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The Oncologist, Vol. 13, No. 1, 25-38, January 2008; doi:10.1634/theoncologist.2007-0097
© 2008 AlphaMed Press

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 Application of PET/CT in the Development of Novel Anticancer Drugs
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Clinical Pharmacology: Concise Drug Reviews

Application of PET/CT in the Development of Novel Anticancer Drugs

David S. Bossa, Renato Valdes Olmosb, Michiel Sinaasappelb, Jos H. Beijnena,c,d, Jan H. M. Schellensa,c

aDivision of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; bDepartment of Nuclear Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands; cUtrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht, The Netherlands; dDepartment of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands

Key Words. Positron emission tomography • Radiopharmaceuticals • Drug evaluation • Neoplasms

Correspondence: Correspondence: Jan H. M. Schellens, M.D., Ph.D., The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Telephone: 31-20-512-2569; Fax: 31-20-512-2572; e-mail: jhm{at}nki.nl

Received May 28, 2007; accepted for publication November 29, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Footnotes
 Learning Objectives
Abstract
 Introduction
 Principles of PET
 Combining PET with CT
 PET/CT in Cancer Drug...
 Conclusions and Future...
 References
 
After completing this course, the reader will be able to:

  1. Describe the advantages of combined PET/CT over single PET and single CT imaging.
  2. Mention the applications of combined PET/CT in the evaluation of novel anticancer drugs.
  3. Describe which radiotracers are used for pharmacokinetic and pharmacodynamic measurements in anticancer drug development.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Footnotes
 Learning Objectives
 Abstract
Introduction
 Principles of PET
 Combining PET with CT
 PET/CT in Cancer Drug...
 Conclusions and Future...
 References
 
Combined positron emission tomography/computed tomography (PET/CT) is a relatively new imaging modality, combining the functional images of PET with the anatomical information of CT. Since its commercial introduction about 5 years ago, PET/CT has become an important tool in oncology. Currently, the technique is used for primary staging and restaging of cancer patients, as well as for surgery and radiation therapy planning. The abilities of PET/CT to measure early treatment response as well as drug distribution within the body make this technique very useful in the development of novel anticancer drugs. In this paper, the recent literature on the current role of PET/CT in drug development is reviewed.


   INTRODUCTION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
Principles of PET
 Combining PET with CT
 PET/CT in Cancer Drug...
 Conclusions and Future...
 References
 
Cancer is one of the leading causes of morbidity and mortality in developed countries, accounting for approximately 560,000 deaths in 2007 in the U.S. alone, as estimated by the American Cancer Society [1].

Imaging techniques have become indispensable to the practice of oncology for screening programs, staging, diagnosis, early response measurement, and tumor surveillance during follow-up. Anatomical imaging techniques like computed tomography (CT) and magnetic resonance imaging (MRI) have benefited from improvements in spatial and temporal resolution over the years, and are widely used in all phases of cancer management. However, both techniques have their limitations. They rely on morphological changes, which limits discriminating pathophysiological processes such as inflammation versus metastasis in enlarged lymph nodes or fibrosis versus recurrent tumor in a residual mass. Moreover, the staging of early tumors is hampered, because morphological changes occur later in the course of the disease. MRI can also be used for functional imaging, but the technique at its current stage of development is hampered by low sensitivity. Imaging modalities like positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetic resonance spectroscopy (MRS) rely on functional and metabolic changes and are valuable for cancer imaging.


   PRINCIPLES OF PET
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Principles of PET
Combining PET with CT
 PET/CT in Cancer Drug...
 Conclusions and Future...
 References
 
PET is a popular modality in oncology. The technique is based on the detection of photons released by annihilation of positrons emitted by radiopharmaceuticals. Positron-emitting radionuclides are produced in a cyclotron by bombarding target material with accelerated protons. Positron-emitting radionuclides can be used to synthesize radiopharmaceuticals that act as substrates for endogenous pathways. In the body, these radiopharmaceuticals emit positrons that undergo annihilation with nearby electrons, resulting in the release of two photons. These so-called annihilation photons (511 keV) leave at an angle of 180 degrees and are detected by coincidence imaging as they strike scintillation crystals. The resulting data can be reconstructed to reveal the distribution of radiotracer within the subject.

One of the major advantages of PET as an imaging modality is its versatility. Currently, many different positron emitters with different characteristics are available (Table 1), making it possible to label a wide variety of radiopharmaceuticals [2]. The availability of these novel radiopharmaceuticals enables visualization with high sensitivity of tumor metabolism, cellular proliferation, specific cell surface receptors, angiogenesis, and tumor hypoxia.


