Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section C – Diagnosing Cancer: Pathology and Laboratory Medicine

Chapter 21 – Imaging

Richard L. Wahl

SUMMARY OF KEY POINTS

  

   

Noninvasive medical imaging often is essential to cancer management at multiple times in the course of the illness.

  

   

Imaging currently is used for screening to detect cancer, characterizing lesions, performing locoregional and systemic staging, providing prognostic information, assessing response during and after therapy, restaging after treatment, performing follow-up of patients for recurrence, and precisely guiding therapies such as external beam radiation, brachytherapy, or thermal ablation.

  

   

More invasive interventional radiologic procedures also can guide and monitor vascular or intraluminal delivery of treatments such as radioactive microspheres, embolic materials, radiofrequency or cryoablation, and therapeutic drugs.

  

   

Imaging methods range from the traditional anatomic methods—x-ray, computed tomography (CT), and ultrasound—to the more functional methods of magnetic resonance imaging (MRI) and nuclear medicine methods, including positron emission tomography (PET) and single-photon-emission computed tomography (SPECT), and planar nuclear imaging. Optical imaging is promising, but limited by penetration of tissues to superficial structures in most cases.

  

   

Plain films and mammography remain useful techniques, with mammography the only imaging method clearly proven effective when applied in the screening setting.

  

   

CT remains the cornerstone technology for most oncologic imaging, and CT technology allowing for rapid-sequence angiography is finding new applications, as is three-dimensional reconstruction of CT data sets. Screening data with CT-colonography continues to improve, and in some studies it has been found to be comparable to traditional colonoscopy for colon cancer screening. CT scanning for lung cancer screening remains under evaluation and shows promise in high-risk populations.

  

   

MRI is the imaging tool of choice for central nervous system, spinal, and musculoskeletal neoplasms, as well as in assessing vascular and some hepatobiliary and pelvic lesions. MRI also can be used to detect breast cancers, especially in women with dense breasts. Recent concerns regarding gadolinium-associated nephrogenic systemic fibrosis (NSF) have led to cautions in the use of MRI contrast medium in patients with impaired renal function.

  

   

Bone scans using single-photon methods (99mTc methylene diphosphonate) remain the dominant procedure for detecting suspected bone metastases; however, this technology probably is less sensitive than MRI and PET techniques for detecting bone metastases of many tumors.

  

   

PET and PET/CT technology using 18fluorodeoxyglucose (FDG) continues to grow in a wide variety of applications and its use is becoming increasingly routine in the management of patients with cancer at varying states of the disease process. PET is used with increasing frequency in the staging and follow-up of lung, colorectal, and head and neck cancers, as well as lymphomas and other types of tumors, and is now a routine tool in lymphoma management at several points in the disease. PET with non-FDG tracers is a promising research area with growing clinical applications.

  

   

The fusion of anatomic and functional images to create hybrid “anatomolecular images” with software or dedicated instruments such as PET/CT or SPECT/CT devices also is seeing rapid growth in applications in cancer imaging. Fully diagnostic CT scans coupled with PET imaging in the form of PET/CT often provide valuable composite imaging for cancer management.

  

   

Imaging management for staging lung cancer and characterizing solitary pulmonary nodules often includes PET in addition to CT when the technology is available because PET has high accuracy in lung cancer assessments compared with CT.

  

   

Imaging management of suspected recurrences of colorectal cancer, head and neck cancer, lymphoma, and several other cancers often now includes the use of PET in addition to CT. Use of PET at earlier stages in the workup is becoming increasingly common, as is the use of PET in early assessments of the efficacy of cancer therapies.

  

   

In prostate cancer, available imaging methods remain suboptimal for detection of primary tumor and early determination of local or systemic tumor spread. MRI nodal contrast agents are promising but not yet routinely available, and MR spectroscopy has had only limited success in the prostate.

  

   

Visceral angiography for diagnostic purposes is being supplanted by CT and MRI methods; however, it remains important as a tool for intravascular delivery of therapies such as chemotherapy, coils, or radioactive microspheres.

  

   

CT, ultrasound, fluoroscopy, and innovative MRI systems can guide interventional procedures such as thermal and cryotherapeutic lesion ablations.

  

   

Highly specific probe-reporter systems are being developed to allow for optical and radionuclide imaging of transfected gene biodistribution and function.

  

   

Combined anatomic and functional information is being applied to allow for more precise planning of external beam radiation therapy, including IMRT and conformal therapy, methods that potentially allow for increasing dose escalation and minimization of toxicity to normal tissues.

  

   

Emerging imaging methods are proving increasingly useful in providing information on the physiology and molecular characteristics of lesions, which means that a multiparametric biologic imaging phenotype for tumors can be obtained. This phenotype can more precisely guide individualized tumor treatment to yield a higher probability of success without excessive toxicity for treatment of the selected neoplastic process.

INTRODUCTION

Noninvasive imaging is of fundamental and increasing importance in the daily management of the patient with cancer. Although physical examination and laboratory diagnosis remain key for planning treatment, for solid tumor management, imaging tests represent a major objective metric of disease activity and may be used at different times during the course of the disease to monitor the efficacy (or lack of efficacy) of treatment. Imaging tumor size is an objective endpoint in disease management used to compare different types of cancer treatment and treatment across institutions. The use of imaging also is increasing in the drug development process and in developing new cancer therapies.

Specific clinical questions addressed by imaging include screening for the presence of cancer, characterizing anatomic lesions as malignant or benign, and staging a neoplasm—that is, determining the size and local extent of a primary lesion and determining whether it is localized or locoregionally or systemically metastatic. Such studies are essential for determining whether the patient is a candidate for surgical resection, identifying the extent of the field for radiation therapy, and determining whether systemic chemotherapy is appropriate. Initial staging of tumor size and extent also can provide important prognostic data. During the course of treatment, imaging is used to determine response of the cancer. Imaging also is used to follow patients for recurrence or development of second malignancies. Imaging is being used more often as a method to assist delivery of minimally invasive therapeutic procedures to ablate cancers and to guide the dosing of therapeutic drugs, including radiopharmaceuticals, more precisely.[1]

Imaging often is the best means of noninvasively identifying and assessing tumors. With information gleaned from imaging studies, the prognosis can be established and treatment decisions made with greater certainty. Before discussing the varying imaging methods available for cancer, this chapter considers some general principles that are applicable to all imaging tests.

Tasks for Imaging

The major roles of imaging in the current and evolving practice of cancer management are shown in Table 21-1 .

Table 21-1   -- Imaging in Cancer: Key Current Clinical Uses in Cancer Management

  

 

SCREENING

  

 

Lesion characterization: malignant or benign, size, local invasion

  

 

Tumor staging: locoregional, systemic, at initial presentation or on retreatment

  

 

Size and extent of tumor: to plan radiation or other local therapy

  

 

Prognostic information

  

 

Defining sites for biopsy and subsequent analysis by pathology

  

 

Guidance of interventional therapy

  

 

Assessment of response to treatment

  

 

Restaging tumor after treatment

  

 

Assessment of normal organ function or status before, during, and after treatment

  

 

Assessment for toxicity or complications of treatment

  

 

90% SENSITIVE AND SPECIFIC TEST

  

 

50% Prevalence of cancer in the population imaged

  

 

1000 Independent scans

  

 

50 False-positive findings in healthy patients (10% of 500)

  

 

450 True-positive findings in patients with disease (90% of 500)

  

 

Positive predictive value (disease positive/test positive): 450/500 (90%)

  

 

Possible conclusion: An excellent test!

  

 

90% SENSITIVE AND SPECIFIC TEST

  

 

10% Prevalence of cancer in the population imaged

  

 

1000 Independent scans

  

 

90 False-positive findings in healthy patients (10% of 900)

  

 

90 True-positive findings in patients with disease (10% of 900)

  

 

Positive predictive value (disease positive/test positive): 50/100 (50%)

  

 

Possible conclusion: A rather lousy test!

  

 

But these are the same test!

 

 

GENERAL CONSIDERATIONS

Performance of Imaging Tests

Noninvasive imaging is used to perform a wide variety of important tasks. Although the best way to determine the medical utility of a diagnostic test can be argued, a few key concepts are required to understand and compare diagnostic tests. These can be applied to one of the most basic tasks (i.e., determining whether tumor is present) and also to the ability of imaging to predict resectability or response to treatment.

Sensitivity

Sensitivity describes how often the imaging test would give a “positive result” in a patient with cancer (i.e., true-positive [TP] finding). Ideally, the test precisely detects and locates one or multiple cancers in a given patient. Thus,

Sensitivity can be calculated on a per-patient basis or a per-malignant lesion basis. The per-patient basis most commonly is used in screening studies for early diagnosis, whereas the per-lesion basis may be used in patients expected to have multiple sites of tumor. Per-lesion detection analyses can be misleading because they can be heavily biased by a single patient's results if that patient has multiple tumor foci.

