PurposeHypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers.MethodsA comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016.ResultsA variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels.ConclusionEven though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.

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Effective anticancer therapy induces tumor cell death through apoptosis. Noninvasive monitoring of apoptosis during therapy may provide predictive outcome information and help tailor treatment. A caspase-3-specific imaging radiotracer, 18 F-, has been developed for use in PET studies. We report the safety, biodistribution, and internal radiation dosimetry profiles of 18 F-ICMT-11 in 8 healthy human volunteers. Methods: 18 F-ICMT-11 was intravenously administered as a bolus injection (mean 6 SD, 159 6 2.75 MBq; range, 154-161 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at 6 time points, up to 4 h after tracer injection. Serial whole blood, plasma, and urine samples were collected for radioactivity measurement and radiotracer stability. In vivo 18 F activities were determined from quantitative analysis of the images, and time-activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time-activity curve, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using OLINDA/EXM 1.1. Results: Injection of 18 F-ICMT-11 was well tolerated in all subjects, with no serious tracer-related adverse events reported. The mean effective dose averaged over both men and women was estimated to be 0.025 6 0.004 mSv/MBq (men, 0.022 6 0.004 mSv/MBq; women, 0.027 6 0.004 mSv/MBq). The 5 organs receiving the highest absorbed dose (mGy/MBq), averaged over both men and women, were the gallbladder wall (0.59 6 0.44), small intestine (0.12 6 0.05), upper large intestinal wall (0.08 6 0.07), urinary bladder wall (0.08 6 0.02), and liver (0.07 6 0.01). Elimination was both renal and via the hepatobiliary system. Conclusion: 18 F-ICMT-11 is a safe PET tracer with a dosimetry profile comparable to other common 18 F PET tracers. These data support the further development of 18 F-ICMT-11 for clinical imaging of apoptosis.

Purpose: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [18 F]-3 0 deoxy-3 0 -fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer. Experimental Design: This was a prospective unblinded study in 20 patients with American Joint Committee on Cancer (AJCC) stage II-IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan 2 weeks after initiating the first or second cycle of docetaxel. PET variables were compared with anatomic response midtherapy (after 3 cycles).Results: Average and maximum tumor standardized uptake values at 60 minutes (SUV 60,av and SUV 60, max ) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 Â 10 À5 m 2 /mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P ¼ 0.0003 for SUV 60,av and P ¼ 0.0002 for SUV 60,max ). Reduction in tumor SUV 60,av was associated with target lesion size changes midtherapy (Pearson R for SUV 60,av ¼ 0.64; P ¼ 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV 60,av in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, K i ). Docetaxel significantly reduced K i by 51.1% (AE28.4%, P ¼ 0.0009).Conclusion: Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response midtherapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non-FLT-PET response. Clin Cancer Res; 17(24); 7664-72. Ó2011 AACR.

Purpose Several organizations are developing clinical trials to evaluate adjuvant radiotherapy (RT) for bladder cancer patients at elevated risk of locoregional failure after radical cystectomy. Clinical target volumes (CTVs) and organs at risk (OARs) for this treatment have not been defined in detail. Our purpose was to develop multi-institutional consensus CTVs and OARs for male and female bladder cancer patients undergoing adjuvant RT in clinical trials. Methods and Materials We convened a multi-disciplinary group of bladder cancer specialists from fifteen centers and five countries. Six radiation oncologists and seven urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on CT scans of a male and female cystectomy patient with input from ≥1 urologist. Based on the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another six radiation oncologists, and the cystectomy bed contouring language was again updated. To determine if the revised language produced consistent contours, CTVs and OARs were redrawn by six additional radiation oncologists. We evaluated their contours for level of agreement using the Landis-Koch interpretation of the κ-statistic. Results The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral) whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours. Conclusions Consensus descriptions of CTVs and OARs were successfully developed and can be employed in clinical trials of adjuvant RT for bladder cancer.

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Cancer cells do reprogram their energy metabolism to enable several functions, such as generation of biomass including membrane biosynthesis, and overcoming bioenergetic and redox stress. In this article, we review both established and evolving radioprobes developed in association with positron emission tomography (PET) to detect tumor cell metabolism and effect of treatment. Measurement of enhanced tumor cell glycolysis using 2-deoxy-2-[18F]fluoro-D-glucose is well established in the clinic. Analogs of choline, including [11C]choline and various fluorinated derivatives are being tested in several cancer types clinically with PET. In addition to these, there is an evolving array of metabolic tracers for measuring intracellular transport of glutamine and other amino acids or for measuring glycogenesis, as well as probes used as surrogates for fatty acid synthesis or precursors for fatty acid oxidation. In addition to providing us with opportunities for examining the complex regulation of reprogramed energy metabolism in living subjects, the PET methods open up opportunities for monitoring pharmacological activity of new therapies that directly or indirectly inhibit tumor cell metabolism.

Increased expression of CHKA, detectable by IHC, is seen in malignant lesions. This relatively simple cost-effective technique (IHC) could complement current diagnostic procedures for prostate cancer and, therefore, warrants further investigation.