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  		Table 1. Characteristics of the most commonly used isotopes for positron emission tomography imaging [2]

 
Currently, only two tracers have been approved by the U.S. Food and Drug Administration (FDA) for applications in oncology [3]. The most widely used PET tracer is 18F-fluorodeoxyglucose (18F-FDG), a glucose analogue that allows mapping of tumor glucose use. It is known that malignant tumors have an elevated glucose metabolism [4]. The value of FDG-PET for staging, restaging, and follow-up of various malignancies was reviewed recently by Gambhir et al. [5], Rohren et al. [6], Juweid and Cheson [7], and others. 18F-fluoride is indicated for PET imaging as a bone imaging agent to define areas of altered osteogenic activity. The value of 18F-fluoride for bone imaging was reviewed recently [8, 9]. All other tracers mentioned in this paper are used for research purposes.

Standardized uptake values (SUVs) provide a normalized quantitative measure of tissue FDG accumulation by normalizing the tissue radioactivity measured with PET to the injected dose and the body weight of the patient [10]. SUVs provide highly reproducible parameters of tumor glucose use, allowing comparison among PET studies performed in different patients or in the same patient at different time points [11, 12]. In must be noted that, in order to compare different scans, strict PET protocols have to be followed to minimize the variation among FDG-PET studies. When comparing scans it is very important that the time elapsed between injection of the FDG and the scan is constant.

Dynamic scans can provide information about tracer distribution over time. The first dynamic PET studies with FDG were performed as early as the 1980s [13]. Kissel et al. [14] described a model to quantify the intracellular 5-fluorouracil (5-FU) concentration in liver metastases with dynamic PET in 1997. Since then, many dynamic PET studies have been published with various tracers [15–17]. The concept and applications of compartmental modeling and PET were reviewed recently [18].

Apart from these advantages, the technique also has its limitations. FDG is not entirely specific to malignant tissue. Some benign processes may also show enhanced glycolysis [19]. This can lead to false-positive FDG-PET results.

Moreover, despite recent technical improvements, PET is still limited by a relatively low spatial resolution compared with anatomical imaging modalities like CT or MRI. Other disadvantages are the high cost and the need for a cyclotron in order to generate positron-emitting radionuclides, because some PET radiotracers (i.e., 15O, 13N, and 11C) have a short half-life, necessitating on-site synthesis of the PET tracer.


   COMBINING PET WITH CT
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Principles of PET
 Combining PET with CT
PET/CT in Cancer Drug...
 Conclusions and Future...
 References
 
When examining the different but complementary advantages of both functional and anatomical imaging modalities, it is clear that combining these imaging modalities within one scanning gantry has great potential. In this regard, PET/CT has been shown to be the most useful combination, although other combined modalities, like SPECT/CT, MRS/MRI, and recently PET/MRI, have also shown promising results.

The PET/CT scanner is capable of acquiring accurately aligned anatomical and functional images of a patient from a single investigation [20]. Temporal and spatial differences between PET and CT images are minimized as the patient remains positioned on the same bed for both imaging techniques. A combined PET/CT scan can use CT images for attenuation correction. Attenuation correction is generally applied to achieve count rate values independent of tissue electron density [21]. Single PET machines use transmission scans for attenuation correction, which takes longer (about 15 minutes) than correction via CT scan (1 minute). The greater imaging speed is beneficial in more than one way. Because it increases patient throughput (which is also beneficial for patients because for many patients a 1-hour scan is too long), it leads to a more efficient use of FDG and other radiopharmaceuticals, and it reduces the imaging cost per patient [22]. However, PET examinations corrected for attenuation using CT images may be hampered by artifacts that are not seen in PET images corrected by the use of transmission scans, like CT contrast agents and metal artifacts [23, 24]. Using segmented CT transmission maps can solve these problems. Segmentation is used to divide the CT image into regions representing different tissue types. Areas that appear denser than bone (higher CT value) are assigned to the soft tissue segment, thereby abolishing the overestimated FDG signal [25].

Since its commercial introduction about 5 years ago, the combined PET/CT scanner led to a dramatic change in cancer imaging, with the majority of PET systems now being sold as PET/CT machines across the world. Combined PET/CT is a powerful tool for the staging of various malignancies [26, 27], surgery and radiotherapy planning [28–30], and the assessment of response early in the course of treatment [31, 32].