It can be difficult to judge how good a test is by reading the literature. Sensitivity is supposed to be substantially independent of study composition, but as discussed in the next section, certain imaging tests may be insensitive for some very early-stage disease, but very, very sensitive for more advanced disease. Thus, the patient population and, very often, the tumor burden and average tumor size can make a difference in the sensitivity of a test. Virtually all noninvasive imaging tests are less sensitive for small-volume disease than for large-volume disease. For example, if an imaging test is used in a patient population in which patients have advanced disease before seeking medical attention (e.g., they are symptomatic at presentation), the imaging test may have far greater sensitivity than if it were used in patients with earlier-stage, smaller tumors. For example, positron emission tomography (PET) with 18fluorodeoxyglucose (FDG) has been reported to be more than 90% sensitive for detecting metastatic melanoma, but it is less than 20% sensitive in detecting early (low tumor volume) nodal metastases of melanoma at initial surgical resection. A test with high sensitivity has a low number of false-negative results.[2] The false-negative fraction usually is expressed as 1 - sensitivity.[3]

Specificity

Specificity is the frequency with which a test result is negative if no disease is present, or the true-negative (TN) ratio. As a percentage, specificity is

Again, specificity can be calculated on a per-patient basis or a per-lesion or per-region basis. The per-patient calculations commonly are performed in the screening setting. They also can be done per region of the body (e.g., Is the liver free of tumor? Are the draining lymph nodes free of tumor?). Specificity can be affected substantially if there is a population characteristic that can result in false-positive results for the imaging test. For example, inflammatory and infectious lung disease, such as active tuberculosis or sarcoidosis, if present in a patient population, can result in false-positive findings on PET or CT scans or other imaging methods. In this situation, the specificity of FDG-PET, and likely of CT, for staging the mediastinum for cancer would vary. Thus, the specificity of PET for assessing mediastinal lymph nodes may be much lower in areas of the world with endogenous TB than in developed areas without it. Therefore, an imaging test that is very useful in one part of the world may be far less useful in another part of the world. A highly specific test has a low frequency of false-positive results (i.e., a low frequency of a positive test results in the patient population that does not have the disease). The ideal imaging test has both high sensitivity and high specificity, although none of our current imaging tests have perfect sensitivity and specificity.[2]

Accuracy of Imaging

For detection of disease, a binary, yes-or-no answer as to whether disease is present or absent is desirable. When such binary answers can be provided, it is simple to mathematically provide an accuracy value for a diagnostic imaging test. Thus, accuracy is 

A highly accurate test is one with a low prevalence of false-positive and false-negative results.

Positive and Negative Predictive Values

Sensitivity and specificity define a test reasonably well, but its performance in a specific patient is affected by the characteristics of the population from which the patient is drawn. A physician normally wants to know whether an individual patient has cancer and whether the tumor is localized or metastatic. The correct answer is binary in most cases, but imaging does not always reveal the true status of the individual patient. Thus, the statistical likelihood of the accuracy of the result might be conveyed in the clinical imaging test report. This statistical likelihood will be related to the accuracy of the test as well as to the patient population characteristics. Thus, the positive predictive value often is of considerable clinical relevance. For example, the positive predictive value of a test with 90% sensitivity and 90% specificity will vary markedly, depending on the frequency of disease in the population. With these test performance characteristics, the clinician could reach two different conclusions regarding the same imaging test.

Thus, a test that is effective in a patient population with a high prevalence of a disease may be far less valuable in a patient population with a lower prevalence of the same disease, because there would be far too many false-positive results. The most effective use of imaging technology is in groups of patients in whom the imaging characteristics are expected to be robust enough to allow for predictions in individual patients. These challenges are particularly apparent when a test that was developed in a patient population with disease is used to evaluate individuals with a low prevalence of tumor (i.e., screening). In this situation, the number of false-positive findings may rise dramatically, sometimes nearly completely negating the value of the test.[4]

Receiver Operator Characteristic Curves

Cancer imaging tests are interpreted by imaging specialists, often radiologists. As with all of medicine, there is considerable science involved in image interpretation, but the human element, or “art,” as it is referred to in some settings, also is involved. In developed countries, medical specialty boards have been established to ensure that practitioners have a basal level of training and knowledge, thereby providing some level of uniformity to image interpretations. However, even with board certification and extensive training, not all imaging specialists interpret a given imaging study in the same manner. Thus, although the goal of an imaging test often is a simple binary “yes, there is tumor” or “no, there is not tumor” answer, there are varying degrees of certainty in the interpretation of an image in most instances. Some readers read with high sensitivity, whereas others read with high specificity. Unless a test is very robust, it is hard to achieve both high sensitivity and high specificity.[5]

An example of a receiver operator characteristic (ROC) curve is shown in Figure 21-1 . This set of curves reflects the performance of PET imaging in detecting axillary metastases in patients with newly diagnosed breast cancer. The axes of the curves are the true-positive fraction (sensitivity/100), which forms the y-axis, and the false- positive fraction (1 - specificity/100), which forms the x-axis, on a scale of 0 to 1. A perfect diagnostic test would yield no false-positive or false-negative results. The greater the area under an ROC curve, the greater the accuracy of the test. The results shown in the figure are from three readers who graded PET scans using a five-point certainty scale (i.e., not a simple yes/no, but a continuum from definitely abnormal to definitely normal). The three readers had similar ROC curves, indicating that they were of generally comparable accuracy. For the same test, however, two readers may be reading at different points on the ROC curve, meaning that one is more sensitive and one is more specific, but both are of equal accuracy. An excellent reader may have a greater area under the ROC curve than a less skilled reader, meaning that the more experienced (and more capable) reader is both more sensitive and more specific than a less experienced (and less capable) reader. Nonetheless, virtually none of our imaging tests is perfect, and varying “cut points” between disease and normalcy often are made, affecting the overall performance of the test. In this study, the area under the curve (AUC) of 0.7 to 0.76 was not viewed as sufficiently good for the task of nodal detection of metastatic cancer spread to the axilla. Despite this, a very high sensitivity or a very high specificity can be achieved depending on which part of the curve one operates in. A higher, hypothetical curve, with an AUC of 0.9, is shown for a more robust test, such as a higher-resolution PET system devoted to imaging the axilla. In practice, sentinel node sampling, often guided by imaging or a radionuclide-sensitive probe system, is assuming a very important role in this area of tumor staging.[6]

 
 

Figure 21-1  Receiver operator characteristic (ROC) curves plotting the true-positive fraction (TPF) [sensitivity] vs. the false-positive fraction (FPF) [1 - specificity] for the three independent readers of the entire analysis data set. A hypothetical curve for the test if it had 95% accuracy also is shown. Az, estimated area under the ROC curve.

 

 

Other Approaches to Assessing the Value of Imaging

Although sensitivity, specificity, and accuracy commonly are used to characterize the tumor detection process, other metrics may be of greater importance. For example, some studies have focused on how often imaging substantially changes management. This kind of study is of great practical interest, but the optimal methods to assess such changes in treatment decisions are evolving. Ideally, one would like to show that the use of imaging, especially a new imaging technology, when applied randomly to half of the study population, provided a reduction in the number of adverse events in the imaged population or improved survival. As an example, a reduction in the number of “futile thoracotomies” has been used as a metric of success for PET vs. CT in planning the treatment of newly diagnosed lung cancer.[7]Ideally, randomization of patients to imaged versus not imaged groups can be shown to improve survival. However, performance of randomized trials in which half of the patients undergo imaging and the other patients do not (or they obtain different kinds of imaging), with an endpoint of survival, will be of great interest. Unfortunately, such studies are complex because management of patients after imaging may be altered markedly based on the imaging results. Thus, it can be difficult to separate the imaging study effect from the treatment effect. Ultimately, however, for some imaging studies to be adopted, such evaluations of survival will be needed. This point is particularly relevant to screening, as discussed later.

