Abstract
The ability to assay tumor biologic features and the impact of drugs on tumor biology is fundamental to drug development. Advances in our ability to measure genomics, gene expression, protein expression, and cellular biology have led to a host of new targets for anticancer drug therapy. In translating new drugs into clinical trials and clinical practice, these same assays serve to identify patients most likely to benefit from specific anticancer treatments. As cancer therapy becomes more individualized and targeted, there is an increasing need to characterize tumors and identify therapeutic targets to select therapy most likely to be successful in treating the individual patient’s cancer. An example is the identification of HER2 overexpression to predict response to HER2-directed therapies such as trastuzumab and lapatinib [1]. There is a complementary need to assay cancer drug pharmacodynamics, namely the effect of a particular drug on the tumor, to determine whether or not the drug has “hit” the target and whether the drug is likely to be effective in slowing tumor growth and killing the cancer [2]. This is particular important in early drug trials as proof of mechanism and prediction of the likelihood of anticancer activity in patients.
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Keywords
- Positron Emission Tomography
- Apparent Diffusion Coefficient
- Standardize Uptake Value
- Positron Emission Tomography Imaging
- Molecular Imaging
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Introduction
1.1 Overview of Imaging and Cancer Therapy
The ability to assay tumor biologic features and the impact of drugs on tumor biology is fundamental to drug development. Advances in our ability to measure genomics, gene expression, protein expression, and cellular biology have led to a host of new targets for anticancer drug therapy. In translating new drugs into clinical trials and clinical practice, these same assays serve to identify patients most likely to benefit from specific anticancer treatments. As cancer therapy becomes more individualized and targeted, there is an increasing need to characterize tumors and identify therapeutic targets to select therapy most likely to be successful in treating the individual patient’s cancer. An example is the identification of HER2 overexpression to predict response to HER2-directed therapies such as trastuzumab and lapatinib [1]. There is a complementary need to assay cancer drug pharmacodynamics, namely the effect of a particular drug on the tumor, to determine whether or not the drug has “hit” the target and whether the drug is likely to be effective in slowing tumor growth and killing the cancer [2]. This is particular important in early drug trials as proof of mechanism and prediction of the likelihood of anticancer activity in patients.
Thus far assays to identify cancer therapeutic targets or anticancer drug pharmacodynamics have been based upon in vitro assay of tissue or blood samples. Advances in both technology and cancer science have led to the ability to perform noninvasive molecular assays. An example is the use of reporter genes whose expression results in the production of material such as green fluorescent protein or luciferase that can be detected without tissue sampling [3]. Another advance, applicable to the entire range of biological systems from cell culture to humans, is functional and molecular imaging [4, 5], which is the focus of this review. Imaging has traditionally relied on structural and anatomic features to detect cancer and determine its extent [6]. This traditional form of imaging, often termed anatomic imaging, has made an important contribution to cancer care, and is widely used in the detection and staging of cancer patients using methods such as X-ray mammography and computed tomography (CT) [7]. More recently, imaging has expanded to include the ability to image regional biochemistry and molecular biology, often termed molecular imaging [4]. The focus for molecular imaging is not structure, but rather regional biology. Quantitative analysis is an important feature of this type of imaging, for example, the ability to measure regional tumor receptor expression [8, 9]. As such, molecular imaging can be considered an in vivo assay technique, capable of measuring regional tumor biology without perturbing it. This makes molecular imaging a unique tool for anticancer drug development, complementary to traditional assay methods.
1.2 Differences Between Imaging and Tissue/Blood Assays
It is important to keep in perspective inherent differences in capabilities between tissue-based assays and in vivo assays using molecular imaging. Imaging is noninvasive and therefore better suited to serial assay. This is especially important in imaging specific drug pharmacodynamics and early tumor response. In addition, imaging typically surveys the entire animal or patient and therefore avoids sampling error that can occur for assays that require tissue sampling, especially when there is significant tumor heterogeneity. However, while sample-based methods can assay many different processes at once, for example, the expression of an array of genes [10], imaging can typically sample at most a few processes at the same time. Also, while it is possible to “batch” processing for many samples at the same time, imaging needs to be performed one subject at a time. Furthermore, the need for sophisticated equipment and imaging probes makes imaging typically more expensive than sample-based assays. These last two factors limit the number of subjects that can be studied by imaging compared with sample assay. In general, imaging methods are complementary to assay-based methods and best used to test novel drugs in the later stages of preclinical testing and early clinical trials, with more focused and limited use of imaging in later-stage drug trials.
1.3 Appropriate Roles
It is also important to note that different approaches to imaging may be needed at different stages of drug testing. In early drug trials, it is important to gain knowledge about the mechanism of action and potential efficacy of the new drug. It may also be important to test imaging methods of response assessment for future use as endpoints in larger drug trials. Novel drugs may affect imaging probe metabolism and biodistribution in unexpected ways, confounding the interpretation of the imaging study. The differing approach to imaging for different trials is discussed in more detail below.
