cell invasion and metastasis in vivo and promotes pancreatic cancer cell invasion and metastasis by transcriptionally activating the RhoC-ROCK1 signaling pathway.Implications: HIF3a is overexpressed in pancreatic cancer, and targeting the HIF3a/RhoC-ROCK1 signaling pathway may be a novel therapeutic approach for the treatment of pancreatic cancer invasion and metastasis.

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“…There are several limitations to our study including the lack of voxel-by-voxel correlation between repeated scans. As studies have shown that the pancreas is prone to respiratory motion ([25,26], correction for respiratory motion using 4D acquisition would be worthwhile in future studies of serial imaging for testing response to radiation.…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer

Chan

Arlinghaus

Cardin

et al. 2016

Radiotherapy and Oncology

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Background and purpose This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer. Material and methods Twenty-one patients received escalating doses of vorinostat (100–400 mg daily) during radiation. Capecitabine was given 1000 mg q12 on the days of radiation. Radiation consisted of 30 Gy in 10 fractions. Vorinostat dose escalation followed the standard 3 + 3 design. No dose escalation beyond 400 mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity. Results The MTD of vorinostat was 400 mg. Dose limiting toxicities occurred in one patient each at dose levels 100 mg, 300 mg, and 400 mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1 years (95% confidence interval 0.78–1.35). Conclusions The combination of vorinostat 400 mg daily M–F and capecitabine 1000 mg q12 M–F with radiation (30 Gy in 10 fractions) was well tolerated with encouraging median overall survival.

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Feasibility and repeatability of PET with the hypoxia tracer [18F]HX4 in oesophageal and pancreatic cancer

Abstract: PET scanning with [(18)F]HX4 was feasible in both EC and PC patients. Amount and location of elevated [(18)F]HX4 uptake showed good repeatability, suggesting [(18)F]HX4 PET could be a promising tool for radiation therapy planning and treatment response monitoring in EC and PC patients.

Cited by 44 publications

References 50 publications

Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on ¹⁸F-Fluoroazomyin Arabinoside Uptake

Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on ¹⁸F-Fluoroazomyin Arabinoside Uptake

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer

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Feasibility and repeatability of PET with the hypoxia tracer [18F]HX4 in oesophageal and pancreatic cancer

Abstract: PET scanning with [(18)F]HX4 was feasible in both EC and PC patients. Amount and location of elevated [(18)F]HX4 uptake showed good repeatability, suggesting [(18)F]HX4 PET could be a promising tool for radiation therapy planning and treatment response monitoring in EC and PC patients.

Cited by 44 publications

References 50 publications

Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake

Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer

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Resources

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Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on ¹⁸F-Fluoroazomyin Arabinoside Uptake

Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on ¹⁸F-Fluoroazomyin Arabinoside Uptake