Screening Concepts and Challenges

Screening programs for cancer often have taken the form of laboratory tests such as the Papanicolaou (Pap) smear, or, more recently, blood tests for tumor markers. The success of the Pap smear in reducing societal mortality rates from cervical cancer is incontrovertible. The use of imaging in screening for cancer is an example of success and considerable interest, but also a source of considerable controversy. As discussed in detail in the chapter on breast cancer (see Chapter 95 ), screening mammography programs have been shown to be capable of saving lives in women older than 50 years of age. These programs also may save lives in women 40 to 50 years of age, but the data are less compelling.[8]

Studies have been initiated in which CT scanning is used in an attempt to detect early lung cancer.[9] Screening high risk populations with CT imaging has not yet been proven to affect mortality. However, the Early Lung Cancer Action Project (ELCAP), a large study screening patients at increased risk of lung cancer with low-dose CT, reported promising results in 1999.[10] Preliminary results from that trial showed that lung cancers are detected at a smaller size and that patients whose cancers are detected by screening live longer following diagnosis than patients whose tumors are not detected by screening. Whether this turns into longer-term survival for the screened population remains unclear. The ELCAP study further evaluated 31,567 asymptomatic persons at risk for lung cancer using low-dose CT from 1993 through 2005, and from 1994 through 2005; 27,456 repeated screenings were performed.[11] A diagnosis of lung cancer was made in 484 participants based on screening. Of particular note, 412 patients (85%) had clinical stage I lung cancer. Ten-year survival approached 90% in this group. [10] [11] This study clearly demonstrated that annual spiral CT screening can detect lung cancer that is curable. Another large randomized trial of lung cancer screening currently is underway in which both CT scanning and chest x-ray screening are used. This trial has raised some controversies, because many small pulmonary nodules are identified that are not malignant, the costs of the trial as well as of the medical care for incidentally detected lesions are substantial, and a substantial radiation burden, which, in principle, could be carcinogenic, is delivered to patients receiving the screening. However, there is considerable hope that screening programs can achieve a reduction in lung cancer mortality. For example, as discussed later in this chapter, CT colonography holds excellent promise as a screening method for colon cancer, as an alternative to optical colonoscopy.

Other areas in which screening by noninvasive imaging has been performed include colorectal cancer, where virtual colonoscopy can be used to look for early colon cancers, and in the pelvis in women who are at risk for ovarian cancer. More recently, screening CT centers offering a virtual evaluation of the entire body have become available, and even more recently, MRI and PET screening have been offered in some locales. The growth of these centers has been driven emotionally and economically; these tests are not yet well-founded scientifically in the screening setting.

Screening carries challenges, risks, and costs that are beyond the scope of this overview chapter. However, several key points apply to all screening approaches, including those using noninvasive imaging. These points include (1) whether a screening program is reasonable to consider; (2) lead time bias; (3) length bias; and (4) the overall cost implications of screening, especially the costs of investigating false-positive results.

The requirements that a screening program must meet to be considered “reasonable” may differ substantially based on the specific society's values and a specific individual's perception of risk. However, in general, the following characteristics are important for cancer screening:

  

   

The cancer must have a considerable public health effect.

  

   

The disease must have an asymptomatic period in which detection by imaging is possible.

  

   

A therapeutic intervention that can lead to better survival or quality of life must be available.

  

   

The prevalence of the disease must be sufficient in the population being screened to justify screening (especially the cost).

  

   

Medical, surgical or other treatment must be available for the early-stage cancer identified by screening.

  

   

There must be a high likelihood that the patients in whom early cancer is identified by image-based screening will go on to have a suitable therapeutic intervention.

Further, the imaging test itself must be acceptable to patients (in terms of level of discomfort and cost), and it must be sufficiently sensitive to identify cancer often and sufficiently specific to minimize false-positive results. Finally, the costs of the screening process must be compatible with the society's or the individual's economic system, and the screening procedure must pose little or no risk to the patient.[4]

Another important consideration in screening programs is lead time bias. This concept, simply stated, indicates that if the natural history of a disease is unchanged, but the diagnosis is made earlier in the course of the illness, the apparent survival will be improved. For example, let us assume that tumor X has a 6-year natural history from its beginning until the death of the patient, and that treatment was ineffective. The disease might become clinically detectable after 4 years and lead to death in 6 years, a 2-year survival after diagnosis. With screening, if the tumor is detected 3 years after the onset of disease and no improvement in treatment occurs, then the survival in the screened population would appear to increase from 2 to 3 years after diagnosis. This illusion of improved survival in the screened population is a considerable concern and can lead to inappropriate enthusiasm for screening programs.[4]

Another important consideration in screening is the possibility of length bias. This is a more complex concept, but it may be related to the types of cancer that can be detected by screening programs. A possibility is that very rapidly growing and presumably highly lethal cancers are less likely to be detected by annual screening programs, whereas more slowly growing cancers, which have an intrinsically better prognosis, may be detected more frequently by screening. In fact, some of the early cancer discovered may not be biologically relevant at all. If so, the patients with cancers identified in the screened population could appear to have a better survival than the patients with cancers identified in the unscreened population.

A third factor is the selection bias that is difficult to control for in observational studies. Selection bias occurs when there are unintended differences between the groups observed that, while they are associated with the variable used to sort the groups—for example, exposure in case-control studies and outcome in cohort studies—affect measurement of the study variable.[12] For instance, in a case control design on the effects on disease specific mortality of a particular screening program, investigators would look at patients who have died from the disease in question, versus those who have not, then determine the rates of the screening intervention in these two populations. However, it is possible that those likeliest to have sought screening were the ones at highest risk for the disease. Results for the screening's effect on mortality could be underestimated in such a scenario. Selection bias also can work in the opposite direction, where the high risk/poor prognosis individuals are less likely to seek screening. With the relative absence of large randomized prospective trials, as is the case when evaluating imaging as a screening tool, we may be tempted to base our conclusions on cohort or case control studies. However, the most accurate conclusions would be drawn from a randomized study design.

Collectively, lead time bias and length bias and, at times, selection bias, can make screening programs appear to improve the survival of patients with cancer. Because of these major biases intrinsic in screening, very large, randomized, studies are required to show that overall cancer-specific mortality (and ideally mortality from all causes) declines as a result of screening programs.

The advent of imaging and other screening tools that uncover a tumor long before it is symptomatic also brings up the need for biomarker discovery to help physicians to determine whether to treat what has been discovered through screening. The experience with prostate specific antigen (PSA) screening in prostate cancer serves to illustrate the point that not all cancers identified by screening eventually lead to death. Discovering and validating biomarkers that can help to distinguish reliably between lethal and nonlethal tumor types will be of great help in reducing unnecessary treatment in patients with less active disease.

Screening Costs

The determination of whether a screening program is valuable is based on its cost and benefit. The concept of quality-adjusted life-years (QALYs) often is applied. This concept is defined as the economic cost to society required to result in 1 additional year of quality life for a member of the society. In many western countries, a figure of $50,000 has been considered a useful guide, with QALYs lower than this amount considered cost-effective. Such a guideline, however, does not necessarily apply when individuals make their own determinations as to whether to pay for a screening test. For example, it is reasonable to expect that those with greater disposable income would be willing to pay more per QALY than those with less disposable income. Thus, it can be difficult to generalize about the cost efficacy of screening procedures.[13]

Even when people choose to undergo a screening test at their own expense, considerable costs can be transferred to society as a result of the screening program. For example, if a screening test has a high rate of false-positive results, a substantial number of follow-up biopsies or procedures will occur and can cost a great deal of money. Such costs can dramatically raise the total cost per QALY. Particularly invasive procedures also can increase the likelihood of morbidity or death as a result of additional investigations. To determine the true cost per QALY associated with screening, these additional costs and risks must be considered. Thus, screening remains an area of great promise, but also of considerable controversy. Screening beyond breast imaging must overcome major hurdles before it is likely to be accepted. It is quite possible, however, that in high-risk patient groups, such as those with a family history of cancer or major carcinogen exposure, with a high penetrance or of early onset, that screening may prove of greater value than in the general population.

Size of Detectable Lesions

Noninvasive imaging methods in humans cannot detect and localize a single malignant cell, although flow cytometric methods are very sensitive for finding a very few cancer cells in a patient's blood. Imaging methods are improving, however, and detection of a much smaller number of cells is possible in small animal models. However, it has been estimated that by the time a tumor reaches 3 to 5 mm in diameter, which is the lower limit in size for detection by the best current noninvasive methods in humans, the tumor has undergone more than 25 doublings and contains 0.1 to 1 billion cells, depending on their size.[1] In contrast, a cytologist, on a very good day, may be able to identify a single cell as malignant using a microscope.

Realistically, even for histologic assessment of malignancy, typically a group of tumor cells must be present before cancer is diagnosed. However, light microscopy and more sensitive techniques such as immunohistochemistry and polymerase chain reactions mean that pathologic techniques potentially will be more sensitive than imaging methods. One very important proviso is that for pathologic methods to be effective, actual examination of the malignant cells is required; the sample containing the tumor must be cut appropriately and viewed under a microscope. This task may be impossible, because the 8-mm sections that are used for pathologic examination typically are taken only from a small portion of a tumor or lymph node, whereas most of the tumor or node will be unexamined (e.g., to assess a 1-cm node using 8-mm-thick sections, approximately 125 sections would be required). This large number of sections is not typically obtained. Despite the markedly superior sensitivity of histologic methods over noninvasive imaging, there is a major sampling error issue, and, paradoxically, imaging in some diseases potentially may be more sensitive than histologic examination for cancer. This situation can arise in mammography, where small tumor foci can be seen on the mammogram but can be missed on cytological sampling, possibly due to sampling error. When tumors are imaged by noninvasive methods, the entire tumor is visualized, not just a small portion. So, paradoxically, imaging, despite limited resolution, can be more sensitive than cytology or pathology. However, if exhaustive and thorough sampling is performed, with microscopic examination of tissue, there usually is greater sensitivity for tumor than there is with current noninvasive imaging techniques.