1.3.1 Early Drug Trials (Phase I/Early Phase II)
In this setting, the imaging is not used to establish a clinical endpoint such as response or survival but rather it is to select patients appropriate for a particular targeted therapy and to confirm an effect of the drug on the tumor in patients. This setting will differ from late phase trials in the need for more detailed, likely kinetic, analysis of imaging studies to evaluate drug mechanisms and drug effect on the imaging probe in early evaluation of the drug in patients. This detailed imaging approach is possible in early trials, where patient numbers are smaller and trials occur in a limited number of centers, as compared to larger clinical trials or in a routine clinical setting, which involve more patients in a much larger number of centers. More complex analysis is often needed in early drug trials: (1) to obtain more detailed information of drug affect on tumor and normal tissues and (2) since the drug may affect imaging probe clearance and biodistribution and lead to misleading results for simple static uptake measures such as standardized uptake value (SUV) in positron emission tomography (PET) [11, 12]. In early drug trials, patient numbers will be small, and it may be feasible to use less widely available imaging probes, for example, the short-lived, but very useful, 11C (half-life = 20 min) for PET. 11C allows serial PET studies in the same imaging session and may therefore be very useful to measure tissue properties, such as drug transport, before and after administration of the drug being tested. This approach was recently used to study drug transport across the blood–brain barrier and the effect of P-glycoprotein transport inhibition [13].
1.3.2 Late Phase II/III Drug Trials
In later drug trials, molecular imaging may be particularly helpful as an early indicator of, or even potential surrogate endpoint for, drug response. Current clinical trials rely on tumor size as the endpoint for response evaluation [14]; however, it is likely that in vivo molecular imaging measures will provide equally if not more helpful predictive endpoints. This may be especially true for targeted therapies, which are often cytostatic rather than cytotoxic, and therefore result in no appreciable change in tumor mass or size. For these trials, imaging approaches and probes must be widely available. For PET imaging in larger clinical trials, labeling with 18F, which can be shipped from regional cyclotrons, or possibly longer-lived positron emitters such as 64Cu or 124I, which can be shipped and even used for on-site chemistry, will most likely be needed. In addition, the need for shorter imaging times and robust data analysis will likely favor simple and/or static imaging measures versus the more complex dynamic acquisition and kinetic modeling possible in earlier trials. In phase II/III trials, since both drug and imaging application are undergoing prospective clinical testing, it can be quite confusing to try to combine new treatment and new imaging treatment evaluation in a single clinical trial. The molecular imaging study will often need to be tested first as an exploratory endpoint or as a correlative measure in the drug therapy trial before it can be considered as an endpoint itself [6].
1.3.3 Clinical Drug Therapy
Because it can quantify in vivo tumor biology changes over time, molecular imaging is likely to be very helpful to guide clinical drug therapy in established drugs. Here, the clinical trial focuses upon the imaging study itself, and not the therapy drug. The drug should have been previously tested with established indications for its use in cancer therapy. Well-designed studies should evaluate the ability of the imaging to guide the particular cancer therapy and ideally to improve patient outcome, such as survival. A particularly attractive design for this type of study is to randomize patients to use or not use the imaging study to guide patient treatment in order to test whether the use of the imaging improves outcome [15]. Here again, as in phase II/III trials, widely available imaging probes and simpler image acquisition and analysis schemes are likely to be favored.
2 Novel Imaging Methods for Drug Development:Overview of Imaging Modalities
The imaging modalities most commonly used in molecular imaging are listed in Table 11.1. Common among these modalities is the ability to image functional and molecular tissue properties such as perfusion, metabolism, and receptor or oncogene expression [8, 16–23]. This section provides a brief description of each modality, along with its advantages and disadvantages.
2.1 Magnetic Resonance Imaging
Magnetic resonance (MR) relies upon the interaction of atomic nuclei with radiofrequency signals in the presence of strong magnetic fields. MR imaging (MRI) offers high spatial resolution and functional contrast agents using magnetic elements such as Gd and Fe [18, 24]. MRI using nonspecific contrast agents such as Gd-DTPA has become an important part of clinical cancer care [25]. More detailed and quantitative approaches to dynamic contrast-enhanced (DCE) MRI have been increasingly used to examine tumor perfusion and capillary permeability as an indicator of tumor angiogenesis [26–29] and as a measure of response to antivascular therapy [30, 31]. More specific and targeted MRI agents have also been developed and undergone preliminary testing [32]; however, the range of possible molecular targets is somewhat constrained by the need to include a magnetically active atom such as Gd or Fe. Recent advances in pulse sequences and image acquisition have led to the ability to measure other tissue properties, such as water diffusion, which can provide information on cellularity and interstitial transport without the need for contrast [33, 34], and may provide an early indication of therapeutic efficacy [35, 36]. An advantage of MRI is its high spatial resolution and image quality, especially with increasing magnetic field strength, making it applicable to both small animals and patient imaging. Limitations include the cost of the imaging system and the thus far somewhat limited range of imaging probes that serve as MR contrast agents, although new approaches tested in preclinical models will provide increased capabilities for animal research and may be able to be translated to patient studies [32].