   PET/CT IN CANCER DRUG DEVELOPMENT
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Principles of PET
 Combining PET with CT
 PET/CT in Cancer Drug...
Conclusions and Future...
 References
 
Over the last decade, advances in our knowledge of tumor biology and chemistry have led to the discovery of numerous potential therapeutic cancer targets, and of lead compounds for therapeutic applications [33, 34]. Despite all these new targets, the number of annual new drug approvals remained constant between 1990 and 2004, and the reason for this is likely multifactorial [35]. One of the potential drawbacks in the development of new drugs is the increasing cost, which results from increasing preclinical evaluation and clinical trial expenditures [36]. Earlier identification of drug failure in phase I or phase II trials could lead to a major decrease in the development cost per drug [37]. The combined PET/CT scanner could be a useful imaging modality in various phases of drug development. Small-animal PET/CT can be used in preclinical studies, selecting drug candidates for clinical trials. PET/CT can be used to enrich the patient population of early clinical trials and for the assessment of drug biodistribution by labeling the drug with a positron-emitting radionuclide. Moreover, FDG-PET/CT has already been shown to be a reliable predictor of treatment response. Other tracers for response evaluation are under investigation. Finally, PET/CT can be a useful tool to investigate the pharmacodynamics of novel anticancer agents.

Preclinical Studies (Small-Animal PET/CT)
Prior to any clinical study, in vivo preclinical studies are performed to demonstrate that the drug of interest reaches its target, has beneficial pharmacokinetics, and shows a good safety profile. Drug activity in animal studies is commonly determined by measuring the size of tumors that have been implanted s.c. External calipers are currently the standard for external repeated measurements of tumor size [38, 39]. However, the accuracy of these measurements is affected by the s.c. fat layer thickness, as well as by hair and fur. In order to demonstrate metabolic responses in small animals, FDG-PET with specially designed high-resolution small-animal scanning equipment has been used [39, 40]. The spatial resolution of these PET scanners (approximately 1 mm) is superior to that of PET scanners used in the clinic (4 mm).

As with conventional PET imaging, FDG [41] and 3'-deoxy-3'-18F-fluorothymidine (FLT) [42] are commonly used small-animal PET tracers for determining treatment response to novel anticancer agents in preclinical mouse models. Other tracers are also used. One recent example is small-animal PET with the 18F-3-hydroxymethylbutylguanine tracer, which can be used to visualize an antitumor immune response as a measure of immunotherapy activity [43]. 124I-iodo-azomycin-galactoside is a promising tracer for imaging of hypoxia in mice with serial small-animal PET scanning [44]. Another useful application of small-animal PET is the monitoring of gene expression by reporter gene systems. Target tissues expressing PET reporter genes, like herpes simplex virus type 1 thymidine kinase [45], can sequester systemically delivered PET reporter probes, enabling the monitoring of gene expression and distribution. The characteristics of the most frequently used PET reporter gene systems were reviewed recently [46, 47].

The lack of sufficient anatomical detail hampers the accuracy of single PET measurements. Combined PET/CT in animal studies was first reported using a clinical PET/CT scanner in rabbit and rat studies [48]. More recently, a combined small-animal PET/CT scanner was brought into practice. The CT part of the scanner has been shown to be superior to external caliper measurements in estimating tumor size [49], while FDG-PET can be used for assessing metabolic response. A disadvantage of using an imaging modality like PET/CT in preclinical studies is that it is more expensive than measurements of tumor size by external calipers.

Patient Selection and Response Prediction
The vast majority of phase I clinical trials are performed on a broad population of patients with a wide variety of malignancies. This is a result of the aim of these studies, which is not to evaluate response but rather to obtain toxicity and safety data. The introduction of many novel anticancer drug targets has, for example, led to the opportunity for therapy individualization, with trastuzumab [50]. Such an enrichment of patient populations in phase I studies would lead to higher response rates in these studies and earlier identification of failing drug candidates. Functional imaging techniques like PET might aid in patient selection and prediction of response to novel anticancer agents. Examples of radiotracers used for patient selection and therapy individualization are tracers targeting various receptors involved in cell proliferation and differentiation and tracers for imaging of multidrug resistance.