Stage Migration

One of the major goals of noninvasive imaging is to stage the tumor precisely to allow the clinician to best choose treatment and determine the prognosis. The evolving concepts of tumor staging are discussed elsewhere in this text, but improvements in detection technology can change the understanding of the natural history of a given stage of disease. Patients with small or microscopic metastases to the mediastinum are likely to do better than patients with bulky metastases, but both may have the same stage of disease. As the sensitivity for detecting small lesions improves, it becomes possible to identify more patients with small primary tumors and small metastases to the lymph nodes or systemic disease. Thus, when primary tumors are detected at ever earlier and less advanced stages as imaging methods improve, patients are assigned to a higher stage than was used historically. Their presence in the advanced-stage group appears to improve survival and outcome in that group. Moreover, the outcome of the lower-staged group also may improve because a subset of patients with now-detectable tumors has been removed from that group. The outcome of the overall group will not have changed. Thus, one has to be very cautious in extrapolating historical survival data based on an insensitive staging method with that seen with a more sensitive method.[4]

MAJOR IMAGING MODALITIES

Broadly stated, cancer imaging can be performed using anatomic or functional imaging methods.[1] The traditional imaging of the patient with cancer, and the most established methods, are based on anatomic imaging. However, interest is increasing in more functional methods in cancer imaging. Further, several anatomic imaging methods offer functional components that complement the anatomic method. Hybrid images, derived from and displaying both functional and anatomic data, also are becoming more widely available, often coming from the same hybrid imaging machine. [14] [15] Imaging data are increasingly digital or digitized and suitable for postprocessing and image exchange. The major imaging modalities are discussed in the following section.

Plain Film X-Rays

The traditional x-ray remains an important part of cancer imaging. It commonly is used to detect bone tumors and can be used to detect lung cancers in the thorax. The method displays mainly water and calcium density and is affected by overlapping tissue in front of or behind the lesion. X-rays have become increasingly digitized in the last few years, with the introduction of film digitization and phosphor screen capture devices. X-rays offer exceptional resolution, but provide relatively little image contrast if there is not much calcium present. The radiation dose from a plain film x-ray depends on which portion of the body is being examined. In most centers, plain film radiographs for cancer management are being used less often, with CT scanning increasingly replacing radiographs in the abdomen and MRI in the brain and extremities.[16]

Mammography

Mammography is a specialized form of plain x-ray. Very high-resolution images of the breast are obtained using specialized devices optimized for breast cancer detection. Digital mammography is now available, and offers greater flexibility of image display because of the digital image format. A limitation of the digital format, however, is the field of view of the imaging phosphor, which may be too small to fully include some breast tissue. In the last several years, there has been a major shift toward digital mammography. The recent Digital Mammographic Imaging Screening Trial (DMIST), which included nearly 50,000 women, showed comparable overall accuracy between film screen and digital mammography in the overall study. A higher accuracy for cancer detection in women under 50, women with radiodense breasts, and pre- and perimenopausal women was seen with digital mammography as compared with film-screen mammography.[17] Despite this higher accuracy, the reported sensitivity for both techniques for cancers was only 41% with a positive predictive value of 12%, albeit with 98% specificity. This is far from ideal performance for a screening test. The move to digital mammography is in part to increase diagnostic accuracy but also to allow digital images to be viewed on picture archiving and communication system (PACS), as is the case with virtually all other diagnostic imaging methods in more and more imaging centers. [17] [18] A newer technique, tomosynthesis, is under evaluation in which a number of “slices” of the breast are generated during a mammographic image acquisition. This approach offers considerable promise going forward, but is early in its evolution technically.

Computed Tomography

CT is now established as the dominant imaging technique for cancer detection and follow-up. Currently, tumor response and staging criteria very commonly are based on tumor size as measured on CT. CT scanners acquire images using an x-ray source and digital detector elements. The x-ray source rotates rapidly around the patient, commonly with a single scan level taken in 0.5 seconds or less. Faster and faster rotation speeds of the scanners, along with multiple simultaneous detectors capable of imaging multiple slice thicknesses in a rapid spiral motion, are being used. Scanners with 16 and 64 simultaneous slices are commonly in use, with scanners with 256 slices now in use in some devices. Large-field-of-view detectors may allow even more of the body to be evaluated nearly instantaneously. Current fast scanners can potentially evaluate the entire body in a fraction of a minute. Although such evaluations provide key information about lesion size, some lesions may elude detection unless contrast medium is given intravenously, orally, or both. With such devices, it also is possible to capture contrast in arteries or veins to provide superior visualization of these structures, which can then be displayed three-dimensionally or in a volume-rendered fashion. While more slices in a CT scanner make for faster CT scans, it is not clear that having more slices always results in a superior diagnostic quality scan. More slices and faster scans do mean that whole-body scans in a single breath hold can be obtained, which is advantageous, because it can reduce the frequency of breathing artifacts. A clear disadvantage of CT is its cost, both technically and in terms of the radiation dose. In the past several years, increased concern has developed regarding the total radiation dose being delivered by CT, particularly in children, due to the potential risks of carcinogenesis. Although CT is an exceptional technique, it remains a predominantly anatomic imaging method. While there is information in the timing of IV CT contrast enhancement, it is not easily extracted without a substantial radiation dose from repeated images. Thus, only a limited number of post-IV contrast images are obtained with CT, to limit radiation dose. All CT images are digital. A major challenge with CT is the large amount of image data generated for analysis, data that can take the radiologist a long time to interpret fully.[19]

Angiography

Historically, angiography has been performed after intravascular insertion of catheters into arteries, followed by rapid injection of iodinated contrast media, along with rapid-sequence filming of the images. The improving ability of rapid-sequence CT scanning to show the vascular anatomy (CT angiography) has caused it to rapidly replace angiography for diagnostic purposes. Angiography still can be used to produce the most precise maps of vascular anatomy before organ transplantation or radical cancer surgery. Most angiography now is performed using digital image-capture devices, known as digital angiography.

Angiographic delivery of therapy is, however, an important area. This form of imaging can allow for therapeutic delivery of embolization materials such as coils, delivery of chemotherapeutic agents regionally, or delivery of radioactive microspheres, for example.

Angiography has high resolution, but typically delivers a high dose of radiation energy to the patient. The use of angiography remains essential for studies to evaluate GI bleeding, but with CT angiography continuing to improve in quality, the use of diagnostic angiography has become less frequent in routine clinical practice.[20]

Ultrasound

Ultrasound uses reflected beams of high-frequency sound rather than ionizing radiation to generate images. Ultrasound provides high resolution and some functional information, specifically about the presence and direction of blood flow in tissues. It also provides some information regarding tissue characterization properties, and is very effective in determining whether a tissue is cystic or solid. The method also is excellent for detecting vascular structures and determining extent of flow. Ultrasound provides real-time imaging capability to guide biopsies and procedures effectively. Ultrasound is less effective in the evaluation of deeper structures, and requires access to a sonographic window. Thus, it has only a modest role in evaluating deep abdominal structures. Ultrasound is used commonly in evaluations of the pelvis, neck (including the thyroid), and gallbladder and liver areas. Agents that can enhance the visualization of vessels or can be specifically retained in clots are under evaluation, suggesting that ultrasound can offer some functional information beyond the purely anatomic.[21]

Ultrasound contrast agents are being applied to a limited extent. Currently, these agents are mainly for intravascular use. High-energy focused ultrasound remains under development as a tool to ablate, or at least deliver thermal energy to, tumors with therapeutic intent. Ultrasound coupled with needle aspiration biopsy has been used in some settings as a minimally invasive procedure to characterize nodal metastases. Ultrasound combined with mammography also is being evaluated as a screening method for breast cancers, but results in high-risk patients have shown disappointingly low detection rates relative to MRI.[22]

Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy

In many clinical settings, MRI, as applied in imaging for most cancers, is used predominantly as an anatomic imaging method that does not use ionizing radiation. MRI offers superb contrast resolution between tissues and excellent spatial resolution. MRI also offers a variety of forms of functional information. However, it does not offer the level of temporal resolution, in general, seen with ultrasound, fluoroscopy, or recent-generation, multiple-slice CT scanners. However, MRI technology has moved forward inexorably, and rapid-pulse sequences allowing gating of images now are available for several types of scanners. MR images can be of a variety of pulse sequences, allowing visualization of several parameters. However, visualization of hydrogen nuclei is the major approach with conventional 1.5T and 3T (Tesla) machines. Visualization of blood, especially with contrast materials such as gadolinium chelates, and of altered vascular permeability is routinely applied.[23]

MRI is the preferred procedure in evaluating neoplasms of the brain and spinal cord regions as well as musculoskeletal tumors. MRI also is being used with increasing frequency in the evaluation of tumors of the extremities, such as sarcomas. With gadolinium contrast enhancement, MRI also can be useful in locating tumors of the breast, which appear as areas of contrast enhancement. Such studies have shown the higher sensitivity of MRI versus mammography. However, there remain concerns that MRI may achieve this sensitivity with an accompanying relatively high false-positive rate, depending on the methods used for interpretation. Still, MRI probably is our most accurate technique for detecting and characterizing breast masses. MRI also can provide valuable information about tumors in close proximity to vascular structures as well as in the liver and upper abdomen. Tumors in the upper abdomen and liver can be degraded in their appearance on MRI because of respiratory motion artifacts. Therefore, this approach is applied less commonly than in other situations, such as in the lower pelvis, where there often is less respiratory motion artifact. Research currently is working on developing agents that can facilitate specific MRI contrast enhancement. More rapid whole-body MRI acquisition methods also are under evaluation, which may broaden the use of MRI.

In magnetic resonance spectroscopy (MRS), tissue characterization can be achieved by sampling its magnetic spectrum at 1.5T. Some devices now provide a 3T or higher field strength signal for evaluation, offering the possibility of more refined tissue characterization. Opportunities to detect increased content of choline (often increased in tumor foci) versus other substituents can be helpful in separating tumor from nonmalignant tissues in the brain and elsewhere. Spectroscopy also can provide information on lactate concentration and pH, among other parameters. A limitation of spectroscopy is resolution, which typically is not nearly as fine as that of MRI itself. Thus, spectroscopy has only limited application in most oncologic practice.[24]

Recently, diffusion MRI has shown promise in tumor response assessment. This depends on the freer movement of nuclei in areas of necrosis as compared with the motion of nuclei in fully viable tumors. This technique is demonstrating considerable potential for response assessment in brain tumors and recently has shown promise in tumors in the bones.[25]

Nephrogenic systemic fibrosis (NSF) recently has been linked to Gd-containing MRI contrast agents.[26] This condition has been described in patients with substantially impaired renal function who receive MRI contrast intravenously. “Black box” warning labels now appear on the product inserts for MRI, and we are seeing increased use of alternative imaging methods to MRI in patients with low creatinine clearance rates followed by sequential imaging studies. Gadolinium may be responsible in part for this process as it has been found in the skin of some of such affected patients. [27] [28] In 2007, black box warning labels were added to the package inserts related to Gd-containing MRI contrast ( Box 21-1 ).

Box 21-1 

FDA BLACK-BOX WARNING REGARDING GADOLINIUM MRI CONTRAST MEDIUM

Warning: Nephrogenic Systemic Fibrosis

Gadolinium-based contrast agents increase the risk for nephrogenic systemic fi brosis (NSF) in patients with

  

   

Acute or chronic severe renal insuffi ciency (glomerular fi ltration rate <30 mL/min/1.73 m2)

OR

  

   

Acute renal insuffi ciency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.

With these patients, avoid the use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with noncontrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fi brosis affecting the skin, muscle, and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a suffi cient period of time for elimination of the agent from the body prior to any readministration (See WARNINGS).

An exciting area of application of MRI technology is in the field of whole-body MRI. Such a test may begin to offer whole-body cancer surveys with no ionizing radiation delivered to the patient. Such applications to date have been less sensitive than whole-body PET imaging, but this area is emerging very rapidly[29] (Figs. 21-2 and 21-3 [2] [3]).

 
 

Figure 21-2  Representative 64-year-old patient with metastatic disease. A, Tc99m MDP bone scan obtained after injection of the istotope 21 μCi. The bone scan demonstrates multiple areas of increased uptake in the calvarium, sternum, ribs, vertebra, pelvis, and femur. Degenerative and inflammation changes are noted in the left knee and left ankle (postfracture due to fall). B, Axial diffusion-weighted images (b = 300–600 s/mm2) of corresponding areas of metastatic sites. Note that the sternum metastases are clearly seen, as are those in the rib and femur (arrows). C, Sagittal image showing whole-body coverage.

 

 

 
 

Figure 21-3  This 72-year-old man had colorectal cancer and metastatic disease in the liver. A, Diffusion-weighted images of different b values in the liver. B, Corresponding PET, CT, and PET/CT images.

 

 

Nuclear Medicine and Positron Emission Tomography

Radionuclide methods can provide a great deal of functional information, but the anatomic resolution often is limited. Broadly, there are single-photon and positron-emitting isotopes. Single-photon emitters typically have longer half-lives than positron emitters, and decay in a different fashion, emitting gamma rays. Depending on the ligand attached to the radioactive isotope, a wide variety of processes can be imaged. For single-photon imaging, the most common isotope is 99mTc, which can be used to image bone (bone scan with 99mTc methylene diphosphonate) or thyroid (technetium pertechnetate), for example. With positron emitters, the most commonly used tracer is F18, which is used as the radiolabel for FDG, an agent that images glycolysis in vivo. Because tumors have increased glycolytic metabolism in general, use of this agent in tumor imaging is increasing very rapidly, especially in lung and colorectal tumors and lymphomas.[30]

Both PET and SPECT have very high sensitivity for a small number of radioactive molecules in vivo as well as the ability to quantitate the radioactivity concentration precisely. Thus, these methods are important as both clinical and research tools. The intrin sic lack of anatomic resolution for PET and SPECT can be partly addressed by fusing the PET or SPECT images to CT using computer software. More recently, dedicated hybrid imaging devices, including both PET and CT or SPECT and CT in a single device, have been applied to the imaging practice of cancer.

Higher doses of radioactive isotopes also can be therapeutic. For example, 131I is used for the treatment of thyroid cancer, as sodium iodide. The same isotope, conjugated to an anti-CD20 monoclonal antibody, has been approved by the U.S. Food and Drug Administration to treat low-grade and transformed β-cell non-Hodgkin's lymphoma that is considered refractory to standard treatments. The tracer doses are used to guide the treatment doses in such instances or at least to determine if the radioantibody has any unexpected targeting behavior.[31]

Optical Imaging Methods

Optical imaging methods are applied in a variety of ways. The external physical examination of a patient involves visual interrogation of reflected light. Infrared and transmitted light also are used to a limited extent in evaluating small parts of the body. Optical imaging has been limited in clinical deployment by the limited penetration depth of a variety of forms of light in the body. Thus, this type of approach may prove of greatest utility in evaluating small animals as part of experimental studies, or for superficial organs, such as the breast. Similarly, the technique may have greater utility in evaluating intraoperative procedures. The possibility of constructing light-emitting contrast media is a real one, and optical imaging has the potential to provide remarkable sensitivity and resolution in superficial structures. However, it is not routinely applied in cancer imaging, with the exception of visualization of the interior of the eye, visualization of the cervix, and endoscopy from above and below.[32] The strengths and weaknesses of the major imaging methods are contrasted in Table 21-2 .


Table 21-2   -- Imaging Methods

Modality

Resolution

Sensitivity

Specificity

Functional Imaging Ability

Magnetic resonance imaging

1–2 mm

Moderate

Moderate

Moderate with spectroscopy

Computed tomography

1–2 mm

Moderate

Moderate

Low, except angiography

Radiographs

1–2 mm

Low

Moderate

Very little

Single-photon-emission computed tomography

1 cm

High

Moderate

Excellent

Positron emission tomography

5 mm

High

Relatively high

Excellent

Ultrasound

2 mm

Low

Low

Some, especially with contrast

Mammography

1–2 mm

Moderate

Relatively low

None

Angiography

1–2 mm

Moderate

Moderate

Low

Bragg DG, Rubin P, Hricak H: Imaging strategies for oncologic diagnosis and multidisciplinary treatment. In Bragg D, Rubin P, Hricak H (eds): Oncologic Imaging, 2nd ed. Philadelphia, WB Saunders, 2002, pp 3–20.