2.2 Magnetic Resonance Spectroscopy
MR spectroscopy (MRS) takes advantage of the ability of nuclear magnetic resonance to identify specific chemical signatures and measures the regional concentrations of biochemical species, using methods similar to those developed for basic chemical assays [17, 21, 37]. Much of the current work in patients uses hydrogen spectroscopy; however, spectroscopy for other biologically relevant nuclei such as phosphorus or sodium is also possible [21]. MRS can quantify the concentration of prevalent biochemical species without perturbing the system being imaged and without the need for imaging contrast administration. MRS has considerably more limited spatial resolution compared with MRI; however, recent advances in magnetic field strength and MRS technology have yielded the ability to generate 3D MRS concentration maps (MRS images, MRSI) with resolution on the order of 1 cm or less [17, 37, 38]. Recent studies suggest that changes in local metabolites with therapy may provide a very early indicator of cancer response [39, 40]. MRS has the advantage of being able to directly quantify molecular species without the need for contrast, with the disadvantages of more limited spatial resolution and the need for relatively high abundance to be able to reliably quantify regional biochemical concentration. It shares the need for relatively expensive equipment with MRI, and in fact, requires fairly high field strength, typically 3T or more to be effective for animal and patient studies, particularly outside of the brain [17, 37].
2.3 Radionuclide Imaging
Radionuclide imaging relies on the use of imaging probes, typically termed radiopharmaceuticals, tagged with radioactive nuclei [8, 23, 41]. Position-sensitive radiation detectors identify emitted photons and generate images of regional radiopharmaceutical concentration. This imaging approach, sometimes also termed nuclear medicine, has traditionally relied on gamma emitters such as 99mTc or 131I to form images, and often termed single-photon emission computed tomography (SPECT). Somewhat more recently, advances in both instrumentation and radiochemistry have led to the ability to image positron-emitting nuclei, such as 11C and 18F, in a wide range of molecules in an approach known as PET [42].
Compared with SPECT, PET offers the potential for better spatial resolution, more accurate image quantification, and a wider range of possible imaging probes; however both PET and SPECT have made notable contributions to breast cancer clinical care and research [8, 23, 42, 43]. The chief advantage of radionuclide imaging is the ability to measure probe concentrations in nanomolar and even picomolar range, leading to the ability to measure even the most sensitive molecular processes without perturbing them. A wide range of radiopharmaceuticals has been developed to image diverse aspects of cancer biology [41]. Disadvantages include more limited spatial resolution and the need to produce and distribute relatively short-lived imaging probes. Recent development in dedicated imaging devices for small animals [44] and breast-specific imaging [45] has overcome some of the limitations in spatial resolution; however, inherent spatial resolution is less than for other methods such as CT or MRI. The combination of PET or SPECT with X-ray computed tomography (PET/CT or SPECT/CT) yields coregistered molecular and anatomic images and the opportunity to image molecular biology and anatomy simultaneously [46]. Radionuclide imaging probes and instrumentation are relatively expensive, with costs comparable to MRI.
2.4 Optical Imaging
One of the oldest forms of imaging is optical imaging, using visible light to generate images. In many ways, optical imaging is the earliest form of cancer imaging, in the form of light microscopy. Recent advances in instrumentation, computational algorithms, and imaging probes have led to new capabilities in optical imaging of living organisms, including small animal models and patients [47–49]. A variety of optical methods have been developed that can yield in vivo images with high contrast, and in some cases, considerable detail, down to the microscopic level. Methods can measure regional biology such as vascularity and blood volume using inherent tissue optical properties [47–49], or take advantage of an ever increasing array or optical probes to image-specific molecular processes [50]. Low cost, portability, ease of use, and wide availability of imaging probes are key advantages of optical imaging. Its chief disadvantage is relatively limited tissue penetration. Thus while optical imaging has become an essential tool for animal research in cancer [48], its use in patients has been more limited. While promising early studies in some human tumors point toward future clinical application [47, 50], optical imaging has been mostly confined thus far to the preclinical setting, where it is an important tool for cancer research.
2.5 Ultrasound
Ultrasound imaging works by using acoustical transducers to send and receive ultrasound frequency energy and generate three-dimensional images from either reflection or through transmission [16]. Conventional ultrasound provides high-resolution anatomic detail, and ultrasound plays an important role in cancer diagnosis [51], and is particularly useful for directing tissue biopsy. Doppler technology also provides information on tumor vascularity and with the advent of microbubble contrast agents, tumor perfusion [52]. Recent advances in imaging technology [53] and the development of targeted microbubble contrast agents hold promise for molecular imaging [52]. The portability and relatively low cost of ultrasound make it an ideal tool for both animal and patient imaging, and the ability to measure molecular processes will make ultrasound a valuable tool for cancer research and possibly for drug development. Disadvantages include some operator dependence in image acquisition and interpretation, and some challenges in developing molecularly targeted microbubble contrast agents.