Currently, many novel PET tracers targeting cell surface receptors are being evaluated. The neuroendocrine PET tracers constitute an important class of receptor-targeted PET tracers. Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms originating from neural crest cells that are characterized by peptide receptors at the cell membrane and the presence of neuroamine uptake mechanisms (Figure 1). The role of PET and PET/CT in the imaging of NETs was reviewed recently [51]. An important PET tracer for the assessment of estrogen receptor (ER) status is 16{alpha}-18F-fluoro-17β-estradiol (FES). Currently, the assessment of ER status relies on biopsy specimens and in vitro studies. FES is a ligand for ER, and can be used to assess ER status in breast tumors in vivo. FES-PET has a sensitivity of 76% and specificity of 100%, compared with the in vitro assay of ER status [52], and can be used to predict response to tamoxifen therapy [53]. Fulvestrant is a pure ER antagonist recently approved for the treatment of hormone-sensitive breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Three new 16{alpha}-18F-fluoro-fulvestrant derivatives were prepared with the aim of developing a tracer for PET imaging capable of predicting the potential therapeutic efficacy of selective ER modulators. Unfortunately, the introduction of the 16{alpha}-18F-fluorine led to a dramatic decrease in the apparent binding affinity for ER, making these tracers unsuitable for prediction of response to ER modulators [54]. Other novel tracers targeting the epidermal growth factor receptor [55], human epidermal growth factor receptor 2 [56], and integrin receptor {alpha}vβ3 [57] are under investigation.


Figure 1
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  		Figure 1. Combined imaging modality in a patient with a carcinoid tumor in the central area of the right lung. (A): Axial PET image showing intense tumor uptake of 18F-FDG. (B): In contrast, SPECT/CT shows uptake of 111In-octreotide only in the mediastinal part of the tumor. The lack of tumor uptake of radiolabeled octreotide may be related to poor expression of membrane SSTRs, whereas FDG accumulation is associated with overexpression of glucose transporters (Glut-1 and Glut-3) in the cell membrane. Most carcinoid tumors accumulate more octreotide than FDG because of their low growth rate and marked differentiation. However, there is variability, and individual tumor characterization may be helpful for the therapeutic choice.

Abbreviations: 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography; SPECT/CT, single photon emission computed tomography/computed tomography; SSTR, somatostatin receptor.

 
Overexpression of P-glycoprotein (P-gp) can result in a multidrug resistant (MDR) phenotype of cancer cells and tumors by reducing intracellular accumulation of various cytotoxic agents. The uptake of colchicine, an alkaloid that binds to tubulin, is significantly lower in resistant than in sensitive tumors [58]. Colchicine has a clear intracellular target (tubulin) and is easy to label at a carbon atom, which makes it an attractive MDR tracer. 11C-colchicine PET has been shown to be useful for PET imaging of multidrug resistance in preclinical studies [59–61]. PET with colchicine as a tracer can be used as a diagnostic tool to identify patients who will not respond to treatment with taxanes because of P-gp expression.

PET imaging with these kinds of tracers offers a noninvasive way of selecting patients for early clinical trials. The conventional way of patient selection for targeted therapies is by biopsy procedures, which are invasive and logistically difficult procedures [62].

A major disadvantage of imaging with these kinds of tracers is that receptor-negative tumors cannot be visualized. These tracers are often very specific for one receptor and are not applicable for a wide range of malignancies.

Early Response Measurements in Drug Development
Treatment response measurements are essential in cancer therapy. It is essential to identify patients who do not respond to chemotherapy early in the course of treatment to avoid ineffective therapies and unnecessary side effects. At present, response to treatment is commonly determined by conventional imaging modalities like CT and/or MRI. Anatomical imaging modalities, including CT and MRI, assess tumor response by the size of the primary tumor and/or its metastases, which is followed over time by the clinician [63]. This has its limitations, because it frequently takes several cycles of chemotherapy to demonstrate significant changes in tumor size [64, 65]. Furthermore, many new anticancer drugs that interfere with signal transduction pathways are cytostatic rather than cytotoxic, which is often associated with tumor stabilization as the best treatment response. FDG-PET can measure response to treatment by assessing metabolic changes rather than changes in tumor size. Quantitative assessments of glucose uptake (SUV) before and during treatment can predict early response to treatment in a wide variety of malignancies [66, 67]. When compared with CT, FDG-PET was superior in predicting response to therapy early in the course of treatment in metastatic breast cancer [68] and in advanced soft tissue sarcoma [69]. PET imaging employing 18F-FDG is based on the use of this substrate at sites of enhanced metabolism, that is, tumor tissue. However, besides visualization of the enhanced glucose metabolism of cancer cells, it is also possible to assess tumor response by PET by demonstrating changes in other metabolic processes of cancer cells, for instance, increased amino acid metabolism. This can be determined by labeling amino acids with positron emitters, for which L-1-11C-tyrosine, 18F-fluoro-L-proline, and 11C-methionine are promising tracers to determine early response. Another characteristic of cancer cells that is used in PET measurements is their higher proliferation potential. FLT and 11C-thymidine are among the most promising PET tracers for identifying cell proliferation. Application of all these relatively new tracers, reviewed recently [70–72], might contribute to earlier and more accurate response evaluations than with standard CT-based response measurements. The most striking examples of the use of PET in assessing early treatment response have been observed in studies with imatinib.