 

 

ANATOMIC VERSUS FUNCTIONAL IMAGING

Limitations of Anatomic Imaging of Cancer

Anatomic imaging has been the fundamental approach to cancer imaging for more than 100 years. These methods are quite robust, as is supported by their daily use in managing individual patients with cancer. Anatomic imaging normally detects a phenotypic alteration that is sometimes, but not invariably, associated with cancer—a mass. However, with anatomic imaging, we often do not know whether masses are the result of malignant or benign etiologies, as in solitary pulmonary nodules or borderline-size lymph nodes. Similarly, small cancers are undetectable with traditional anatomic methods, because they have not yet formed a mass. After surgery, it is even more difficult to assess for the presence of recurrent tumor with anatomic methods. Post-treatment scans are complicated by the need for comparisons with normal anatomy to detect altered morphologic findings as a result of cancer. Anatomic methods do not predict the response to treatment and do not quickly document tumors responding to therapy.[33] Despite these challenges, anatomic images remain routine in cancer management. PET, a functional imaging method, helps to address many of the limitations of anatomic imaging, and when combined with anatomic images in fusion images, is emerging as a particularly valuable tool, providing both anatomic precision and functional information in a single image set.[4]

Molecular and Functional Alterations in Cancer

The molecular bases of neoplasia are increasingly well defined. Mutations in genomic DNA precede the development of overt neoplasia.[34] With sufficient alterations in genotype, phenotypic changes occur. These genotypic and phenotypic changes in cancer antedate the development of a discrete mass lesion, and represent potential targets for innovative imaging agents. The concepts of altered “genome,” “proteome,” and “methylome” resulting in alterations in metabolism, consistent with an altered “metabolosome,” are increasingly recognized as present in cancers. PET, because of its superb sensitivity to low signal levels, can detect signals from tracers, targeting such alterations that are preferentially present in cancer.

PET has led the growing field of molecular imaging to the clinic, in part because of the quantitative capabilities of PET and the sensitivity of electronic collimation, but also because of the choice of a proper radiotracer for cancer imaging. Although a wide variety of molecular, proteomic, and metabolic alterations occur in cancers, and many of these can or ultimately may be imaged with PET, the most useful target in the clinical practice of PET is the increased glucose metabolism present in most cancers. Other PET tracers, such as those targeting hypoxia, proliferation, amino acid transport, blood-brain barrier permeability, and protein synthesis, are discussed in the following sections. The challenge with all imaging modalities is how best to integrate them into clinical practice. The next section addresses these issues.

DISEASE-SPECIFIC IMAGING RECOMMENDATIONS

Brief discussions of the role and possible role of imaging in managing several common cancers follow. There is great variation in the imaging workup of specific types of tumors, depending on the type of therapy planned.

In general, the more aggressive and radical the planned treatment, the more critical the need is for accurate determination of the location of all foci of tumor through imaging. Similarly, the intensity and frequency of follow-up imaging examinations must be guided by the potential importance of the information gained. For example, if no effective salvage therapy is available, intensive surveillance for recurrent tumor makes little sense, except to provide reassurance to patients when test results are negative. This may seem self-evident, but it is surprising how practice patterns vary. The National Comprehensive Cancer Network recently has published recommendations on imaging approaches in specific cancers. In addition, the American College of Radiology has provided “appropriateness guidelines” for a variety of cancer therapies. These guidelines inherently lag behind devel-opments in technology, but are based on careful analyses of the literature and expert opinion, and thus are worth consulting as they continue to be updated.

Lung Cancer

The initial diagnosis of lung cancer often is based on incidental detection of an abnormality on an imaging study, although more advanced lung cancer can cause hemoptysis, cough, weight loss, hoarseness, infection, or shortness of breath. There has been a great deal of interest in testing screening programs for lung cancer in high-risk groups such as heavy smokers. Both chest x-ray screening and CT screening have been evaluated. Chest x-ray screening has not been proven to be effective at reducing mortality from lung cancer. CT-based screening programs are of greater interest, and it is clear that these programs can detect lung cancers at an earlier stage, when they are smaller than lung cancers diagnosed by other methods. Patients with such cancers tend to live longer than patients with cancers diagnosed at a more advanced stage. However, detecting additional cancers is dependent upon detection of small lung nodules and many small lung nodules, and most of these are not of malignant etiology. The costs, both economic and in terms of risks from invasive diagnostic procedures, are considerable. In addition, concerns exist that the cancers detected by such an approach may be the more slowly growing cancers. Results from the National Lung Cancer Screening Trial are expected to be forthcoming to help assess this issue in the coming years.

The Fleischner Society has offered guidelines for dealing with small, incidentally detected pulmonary nodules, which involve imaging follow-up for lesions greater than 5 mm in size. Growing lesions require additional investigation.

Certainly, if a solitary pulmonary nodule 8 mm or larger in diameter is identified on a chest x-ray or on screening CT, the workup to determine whether it represents lung cancer can take a variety of forms. Comparison with old anatomic images is essential, but if none are available, a decision must be made whether to perform a biopsy or remove the tumor or follow the abnormality. A variety of factors can be considered, including patient age, smoking history, lesion size, and history of exposure to potential infectious agents.

The morphology of the nodule is investigated to determine whether it has characteristics that suggest malignancy or benignity. The margin and internal density of the lesion are examined. Smooth, well-defined margins suggest a benign nodule, but these also are seen in 21% of malignant nodules.[35] A lobulated margin suggests cells of different lines with uneven growth, but can be seen in 25% of benign nodules. A spiculated margin is highly suggestive of malignancy. Both benign and malignant nodules can be homogeneous and can cavitate. A cavity with a wall thickness of 4 mm or less is likely benign in 95% of cases, a wall thickness of 5 to 15 mm is indeterminate, and a wall thickness of more than 15 mm is likely malignant in 95% of cases.[35] If the lesion contains fat, it is specific for a hamartoma, and 50% of hamartomas have fat on CT.

Benign calcifications are central in the lesion, diffuse and solid, laminated, or popcorn-like. Calcification is seen in 6% of lung cancers on CT, and tends to be eccentric or amorphous.[35] Thus, calcification alone does not indicate benignity in a lung nodule. If contrast is administered and the lesion is monitored over 5 minutes, enhancement of less than 15 Hounsfield units (HU) suggests a benign lesion and enhancement of greater than 20 HU suggests a malignant lesion, with reported sensitivity of as high as 98%, specificity of 73%, and accuracy of 85%.[36] However, these CT criteria rely on very small changes in CT attenuation levels. These subtle changes may be insufficient to allow for reliable stratification of nodules as malignant or benign, because timing of the CT bolus also is an important consideration. The growth rate of the lesion also can be evaluated, but this is difficult for subcentimeter lesions. Computer programs for nodule detection are being developed that also provide lesion volume, and this may prove useful in follow-up.

However, for a significant number of patients, the risk of cancer remains intermediate. For such patients, FDG-PET imaging may be useful. PET has been reported to have sensitivity of approximately 96% for detecting cancer in solitary pulmonary nodules (predominantly ≥1 cm in diameter) in a retrospective meta-analysis,[37] with specificity of approximately 80%. However, some histologies are less well detected, such as those of bronchioloalveolar carcinomas. Nonetheless, the PET scan can help to determine which patients require immediate biopsy or excision of a nodule (i.e., a nodule with intense FDG uptake) versus those who can be observed (some of those with low or no tracer uptake). The use of PET varies widely, but it can be a valuable tool for helping to determine which patients need invasive procedures for pulmonary nodules. Because false-negative findings occur, however, patients who do not have surgery should be followed up regularly for up to 2 years to ensure that there has been no lesion growth. Figure 21-4A shows “hot” and “cold” nodules in the same patient.

 
 

Figure 21-4  A, Images obtained using positron emission tomography (PET) and CT. The upper left image is CT, the upper right image is PET, and the lower left image is a fusion of PET and CT data. The CT scan shows a smaller right apical nodule and a large left upper lung nodule. PET shows increased uptake of 18fluorodeoxyglucose (FDG) in the left apical nodule, consistent with cancer, whereas only minimal uptake is seen in the right apical lesion, consistent with benign disease. Fused PET and CT images confirm the location of increased apical FDG uptake, as in the left lung nodule. B, Whole-body images from PET scans of the patient shown in part A. The images include coronal, sagittal, transverse, and “projection” whole-body views, from left to right. They show cancer in the left upper lung, mediastinal involvement, and a right paratracheal tumor focus. Normal uptake is seen in the heart, brain, and excretory system (bladder).