2.6 Other Imaging
Other imaging modalities such as X-ray radiography and X-ray CT play an important role in structural imaging, but are more limited for molecular imaging. Dynamic contrast CT can be used to measure tissue perfusion, similar to DCE-MRI, with the disadvantage of relatively high radiation exposure. Other techniques are also being investigated [54], but are at relatively early stages of development and not discussed in detail.
3 Imaging to Define Targets and Select Patientsfor Clinical Trials
3.1 Overview
As the name would imply, targeted cancer treatment relies on the presence of therapeutic targets expressed to a greater extent in the tumor than in normal tissue. However, if the tumor does not express the target, the treatment is likely to fail. Therefore, successful development of targeted anticancer therapy relies upon the ability to determine the presence or absence of the target. Current approaches to target expression assay rely on the ability to measure the expression of specific gene products, typically proteins, in tissue samples obtained from biopsy. Examples include the expression of estrogen receptors (ERs), a target for endocrine therapy [55], and HER2, also increasingly a target of tumor-specific treatment in breast cancer and other tumors [1]. Molecular imaging has also been applied to measuring specific protein expression [9, 43]. Advantages of imaging relative to biopsy include imaging’s noninvasiveness, the ability to measure target expression in the entire disease burden and thus the ability to avoid sampling error that can occur with heterogeneous receptor expression, and the potential for serial studies of in vivo drug effects on the target. A very practical consideration is that imaging can assess expression at sites that are challenging to sample and assay, for example, bone metastases, where decalcification can make assay of tumor gene products challenging.
Imaging protein expression, particularly tumor receptors, poses some unique challenges. For receptors, imaging results can be quite sensitive to the molecular quantity of the imaging probe needed to generate the image. Most receptors have high affinity for their ligands and are active at micromolar or nanomolar concentrations of the ligand. Even small molar quantities of the imaging agent may saturate the receptor and limit the ability to visualize receptor expression [56, 57]. For this reason, molecular imaging of tumor receptors has been most successful to date with radionuclide imaging, PET, and SPECT, where it is possible to generate images with nanomolar or picomolar amounts of the imaging probe. For larger molecules, like peptides and monoclonal antibodies, other labels suitable for optical, MR, and ultrasound imaging are possible [9]; however, for small-molecule receptor imaging agents, such as labeled steroids for steroid receptors, radionuclide imaging appears to be the only feasible approach.
3.2 Examples of Imaging Target Expression
Examples of molecular imaging to identify target expression include PET ER imaging in breast cancer [57, 58], PET or MR imaging of 5-FU in GI cancers [59, 60], SPECT and PET imaging of HER2 expression in breast cancer [61, 62], and PET imaging of integrin expression as target for antiangiogenic therapy [63, 64] (see Table 11.2). The application of imaging to measuring ER expression is highlighted in more detail below. Although ER is not a novel cancer target, this example serves to illustrate how imaging can be helpful in identifying target expression and refining patient selection.
Perhaps the earliest specific target in cancer therapy is the ER in breast cancer [65]. The majority of breast cancers express that ER and endocrine therapy has proved to be an important breast cancer treatment [66]. Although only 30–70% of patients whose tumors express ER benefit from endocrine therapy, benefit is rare in patients whose tumor do not express ER or the related progesterone receptor [67–72]. Assay of breast tumor biopsy material is a well-established standard of care for selecting breast cancer patients for endocrine therapy [73]. Preliminary studies using PET imaging of ER expression have shown promise for refining patient selection. A number of agents have been tested for PET ER imaging (reviewed in [57]). Work with 16-α-18F-fluro-17β-estradiol (FES) has been the most promising to date [74]. FES has binding characteristics that are similar to estradiol for both the ER and its transport protein sex hormone binding globulin (SHBG) [75]. Blood clearance curves and protein interactions of FES have been studied in humans and animals. FES is rapidly metabolized in the liver, largely to sulfate and glucuronidate conjugates of FES [76]. Typically in humans about 45% of 18F-FES in circulating plasma is bound to SHBG and is distributed between albumin and SHBG with equilibrium maintained under most circumstances [77, 78]. By 30 min after injection, blood clearance and washout of nonspecifically bound FES are sufficient to permit good-quality ER imaging [76]. The uptake of FES at the tumor site has been validated as a measure of ER expression against in vitro assay of biopsy material using both radioligand binding assays [79] and more recently against immunohistochemistry (IHC) [80].