Example of Assessing Treatment Response in Drug Development: Imatinib
Imatinib is a receptor tyrosine kinase inhibitor that is currently used for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors (GISTs). The development of imatinib has been reviewed extensively, because the drug is one of the first targeted anticancer drugs [73]. Imatinib is a potent inhibitor of the fusion tyrosine kinase Bcr-Abl and of c-Kit, a 145-kDa transmembrane receptor tyrosine kinase that plays a role in the development of a variety of malignancies, including GISTs [74]. FDG-PET revealed early response to treatment with imatinib. A case report of a woman with a GIST showed that the response to imatinib could be assessed by FDG-PET early after the start of therapy [75]. This report, together with a study by Van den Abbeele et al. [76], hallmarked the use of FDG-PET for the assessment of treatment response to imatinib.

This study aimed to compare FDG-PET with anatomical CT imaging in patients with advanced GISTs who received oral daily imatinib. Twenty-three patients were imaged by CT as well as by FDG-PET at baseline, while 14 patients had subsequent FDG-PET and CT scans (one to three imaging studies per patient) between 24 hours and 13 weeks after the initiation of therapy. It appeared that the sites of abnormalities on FDG-PET images correlated with those seen on CT. Moreover, FDG-PET provided additional information about the extent of the disease, the metabolic activity within tumor metastases, and the response to therapy as early as 24 hours following initiation of therapy, which was far earlier than measurable changes could be observed by CT. A lack of metabolic response on FDG-PET was noted in only one of 14 patients. This patient exhibited primary resistance to imatinib and tumor progression visualized by CT and conventional clinical methods [76]. More recent studies confirmed the usefulness of PET in predicting early response to imatinib therapy [69, 77]. An example of a patient with a GIST who had an adequate metabolic response following imatinib therapy is shown in Figure 2. An example of a partial metabolic response to sunitinib, a related small molecule tyrosine kinase inhibitor, is shown in Figure 3.


Figure 2
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  		Figure 2. On the left are FDG-PET scans (A, C) and a CT scan (E) of a patient with a GIST with tumor metastases in the liver before the start of imatinib therapy. This patient had a partial resection of the stomach because of a GIST. However, 1 year after the resection, large metastases were observed in the liver. Both the left and the right lobes of the liver show intense FDG uptake. On the right are FDG-PET (B, D) and CT (F) imaging evaluations after 2 months of imatinib therapy. No pathological FDG uptake can be observed in the liver. Physiological FDG uptake can be seen in the heart, kidneys, bladder, and gut. In contrast, residual tumor on the CT scan remains considerable.

Conclusion: An adequate metabolic response following imatinib treatment.

Abbreviations: CT, computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography; GIST, gastrointestinal stromal tumor.

 


Figure 3
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  		Figure 3. PET/CT fusion images of a 59-year-old man with GIST recurrence in the right abdominal wall. The images show significant residual FDG tumor uptake after 2 months of therapy with sunitinib. However, the SUV decreased from 13.5 (A) to 6.4 (B).

Abbreviations: FDG, fluorodeoxyglucose; GIST, gastrointestinal stromal tumor; PET/CT, positron emission tomography/computed tomography; SUV, standardized uptake value.

 
Recently, it was shown that imatinib, via inhibition of c-Kit, leads to downregulation of Glut-1, the most prominent transporter of glucose into the cell. Moreover, imatinib inhibits the uptake of glucose into the cell by decreasing the number of a wide variety of other glucose transporters as well as their affinity for glucose [78].

These studies exemplify the importance of PET in the development of a new drug. Early response measurements are important for early screening of effective therapies. In addition to patient selection and response measurement, PET is also used for the assessment of drug biodistribution and pharmacodynamic measurements in the course of drug development.

Assessment of Drug Biodistribution
Assessment of the pharmacokinetics of novel drug candidates is one of the aims of early phase I clinical trials. Parameters including absorption, bioavailability, distribution, and elimination as well as the maximum plasma concentration and area under the plasma concentration versus time curve are major determinants of the toxicity profile and efficacy of any novel drug. Interpatient variability in the pharmacokinetics of novel anticancer drugs in phase I studies is generally high. This is a limitation, because anticancer drugs often have a narrow therapeutic window and are dosed close to the maximum tolerable dose. The high interpatient variability can be attributed to interindividual differences in absorption, distribution, and excretion of anticancer drugs [79]. Recently, the influence of genetic factors on drug efficacy and toxicity was reviewed [80].