 

 

Once lung cancer is diagnosed, an appropriate staging workup should be undertaken. The workup for non-small-cell lung cancer often is done to determine whether the patient is a candidate for surgery. Because FDG-PET imaging is at least 20% more accurate than CT imaging, PET is commonly recommended as a staging procedure for the mediastinum and for systemic evaluation for metastases.[38] In a prospective randomized trial, PET reduced the number of futile thoracotomies by half, from 41% to 21%, vs. algorithms in which PET was not performed.[39] This occurred, in part, because remote foci of metastatic disease that were not identified by standard staging methods were identified by PET. Consensus is developing on how PET should be used in staging non-small-cell lung cancer, but many centers routinely perform PET/CT before surgery, with the incremental benefit being most apparent (in terms of detecting additional remote disease from the primary lesion) in patients with larger primary lung cancers. It usually is considered prudent to perform a biopsy on FDG-avid tissues to prove that they represent cancer. Many would argue that mediastinoscopy is no longer essential for patients who have negative mediastinal PET and CT scans, although in some patients, cancer in nodes is detected only surgically. An example of a positive PET scan with ipsilateral and contralateral mediastinal tumor involvement is shown in Figure 21-4B . The role of PET/CT in lung cancer is to provide a thorough whole-body screening assessment.

For mediastinal nodes, a short-axis diameter of greater than 1 cm is considered abnormal on CT. Larger nodes can be reactive, and nodes smaller than 1 cm can contain tumor, leading to sensitivity of 40% to 67% and specificity of 79% to 86% for metastatic disease.[40]

The hybrid PET/CT technology is significantly superior to PET alone for the staging of lung cancer.[41] The best algorithm for staging the mediastinum is evolving, but PET and PET/CT are the most accurate noninvasive methods. Some argue that mediastinoscopy is necessary in each case, however, because PET may produce false-negative results in patients with a low tumor burden, although the negative predictive value of a negative PET scan and a negative CT scan is approximately 95%. Others, however, would argue that patients with a low tumor burden, below the level of detectability with PET and CT, may be suitable candidates for surgery without mediastinoscopy. Positive PET scans for metastases usually require tissue confirmation of the most advanced site of tumor to avoid false-positive imaging findings that indicate a tumor is not resectable. Figure 21-5 illustrates detection of lung cancer on CT and the use of reformatted virtual images.

 
 

Figure 21-5  Lung cancer. A, Axial CT image (lower left) shows a mediastinal mass (arrows) narrowing the airway. Coronal (top left) and sagittal (top right) reconstructed images show narrowing of the airway by a mass (arrows). The virtual bronchoscopy image (lower right) shows an endoluminal view of the narrowed airway. B, Coronal reconstruction of CT data in a different patient shows a cavitating mass in the left upper lobe.  (Courtesy of Dr. Leo Lawler, Johns Hopkins University.)

 



MRI with contrast is recommended for imaging the brain. It usually is performed if patients have larger primary tumors or any symptoms that suggest central nervous system involvement, although in some centers, MRI with contrast is performed in every patient with lung cancer in whom resection for cure is planned. Evaluation for bone metastases currently is performed by bone scan. Any patient with bone pain or an elevated alkaline phosphatase level should undergo this study. In practice, where PET is available, bone scans are increasingly being replaced by PET scans. This area is evolving, and the bone scan remains the routine procedure in most centers when bone metastases are suspected, but FDG-PET can detect lung cancer metastases to bone that are not detected on CT alone.

In institutions where PET is not available, bone scan, MRI of the brain and CT of the chest and abdomen, to include the adrenals, are recommended. The abdominal CT should be performed with contrast to best evaluate the liver. Figure 21-6 shows extensive mediastinal disease and liver metastases on CT. In some centers, PET and diagnostic quality CT used together provide sufficient diagnostic information that no additional studies are required.

 
 

Figure 21-6  Lung cancer. A, Axial CT scan of the chest with IV contrast shows a mass obstructing the right upper lobe bronchus. B, CT scan of the abdomen shows a metastatic hypodense lesion in the left lobe of the liver.

 

 

For small cell lung cancer, it must be determined whether the disease is extensive or localized before the form of therapy can be decided upon. CT is essential for the chest and upper abdomen. MRI of the brain typically is performed, and a bone scan is done to search for bone metastases. PET scans have been shown to upstage about 10% of patients with limited stage small cell lung cancer to extensive disease and to find lesions not identified by CT. FDG-PET identifies essentially all lesions detectable with CT.[42] Thus, many centers are using FDG-PET more routinely for this type of staging. PET also is useful in the evaluation of small cell lung cancers and mesotheliomas, although the data are evolving, and CT is the established method for this type of evaluation. For follow-up of lung cancer, the guidelines are more challenging because the available therapeutic options often are more limited. PET has a growing role because it can better separate residual scarring from viable tumor than can CT.

Evaluation of the Adrenal

Adrenal masses occur in approximately 9% of the population. These masses can be benign adenomas, metastatic disease from primary tumors such as lung cancer, or primary adrenal cortical carcinoma. CT and MRI are used to distinguish adenomas from malignant lesions in the adrenals. Adrenal adenomas have low attenuation on noncontrast CT as a result of elevated lipid content. If a threshold value of 0 HU is used, sensitivity is 47% and specificity is 100% for the diagnosis of adenoma.[43] If a threshold value of 10 HU is used, sensitivity is 71% and specificity is 98% for the diagnosis of adenoma.

Adenomas take up contrast material, but the washout of contrast material from an adenoma is faster than from a metastatic lesion. On 10-minute delayed images obtained after contrast injection, a decrease in the density of the lesion greater than 50% is specific for an adenoma.[43] If the lesion is atypical on CT, chemical shift imaging on MRI is used to determine whether it is an adenoma. An adenoma has both lipid and water content, and decreases in signal are seen on out-of-phase T1-weighted images. PET has a growing role in evaluating the adrenals, with accuracy of 90% and greater reported in some series. High FDG uptake typically is seen in metastases to the adrenal. Caution is in order, however, in that some adrenal adenomas can have moderately high FDG uptake. Figure 21-7 illustrates detection of adrenal and systemic metastases on CT and PET.

 
 

Figure 21-7  PET and CT image panel shows a variety of PET, CT, and fused images that show diffusely metastatic lung carcinoma. Notable are adrenal metastases that are best seen on the transverse images, although many metastases are visible in a variety of locations. This figure also shows the multiple types of images available from a PET and CT system.

 

 

Breast Cancer

Mammography is the major imaging tool in breast cancer, allowing for early detection of tumors. When properly used, mammographic screening programs have been shown to save lives when compared with unscreened populations, and these programs are routinely implemented in many countries.[44]

Although mammography is a reasonably sensitive and specific procedure, the relatively low prevalence of cancer means that many image-directed biopsies show no tumor; thus, the results of the mammogram were falsely positive. Stereotactic biopsy devices have greatly facilitated nonsurgical breast biopsies. Although the sensitivity of mammography is generally considered “good,” an overall sensitivity of less than 50% was seen for x-ray mammography in the Digital Mammography Imaging Screening Trial (DMIST). Even though this can be improved upon through the use of digital rather than film screen mammography, these results indicate clearly that mammography is far from perfect as a screening tool. Early efforts with tomosynthesis of the breasts, a mammographic method that provides a number of “slices” of the breast for analysis, are promising.[45] This approach can help remove overlying structures from the breast image, potentially improving lesion detection. It also is possible that use of IV contrast may enhance mammographic results.[46] Although other techniques can detect breast cancer, only ultrasound is used fairly commonly in most imaging centers to help to separate cystic from solid lesions or to help to locate and evaluate palpable but mammographically negative lesions. MRI with gadolinium contrast is used because it is a very sensitive technique and can help to determine whether disease is unifocal or multicentric. An example of a positive mammogram is shown in Figure 21-8A .

 
 

Figure 21-8  Breast cancer. A, Mammogram of the right breast shows cancer. B, Axial CT image shows an irregular soft tissue primary mass in the right breast in a different patient. C, Axial CT image with a lung window shows a metastatic nodule in the right lung.  (A, Courtesy of Dr. Nagi Khouri, Johns Hopkins University.)

 



MRI has been evaluated as a tool for characterizing substantially abnormal mammograms or ultrasounds. The prospective multicenter NIH-sponsored trial of 821 patients referred for breast biopsy for American College of Radiology category 4 or 5 mammographic assessment or suspicious clinical or ultrasound findings were studied by MRI and showed an AUC of 0.88 in a population with 404 cancers present, with dichotomized data demonstrating sensitivity of 88% and a specificity of 68%. The positive predictive value was about 72%. The high sensitivity was still insufficient to obviate the need for biopsy in these patients, however.[47] Recently, MRI has been found to detect breast cancer in the contralateral breast of women with newly diagnosed primary breast cancers in approximately 3% to 4% of cases.[48] These additional cancers are found at a rate of about 25% in the lesions identified in this manner (i.e., 75% of the biopsies are negative). In addition, MRI has been used to screen high-risk women (e.g., those with the BRCA1 or 2 mutations) for breast cancer to some advantage. This higher sensitivity comes at the cost of more false-positive results and challenges in biopsy, which have limited deployment of the method. However, increased uniformity of reporting and greater similarities in technique are leading to more use of this methodology, which recently has been comprehensively reviewed.[49] PET methods occasionally are applied in the breast, but they are used for diagnosis infrequently due to the low sensitivity of whole-body PET scanners to small tumors. PET is used more commonly in disseminated disease.