Recent studies illustrate the use of 18F-fluorestradiol (FES) PET to image ER expression in metastatic breast cancer to identify the therapeutic target as a predictor of response to endocrine therapy (Fig. 11.1). Studies by Mortimer, Dehdashti, and colleagues [81] have shown that a high level of FES uptake in advanced tumors predicts a greater likelihood of response to tamoxifen. In another study, in patients with recurrent or metastatic breast cancer from ER primary tumors, many of whom had failed prior to endocrine therapy, FES PET identified a subset of patients with low or absent ER expression, none of whom responded to endocrine therapy [58]. This was approximately 30% of the overall population, and the use of FES as a predictive marker to select patients for treatment other than with hormonal therapy would have increased the response rate from approximately 25 to 50% [58]. These early example illustrates how the use of imaging can help select patient most likely to respond to drug therapy, even or established therapies. Imaging can play an important role in drug development, especially for targeted therapy, by restricting patient selection to those whose tumors clearly express the therapeutic target.
PET imaging of ER expression in breast cancer as a method of identifying the therapeutic target. Both patients shown in the figure had bone metastases arising from ER + primary tumors and both were treated with endocrine therapy. The top patient’s (a) pretherapy FDG and FES PET scans show FES uptake at all sites of active disease seen by FDG PET. A follow-up FDG PET scans shows response to therapy after starting an aromatase inhibitor. The lower patient (b) does not have FES uptake at the site of disease seen on FDG PET (arrow) and had subsequent disease progression on endocrine treatment, shown by the follow-up FDG PET (reprinted from [58])
3.3 Imaging Resistance Factors
Equally important to verifying that the therapeutic target is present is the need to identify potential factors mediating therapeutic resistance. Mechanisms may include factors that block drug transport, abrogate drug effect, or indicate the presence of functional pathways that may make the tumor insensitive to interruption of the chosen target. Examples include drug efflux transporters [82, 83], aberrant tumor perfusion leading to poor drug delivery [84, 85], and hypoxia as a factor mediating broad resistance to anticancer therapy [86, 87]. Some factors, for example, hypoxia and drug efflux transport involve functional in vivo drug resistance mechanisms and may therefore be difficult to assay by in vitro assay of biopsy material. Imaging may be particularly well suited to identifying functional drug resistance, and some notable examples are highlighted below.
Aberrant tumor vasculature may limit the delivery of the drug to the tumor through a variety of mechanisms, including arterial-venous shunting and increased tumor interstitial pressure, limiting drug delivery from the capillaries through the interstitial space to the tumor cells [88]. Some images of recent studies using DCE MRI and other methods have highlighted this phenomenon and show how antivascular therapy can improve drug delivery. Batchelor showed in a small series of glioma patients treated with an antivascular agent that serial perfusion MRI indicated an early response to treatment, with more favorable conditions for drug delivery and lower tissue edema [89]. Another study using perfusion CT to evaluate vascular response showed similar results [90]. These early studies illustrate the potential for imaging to delineate factors important in drug delivery to the tumor and the effect of therapy designed to improve delivery.
Even if the drug reaches the tumor cell, a lack of drug transport into the cell may limit drug efficacy. A number of approaches to imaging drug transport have been tested, many of them focusing on the membrane efflux pump, P-glycoprotein (P-gp) [91, 92]. Some approaches have used model substrates of drug transport as general probes of drug delivery, for example 99mTc-setamibi (MIBI) or 11C-verapamil as a marker of p-gp transport [13, 91, 92]. Studies showed that tumors with rapid efflux of MIBI, as an indicator of p-gp activity, predicted poor response to chemotherapy where the principal agent (epirubicin) is a p-gp substrate [93]. Recent studies using 11C-verapamil showed that the pharmacologic inhibition of p-gp by cyclopsorin increased drug transport across the blood–brain barrier [13]. Other approaches have labeled the cancer drug itself to examine its delivery and uptake in the tumor as a predictor of response, for example [18F]-fluoropaclitaxel [94, 95].
Tumor hypoxia has been implicated as a factor mediating broad resistance to anticancer therapy through a variety of mechanism, including diminishing cell cycling and raising the threshold for cell death [87]. Imaging using either hypoxia-specific probes for PET or hypoxia-specific MR methods has shown considerable promise for identifying regional tumor hypoxia [96, 97]. Several studies have shown that tumor hypoxia identified by PET predicts poor response and early relapse in a variety of tumors including cervical cancer, head and neck cancer, and brain tumors [98–100]. Hypoxia imaging may also be helpful to direct hypoxia-specific therapy, using hypoxia as an anticancer target. A recent study of hypoxia imaging using 18F-fluoromsinidazole (FMISO) PET and the hypoxia-specific therapeutic agent, tirapazemine, in head and neck cancer yielded interesting results in this regard [101]. In this study comparing regimens with and without tirapazemine for advanced head and neck cancer, no benefit was seen in the general patient population. However, in the subset of patients who underwent FMISO PET, the presence of hypoxia determined by FMISO uptake was a significant predictor of tumor response.