Non–steady-state plasma pharmacokinetics often poorly reflect drug levels in normal or tumor tissue. Anticancer drug effects are mediated by interactions with targets such as receptor proteins and drug transporters. PET pharmacokinetic studies might aid in determining intratumoral drug exposure [81].

In one of the first PET studies with radiolabeled pharmaceuticals, the pharmacokinetics of the opiates morphine and heroin were studied in rhesus monkeys [82]. Since then, it has been shown that PET analysis of radiolabeled anticancer drugs can reveal important information about the distribution of these drugs in patients. 18F-fluorouracil is the most common anticancer drug studied with PET. This is because of the ease of 18F-fluorouracil synthesis and the favorable half-life of fluorine [83]. 18F-fluorouracil PET studies can give important information about 18F-fluorouracil biodistribution in tumor and normal tissue, as reviewed by Gupta et al. [84]. A study with 18F-paclitaxel [85] examined the effect of P-gp blockers on paclitaxel biodistribution, while the biodistribution, bioclearance, and in vivo transformation of 13N-cisplatin have also been studied with PET [86]. Tumor uptake of 18F-tamoxifen has been studied by PET. The 18F-tamoxifen uptake in tumors with good responses was significantly higher than in those with poor responses [87]. Tumor uptake of 11C-1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) was compared between i.v. and intra-arterial administration by means of PET measurements. It appeared that intra-arterial administration of 11C-BCNU resulted in 50 times higher intratumoral concentrations [88].

To evaluate the distribution, pharmacokinetics, and dosimetry of the somatostatin analogue 90Y-SMT487, a phase I study was performed with 86Y-SMT487 [89]. Another phase I study investigated both the conventional pharmacokinetics and PET pharmacokinetics of XR5000, a topoisomerase-I and topoisomerase-II inhibitor formerly known as N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). On the basis of conventional pharmacokinetics, a dose schedule was proposed at which potentially therapeutic plasma levels were attained. However, the PET data revealed low tumor exposure and no saturation of tumor exposure at the maximum tolerated dose [90].

Fourteen patients scheduled for fluorouracil chemotherapy received a PET scan with 18F-fluorouracil as a tracer prior to the initiation of chemotherapy. Patients with a high uptake of the radiolabeled drug were more likely to achieve disease stabilization and a longer survival time, as shown in Figure 4 [91]. Unfortunately, we have not found a study correlating plasma pharmacokinetics with PET pharmacokinetics.


Figure 4
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  		Figure 4. (A): Time–activity curve for 18F-labeled fluorouracil positron emission tomography in a liver metastasis, in normal liver tissue, and in normal aorta tissue; (B): Comparison of the 18F-labeled fluorouracil uptake values of the liver metastasis measured with a single positron emission tomography scan 110–120 minutes postadministration (SUV) and their survival time (mean overall survival) in 13 colorectal carcinoma patients with liver metastases after the onset of chemotherapy. A significant correlation coefficient of 0.65 was found between these parameters.

Abbreviation: SUV, standardized uptake value.

Adapted from Moehler M, Dimitrakopoulou-Strauss A, Gutzler F et al. 18F-labeled fluorouracil positron emission tomography and the prognoses of colorectal carcinoma patients with metastases to the liver treated with 5-fluorouracil. Cancer 1998;83:245–253. Copyright 1996 American Cancer Society. This material is reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

 
The main characteristics of the most commonly used PET radiotracers in pharmacokinetic studies are summarized in Table 2.


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  		Table 2. The most common radiotracers in pharmacokinetic PET studies with anticancer agents

 
PET Microdose Studies
One of the major advantages of pharmacokinetic PET studies with radiolabeled drug candidates is that they can be performed at very low drug concentrations, thereby reducing or even preventing unwanted side effects. These studies, referred to as PET microdosing studies or phase 0/pre–phase I clinical trials, can give important information about the distribution of a novel drug. However, they do not provide information about the safety and tolerability of the drug. Recently, the Committee for Human Medicinal Products (CHMP) of the European Agency for the Evaluation of Medicinal Products proposed that a dose one one-hundredth of the pharmacological dose derived from in vitro and animal models could be considered a human microdose [92]. A summary of the requirements for microdose studies, as stated by the CHMP, has been given by Bergstrom et al. [93] and by the FDA in exploratory investigational new drug studies [94], and put into perspective by Marchetti and Schellens [95]. Not many PET microdosing studies have been performed thus far, while its feasibility for studying pharmacokinetics in humans was demonstrated early in the 1990s [96]. An explanation for this might be the high costs of PET microdosing studies. One of the exceptions is a study with 11C-DACA, an acridine carboxamide [97]. This pre–phase I study, performed with a radiotracer dose equivalent to one one-thousandth of the phase I starting dose, showed that valuable distribution data, including tumor concentration and early time point pharmacokinetic data, could be obtained using the PET technique. It should be confirmed whether the pharmacokinetics determined in microdosing studies are correlated with the pharmacokinetics determined at clinically relevant dose levels.