4 Imaging to Assess Early Pharmacodynamics/Response
4.1 Overview
An important aspect of drug development and early clinical testing is the ability to measure early drug effect on the tumor [2]. This may be important in proof of mechanism of action, and also in verifying that drugs which look favorable in preclinical testing are likely to be effective in treating human cancers. The ability to measure early pharmacodynamic measures by anatomic imaging and biopsy has been limited by a number of practical difficulties. The current approach to cancer response assessment relies on changes in tumor size [14], a relatively late and largely mechanism-independent response to anticancer therapy. Furthermore, size is an especially poor indicator of response to cytostatic treatments, where it can be difficult to discern disease stabilization from slow tumor growth and slow increase in tumor size. Serial biopsy may provide early assessment of response, for example, by assaying changes in tumor proliferation [102], and also mechanism-specific indications of drug pharmacodynamics [103]; however, biopsy is practically difficult and potentially morbid, and difficult to perform over the course of time to discern the timing of the onset of drug action. The measurement of early drug response is a task to which functional and molecular imaging is ideally suited.
4.2 Examples of Imaging Early Response
Several recent studies have highlighted the ability of functional and molecular imaging to measure early response to anticancer agents. Much of the early work has relied upon downstream markers of tumor cell “health” to measure early drug effects and predict later tumor shrinkage and response by size criteria. The most widely studied cellular process is glycolysis, owing in part to the widespread availability of the PET glucose analog, 18F-fluorodeoxyglucose (FDG). The earliest studies showed that FDG PET could identify tumor response after a single cycle of chemotherapy, long before size changes had occurred [104–108]. More recent studies have shown that an early decline in glycolysis may also occur in response to targeted therapies, such as imatinib, where declines in FDG uptake may be seen within 24–48 h after starting the drug [109]. Earlier studies suggest that an early decline in glycolysis accompanies treatment with other TKIs, including anti-EGFR agents and sunitinib [110], perhaps in advance of changes in cellular proliferation and cell death [111]. Some have suggested that FDG indicates tumor cell viability in cancer drug response evaluation; however, recent data for TKIs show that FDG tumor uptake precedes changes in cell death [111] and may increase again when the drug is removed. This suggests some caution is needed in interpreting a decline in FDG uptake as a decrease in the number of viable tumor cells.
Another approach to early response evaluation uses MRS and relies on the fact that tumor cells have aberrant expression of certain membrane lipids, for example, choline, which can be quantified by MRS [112]. Early response to treatment results in a decrease of local choline concentration, measured by MRS, in some cases within 24 h of starting chemotherapy [39, 40], presumably as an indicator of tumor cellular dropout. Ongoing clinical trials in breast and other cancers are testing this hypothesis.
Other cellular processes may be more specific to tumor response. Serial biopsy data have suggested that a decline in cellular proliferation is an early and robust indicator of tumor response [102]. Parallel results have been shown by PET cellular proliferation imaging. The earliest studies were performed using 11C-thymidine and showed large, early declines in thymidine retention in response to chemotherapy [113–115]. Changes in thymidine uptake were larger than changes in FDG uptake in the same patients [114] (Fig. 11.2). More recent studies have focused on the thymidine analog, 18F-flourothymidine (FLT), which has a longer isotope label half-life (110 versus 20 min) and fewer labeled metabolites to confound image interpretation [115, 116]. Early studies have shown the ability of serial FLT PET to measure early response to chemotherapy [117–119] with good precision and repeatability [117].
Images of a patient before and after one cycle of chemotherapy for small-cell lung cancer. Left side shows the images of pretherapy 18F-fluordoxyglucose (FDG) and 11C-thymidine (TdR) and right side shows the images after 1 week of therapy. Images show the lung tumor (arrowhead) and vertebral bone marrow metastases (arrow). While both tracers indicate a decline in tracer uptake in response to therapy, the decline is much greater in the thymidine images, confirmed by quantitative analysis. The patient went on to have a complete clinical response after several more cycles of chemotherapy. Some early marrow regeneration is seen in the vertebral body of the posttherapy thymidine image (adapted from [173])
Besides an early decline in cell growth, effective treatments often lead to an early increase in cell death, typically by apoptosis [120]. Imaging directed at phosphytidylserine residues that normally reside on the intracellular membrane surface but that are translocated to the extracellular surface during apoptosis have been developed for apoptosis imaging. The SPECT agent 99mTc-annexin V has demonstrated the ability to image apoptosis in vivo, but use of this metal-labeled agent was confounded by high background, including liver uptake [121]. In early studies using this agent in patients undergoing cancer treatments, the level of uptake in 99mTc-annexin V correlated with in vitro assay of apoptosis on biopsy material, but the level of uptake and target-to-background ratio were only modest [122]. Concern has been expressed that the relatively small number of cells undergoing apoptosis at any one time and the small time window to have access to phosphytidylserine moieties during the apoptotic process [123] may limit the widespread use of Annexin V-based imaging. However, these same considerations may provide an advantage for mechanistic studies of early response that are important in determining optimal timing in multiagent therapy. Annexin tracers labeled for use in PET will offer better image quality, better quantification, and the ability to measure smaller quantities of radiopharmaceutical, and have undergone preliminary validation in animals [124, 125].