While PET is used as a single modality in microdosing studies, combined PET and microdialysis measurements can provide important pharmacokinetic data on intracellular drug concentrations [98]. Microdialysis sampling is a minimally invasive sampling technique that can be used to assess unbound drug concentrations in extracellular spaces. The contribution of this technique to pharmacokinetic and pharmacodynamic studies was reviewed recently [99]. Combined PET and microdialysis measurements are not common at the moment, but might become a useful application in drug development, for which knowledge of intracellular concentrations is important [98].

Pharmacodynamics
Pharmacodynamic evaluations in drug development are often made in phase II and III clinical studies, while phase I studies are mainly focused on dose finding, safety, and tolerability of the involved new drug. Receptor-binding assays for drugs that target defined receptors are a major component of these pharmacodynamic studies. Cancer is often characterized by overexpression or mutation of transmembrane molecules or specific receptors, and several new anticancer therapies target these specific receptors. This makes new, more specific endpoints necessary. Many studies have measured the effects of an investigational drug on surrogate tissues such as skin [100] or circulating lymphocytes [101]. This approach has a number of limitations. First, it provides no information about effects on the tumor tissue. Second, effects on the surrogate target correlate only partially, if at all, with response. Novel drug studies often include serial tumor biopsy sampling. This approach is not always feasible [62] and is often logistically difficult. Studies in which biopsy sampling is incorporated often enroll insufficient numbers of patients to draw firm conclusions [102]. In studies in which enough tumor tissue could be collected, demonstrable target inhibition did not result in tumor responses [100, 103].

Imaging with PET offers a noninvasive way of assessing the biological effects of novel anticancer agents. Besides tracers for imaging receptor binding, new tracers have been developed for imaging apoptosis, antivascular activity and tissue perfusion, tumor hypoxia, and choline accumulation (Table 3).


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  		Table 3. The most common PET radiotracers for response prediction and pharmacodynamic assessments

 
FES is a tracer that can be used for the assessment of ER status and prediction of response to hormonal therapy in breast cancer patients, as mentioned above. However, the tracer also has value during the course of therapy. A decrease in the uptake of FES in breast cancers has been observed following treatment with tamoxifen [104]. The reduction in FES uptake was found to be greater in responding patients than in nonresponding patients [105]. These studies exemplify that FES-PET can be a useful tool for predicting response early in the course of hormonal treatment.

Apoptosis, or programmed cell death, is the likely mechanism behind the tumoricidal effects of both standard chemotherapeutic agents and many novel targeted anticancer drugs. An early event in apoptosis is the exposure of phosphatidylserines, which are normally confined internally within the cell. Annexin V, an endogenous protein, has a high affinity for membrane-bound phosphatidylserine and is capable of detecting apoptosis in vivo.

PET studies in mice with 124I labeled annexin V showed high tracer uptake in Fas-induced apoptotic tissue [106, 107]. 18F-annexin V uptake in nonpathological conditions appeared to be lower than the uptake of the SPECT tracer 99mTc-labeled annexin V, while the uptake of both tracers was threefold higher in ischemic tissue [108]. The uptake of 18F-annexin V in organs of mice treated with cycloheximide correlated well with the results of terminal deoxynucleotide end-labeling assays, which is an established method of measuring degrees of apoptosis [109]. PET with annexin V as a tracer might be valuable for determining response to anticancer treatment in various malignancies, as has already been shown for SPECT/CT with 99mTc-labeled annexin V [110, 111].

Angiogenesis is an essential process for tumors to grow beyond 2–3 mm3. The key mediator of angiogenesis is vascular endothelial growth factor (VEGF), which is therefore an appealing target for anticancer therapeutics [112].

VG76e is a monoclonal antibody that binds to human VEGF. The antibody can be labeled with 124I and used as a tracer for measuring tumor levels of VEGF, as shown in an animal PET study [113]. Measuring VEGF levels by PET might be a useful method to characterize tumors and assess resistance mechanisms.

15O-H2O is another useful PET tracer that has been used extensively to measure tissue perfusion in response to antiangiogenic therapy [114, 115]. A recent study with 15O-H2O and labeled 18F-5-FU showed that treatment with nicotinamide, an amide of vitamin B3, and carbogen, a vasoconstriction inhibitor, before administration of 5-FU, can lead to an increase in tumor perfusion. Pharmacokinetic measurements with 18F-5-FU PET showed a higher delivery of 5-FU to tumor tissue. However, no differences were seen in 18F-5-FU tumor exposure [116].

Tumor hypoxia is associated with poor treatment outcome and survival [117]. 18F- labeled fluoromisonidazole (18F-FMISO) is the most extensively studied PET tracer for imaging tissue oxygenation [118]. FMISO-PET is a promising tool for predicting response to radiotherapy in patients with non-small cell lung cancer or head and neck cancer [119]. FMISO binds covalently to intracellular macromolecules upon reduction at low oxygen levels. In the presence of oxygen, the molecule is reoxygenated to its less reactive parent compound, which is cleared from the tissue [120]. However, clinical application of FMISO as a PET tracer is limited by its unfavorable biokinetics, including slow specific accumulation as well as slow clearance from normoxic tissues. Next-generation PET tracers like 18F-labeled fluoroazomycin arabinoside (18F-FAZA) and 18F-fluoroerythronitroimidazole have been developed to achieve faster clearance by reducing lipophilicity [121, 122]. The feasibility of 18F-FAZA for clinical PET imaging of tumor hypoxia was studied recently. 18F-FAZA-PET appeared feasible in head and neck cancer patients and image quality was adequate for clinical purposes [123].

Choline is a precursor of the membrane phospholipid phosphatidylcholine. The synthesis of phospholipids is tightly regulated by signal transduction cascades. The inhibition of these signal transduction pathways can be investigated by PET with the radiolabeled choline tracer 11C-methylcholine [124, 125]. Moreover, choline-PET might be a valuable diagnostic tool to differentiate between low-grade and high-grade gliomas [126].


   CONCLUSIONS AND FUTURE DIRECTIONS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Principles of PET
 Combining PET with CT
 PET/CT in Cancer Drug...
 Conclusions and Future...
References
 
The opportunity to determine the pharmacokinetic properties of novel anticancer agents, together with response evaluations early in the course of treatment, clearly demonstrates the value of PET in the development of new drugs. CT imaging procedures cannot aid in the measurement of the pharmacokinetic characteristics of novel drugs. Furthermore, PET has superior sensitivity, compared with CT, to determine early response to treatment. These findings raise the question of whether or not combined PET/CT can contribute in the development of new drugs. However, the CT part of the combined PET/CT gantry can aid in drug development. The weakness of PET imaging is its low spatial resolution, while CT is known for its superior spatial resolution. Therefore, combined PET/CT is able to generate metabolic images with better anatomical details. It is this combination that makes PET/CT more accurate in determining early responses to chemotherapy when compared with either PET or CT alone. Another advantage of combining PET and CT in one modality is the faster scanning time, compared with PET alone, which increases patient throughput, leads to a more efficient use of FDG and other radiopharmaceuticals, and reduces the imaging cost per patient. Despite these advantages, PET/CT is not yet the standard imaging modality in cancer drug development. At this moment, PET/CT is mostly used for staging and restaging of the disease.

Drug development is hampered by increasing costs, while the time from drug discovery to product marketing has increased over the years to >10 years nowadays. Less than 10% of drugs tested in phase I studies eventually reach the market. These disappointing statistics clearly demonstrate that improvements have to be made in this field of research. Combined PET/CT might aid in improving these statistics in the years to come. The combined PET/CT scanner could be useful in various preclinical and clinical phases of drug development. Earlier pharmacodynamic measurements in the development of novel anticancer agents might lead to earlier rejection of drug candidates, thereby increasing the efficiency of drug development.


   FOOTNOTES
 
Conception/design: Jan H. M. Schellens

Administrative support: Jan H. M. Schellens

Provision of study materials or patients: Jan H. M. Schellens

Collection/assembly of data: Jan H. M. Schellens

Data analysis and interpretation: Jan H. M. Schellens

Manuscript writing: David S. Boss, Renato Valdes Olmos, Jan H. M. Schellens

Final approval of manuscript: Michiel Sinaasappel, Jos H. Beijnen, Jan H. M. Schellens


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Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Principles of PET
 Combining PET with CT
 PET/CT in Cancer Drug...
 Conclusions and Future...
 References
 

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