Recent studies have suggested that diffusion MRI may provide an indirect measure of cell death and early response to treatment [34, 126]. In diffusion MRI, pulse sequences sensitive to the Brownian motion of water molecules provide an estimate of the apparent diffusion coefficient (ADC) [126]. Studies in preclinical models and early studies in humans show that successful cancer therapy is accompanied by an increase in ADC measured by diffusion MRI, where presumably tumor cell death leads to increased interstitial space and increased ADC. Ongoing trials are testing diffusion MRI as an early indicator of response [34, 35, 127].
4.3 Examples of Imaging Pharmacodynamic Effect
The examples cited above demonstrated that imaging could quantify early antitumor effects by measuring changes in processes such as glycolysis and cellular proliferation that are downstream from the therapeutic target. This provides a valuable early measure of drug effect, but may not provide insight into the mechanism of action, especially for early studies translating preclinical results and seeking to establish proof of mechanism in patients. Some early examples of imaging to measure more specific pharmacodynamics are highlighted below.
Perhaps the most widely studied use of imaging to measure pharmacodynamics has been in application to antivascular therapy. Here, imaging methods designed to measure tumor perfusion, largely DCE-MRI, have been tested as early indicators of specific response to antiangiogenic therapy. Studies have shown that tumor perfusion measured by DCE-MRI declines within days of starting antiangiogenic therapy [27, 89]. Early work using probes more specifically targeted to tumor neovasculature may offer advantages for more specifically indicating response to antiangiogenic therapy [63, 64].
Other studies have taken advantage of drug effect on molecular pathways to provide an early and specific indication of drug effect. An elegant study showed that a transient increase in thymidine retention, measured by PET, provided an indication of the effect of a thymidilate-synthase (TS) inhibitor, where the drug would be expected to transiently increase flux through the deNovo (salvage) pathway traced by thymidine [128]. Patients whose tumors demonstrated the transient increase in thymidine uptake after the TS inhibitor were shown to have a decline in tumor proliferation by Ki-67 assay.
Imaging may provide unique opportunities to study drug–target interaction. Serial studies using FES PET in patients receiving tamoxifen showed that an early decline in FES uptake, indicating effective receptor blockade, was a predictor of subsequent response [81]. Another early study showed that the pure antiestrogen fulvestrant, a potent ER-blocker in preclinical studies, failed to completely block FES uptake in some patients, unlike comparable studies using tamoxifen, which showed complete tumor blockade in nearly all studies [129]. Elegant preclinical studies showed the ability to measure early changes in HER2 expression in response to HSP90 inhibitors, which are expected to lead to decreased HER2 expression in breast cancer [62]. These early examples demonstrate the unique capability of imaging to measure early effects on therapeutic target, which would provide valuable insights in early drug trials.
4.4 Imaging as a Surrogate Endpoint?
An increasing trend in phase II trials of targeted anticancer therapy is the use of time-to-progression or progression-free survival, rather than objective response, as a primary endpoint. This pose challenges in the design and length of trials, especially for more indolent tumors. Early results with functional and molecular imaging, mostly applied to cytoxic chemotherapy, suggest that imaging may provide a reasonable surrogate endpoint for survival. Studies have shown, for example, that an absence of FDG uptake posttherapy predicts significantly better outcome than those with residual uptake for a number of tumor types, including lymphoma, lung cancer, and breast cancer [108, 130, 131]. Others have suggested that changes in FDG uptake early in the course of treatment predict relapse and survival [108, 130–132]. Recent data in breast cancer show that changes in perfusion measured by MRI or PET predict relapse and survival [133, 134], and prognostic information that is independent of tumor size changes and pathologic response [133]. These results suggest that functional and molecular imaging may provide alternate endpoints that predict downstream outcomes better than size-based response criteria; however, more study is needed, in particular in application to targeted agents.
5 Analysis and Reporting of Molecular Imaging Data
5.1 Standardization
The increased sophistication and complexity of functional and molecular imaging techniques poses a challenge in obtaining consistent and reproducible results, especially in multicenter trials. Imaging research has yielded a variety of approaches to acquire and analyze functional and molecular imaging methods, each with its own unique approach, strengths, and weaknesses. This diversity makes for good imaging research and has led to significant advances in imaging methods, but poses a challenge to standardization in clinical trials.
The first step in standardization is to standardize image acquisition methods. This includes the type of data collected, the rate of data sampling, and approach to image generation. In some instances, for example, FDG PET, this also includes a standardized approach to patient preparation for the imaging study [135]. Two recent consensus efforts have led to suggested standards for DCE-MRI and FDG PET, where the US NCI and other organization have helped consensus conferences to determine methods appropriate for clinical trials [135, 136]. This represents a significant step forward, but not all trials have conformed to these standards.
Equally important is the standardization of image analysis and interpretation. For anatomic imaging and size-based criteria for response, the RECIST standard is widely accepted and used in clinical trials [14]. There have been some early attempts to generate similar standards for DCE-MRI and FDG PET [135–137]; however, there are no uniformly agreed upon criteria. One complication is that the expected magnitude and timing of response for functional and molecular imaging may vary considerably for different therapies and different tumor types. It may be necessary to conduct trials specifically designed to establish appropriate response endpoints based upon other outcomes such as survival. This type of study is now going on for several tumors types, including FDG PET in lymphoma studies [138].
Another important measure is the precision and repeatability of the imaging studies. This is best established using the test/retest paradigm, where serial imaging studies are performed without a therapeutic intervention simply to determine the repeatability of the test. This poses a challenge in cancer imaging, where patients are reluctant to forego therapy to complete such tests. Some studies have been conducted showing good precision for some tests, for example, FDG PET [139] and some early test of novel PET radiopharmaceuticals [117].
5.2 Approach to Imaging Analysis
Functional and molecular imaging methods may acquire both spatially and temporally detailed imaging data that lend themselves to a variety of different approaches to image analysis to obtain measures of biologic and clinical relevance [140]. There are varying levels of sophistication, and complexity of image analysis can be tailored to the nature of the biologic question and the type of clinical trial. An illustrative example is the evaluation of FDG PET images. The standard clinical approach to FDG PET imaging is to inject the patient, wait for some fixed time (typically 60 min), and then to perform imaging at a single time point (static imaging) [135]. Regional FDG uptake at this single time point can be measured by the PET imaging process in absolute units (μCi/ml, for example) and then converted to a ratio of the injected dose per unit body weight. This metric is called the SUV [141], and it is widely used in PET clinical practice and clinical trials (Fig. 11.3). More detailed information on the regional tumor glucose metabolism can be obtained by dynamic imaging over time for a single imaging field and compartmental analysis of the resulting data to yield estimates of local FDG kinetics and thus of physiologic parameters such as glucose delivery and glycolytic rate [142]. While the simple, static measures such as SUV typically correlate well with more sophisticated measures such as metabolic rate, some studies have shown that the more detailed approaches have more precision in delineating response [143], particularly for lower levels of tumor uptake [144]. Recent studies, for example, in neoadjuvant chemotherapy of breast cancer [133], have shown that parameters obtained from kinetic analysis yield response and survival prediction not obtained from simple uptake measure such as SUV. This example illustrates the need to consider the question being addressed in early patient studies of novel cancer drugs and the need to consider a range of approaches in image analysis in these early studies.
Diagram illustrating PET quantification methods. Static uptake measures such as the SUV are most frequently used; however, dynamic imaging and kinetic modeling offer the greatest potential insight for quantifying in vivo cancer biological features
6 Summary and Conclusions
Advances in functional and molecular imaging have led to the ability to perform regional, noninvasive assays of cellular and molecular processes in patients. This provides information that is complementary to in vitro assay of biopsy material, particularly in the ability to measure therapeutic target expression across the entire disease burden. Imaging is also particularly well suited to identifying functional drug resistance mechanisms leading to decreased drug delivery to tumor cells or abrogation of antitumor drug effect. Serial quantitative imaging is ideal for measuring early drug effect and for providing insights into drug mechanism of action in patients. However, a number of potential hurdles exist, limiting the application of advanced imaging to clinical drug testing thus far. The number of imaging devices and imaging probed has been limited in the past; however, the increasing use of MRI/MRS and PET in clinical practice has led to significantly increased availability. Diagnostic imaging probes are themselves considered experimental drugs, and the regulatory hurdles associated with the need to obtain approval for both therapeutic drug and the imaging probe introduce logistical challenges. Programs sponsored by the NCI support the generation of INDs for many of the imaging probes, making them more readily available for clinical trials. Finally, imaging, especially more advanced approaches, can be costly. Hopefully, investigators and sponsors will increasingly recognize the value of imaging for gaining insights into drug mechanism and efficacy early in the clinical trial process. The appropriate use of imaging can decrease the overall cost of drug development by more effectively identifying those drugs likely to be successful in anticancer treatment in patients and quickly eliminating those destined for failure.
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Mankoff, D.A. (2011). Imaging Studies in Anticancer Drug Development. In: Garrett-Mayer, E. (eds) Principles of Anticancer Drug Development. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7358-0_11
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