Breast cancer often metastasizes first to locoregional lymph nodes. Current noninvasive imaging methods do not evaluate the axillary nodes effectively. However, imaging can help to define which lymph nodes should be resected for histologic sampling. Sentinel node imaging or detection using a radiation-sensitive probe system is becoming increasingly more important in axillary assessment of patients with breast cancer.[50] This procedure is discussed in more detail elsewhere in the text, but imaging is used, especially in European centers, to better localize the axillary nodes for intraoperative assessment and determine atypical routes of lymphatic drainage. Studies have shown sentinel node sampling procedures to be at least 90% sensitive—which is considered useful sensitivity—relative to axillary dissection, and they are virtually 100% specific.[51] FDG-PET is not sufficiently sensitive to detect small metastases and has an accuracy of only about 75% in axillary nodal staging.[52]

The extent of systemic imaging required in the initial workup of a patient with breast cancer depends on the size of the primary tumor and the status of the axillary nodes at biopsy. It can be argued that the likelihood of systemic metastatic disease is higher for patients with positive nodes; thus, more intensive evaluation may be more appropriate. Some would suggest a baseline bone scan and CT of the chest and abdomen at this time. The frequency of follow-up is debated, given the improbability of curing recurrent systemic disease, and some have advocated only limited biochemical follow-up. However, this area is controversial. Examples of primary and metastatic breast cancers imaged on CT are shown in Figure 21-8B and C . PET is a highly effective tool for evaluating soft tissue involvement and quickly assessing treatment response.[53] FDG-PET imaging can detect disseminated cancers; however, the optimal role of PET in imaging is evolving. PET is now approved for monitoring treatment response of breast cancer.

Prostate Cancer

The role of imaging in newly diagnosed prostate cancer is evolving. Although there is great interest in this area, currently available imaging techniques are far from ideal and continue to evolve. The serum PSA test is controversial, but it has allowed the detection of smaller prostate cancers than generally are detectable clinically, along with opportunities for earlier interventions. In addition, mortality from prostate cancer has declined in the past 15 years. Many believe these two observations are not random associations, though this is discussed in more detail elsewhere in this book. However, this is an area of great controversy, though there is some evidence that early surgical resections are more closely associated with diminished mortality from prostate cancer than is watchful waiting. Thus, imaging in prostate cancer could play several roles: detecting cancer in the prostate; detecting the extent of tumor; and determining whether the tumor has spread beyond the prostate locally or systemically.

Evaluation of the Prostate

Unfortunately, intraprostate carcinoma is not detected particularly well by imaging with ultrasound or other methods. Although transrectal ultrasound has been used to guide biopsies, up to 40% of prostate cancers are isoechoic (and thus undetectable) by this method. Similarly, the positive predictive value of hypoechoic lesions of the prostate typically is well below 50%. Ultrasound can be used to detect abnormalities and guide biopsy of the entire prostate because it does an excellent job of defining the overall shape, size, and location of the prostate for purposes of systematic biopsy. A sextant approach often is used to sample the base, middle, and apex of the prostate bilaterally, in addition to taking biopsy samples of any suspicious areas. Although this technique is less than perfectly accurate for detecting prostate cancers, on ultrasound, tumors in the peripheral zone are more readily visible than tumors in the inner gland. The peripheral zone is echogenic, and tumors that are hypoechoic to it (approximately 60%) can be detected.[54] However, hypoechoic lesions also can be caused by inflammatory processes, and the positive predictive value of ultrasound is approximately 18% to 52%.[54] Contrast enhancement of the prostate on ultrasound has been used to some advantage to enhance detection rates and positive yields on biopsies of the prostate.[55] Similarly, on MRI, cancers that are hypointense on T2-weighted images are seen, but the findings are not specific for tumor. Extension of cancer beyond the prostate capsule is suggested on ultrasound when the capsule margin is irregular or the seminal vesicles are abnormal in morphology; however, sensitivity of as low as 20% has been reported. The sensitivity of MRI for extracapsular invasion is approximately 50%, and specificity is 95%.[54] Patients at intermediate risk for invasion, with a PSA level of 10 to 20 ng/mL and a Gleason score of 5 to 7, may benefit from MRI staging of local extension.[54] MRI methods are improving, especially with the use of spectroscopy. [54] [56] However, spectroscopy is still applied mainly at a few centers with specialized expertise, so it is not yet a routine part of management of prostate cancer. Increased field strength for MRI is now being more systematically assessed and appears promising as a tool to separate benign from malignant prostate tissue by detecting tissue with increased ratios of choline/citrate.[57]

CT has no established role in evaluating the prostate itself or local invasion (25% sensitivity for capsular invasion), although tumors sometimes can be seen on CT ( Fig. 21-9A ). CT is used to detect bladder and rectal invasion, adenopathy, and distant metastases, and MRI is used to assess local extent. Similarly, the sensitivity for detecting nodal metastases has been reported to be as low as 30% with CT. Higher sensitivity can be achieved, but with lower specificity. Pathologic proof is desirable before it is concluded that a patient has metastatic disease to the lymph nodes, and if metastatic disease is demonstrated, radical prostatectomy is considered inappropriate. Large nodal metastases are easily detected on CT imaging, however ( Fig. 21-9B ).

 
 

Figure 21-9  Prostate cancer. A, Axial CT image shows an enlarged prostate with an enhancing mass and irregular margins. B, More superior image shows enlarged bilateral pelvic nodes from metastatic disease.

 

 

It is not clear that MRI is better than CT; however, recent data on MRI using a node-specific paramagnetic contrast agent have shown very high sensitivity and accuracy in the detection of nodal metastases.[56] There is considerable hope for this method, but it has not yet been approved by the FDA.[58] Given the traditionally low sensitivity of CT and MRI to nodal metastases, it has been recommended that the serum PSA level be at least 20 ng/mL before CT is performed. If the CT findings are positive, then biopsy can be performed of the enlarged node or nodal sampling can be performed before radical prostatectomy. CT also is the test of choice for visceral metastases.

A bone scan is a sensitive technique relative to x-rays for bone metastases. The results of a bone scan can be positive when radiographs of bone are essentially normal. The current recommendation is that a radionuclide bone scan be performed only if the serum PSA level at presentation is greater than 10 ng/mL. Only very rarely is a bone scan positive for tumor at lower levels at the time of diagnosis. Some argue that for large primary tumors or very high Gleason scores a bone scan still may be appropriate at staging.

Thus, imaging is used selectively in patients with newly diagnosed prostate cancer. A bone scan commonly is used for recurrent prostate cancer whenever the PSA level begins to rise. New PET methods are promising in prostate cancer, but are not in widespread use in the United States. FDG-PET often is falsely negative in prostate cancer, especially for disease in the earliest stages.[46] Similarly, MRS has shown promise in evaluating the prostate gland and determining whether the tumor has spread beyond the prostate.

Much monitoring of prostate cancer now involves sequential blood tests to measure the PSA level. When the PSA level rises persistently, the tumor has recurred, but determining the site of recurrence often is problematic. Bone scans and CT often are used, with radioantibody imaging for anti-prostate membrane specific antigen antibodies used only infrequently because of limited diagnostic accuracy, although some promising results have been obtained by experienced groups.

Colon Cancer

The role of noninvasive imaging in the diagnosis of the primary lesion in colon cancer has changed over the last several decades. At one time, barium enema studies were used extensively to search for colorectal cancer. They have been replaced, in large measure, by fiberoptic colonoscopy. However, there is a growing level of interest in virtual colonoscopy, which is performed using CT scanning and per-rectum insufflation after thorough bowel preparation. This procedure is used to a limited extent for screening. The technique faces challenges because it requires bowel preparation and interpretation is quite time-consuming. Screening for colon cancer is an area of considerable opportunity for noninvasive imaging. Infrequently, these cancers can be detected by other methods such as ultrasound. The performance of virtual colonoscopy has been directly compared to that of optical colonoscopy in a study of over 6000 patients. Patients were randomized to either an optical or CT colonographic (CTC) group and were compared for the detection of advanced neoplasia and the total number of harvested polyps. Advanced neoplasia was confirmed in 100 of the 3120 patients in the CTC group (3.2%) and in 107 of the 3163 patients in the OC group (3.4%). There were seven colonic perforations in the OC group and none in the CTC group. Primary CTC and OC screening strategies resulted in similar detection rates for advanced neoplasia, although the numbers of polypectomies and complications were considerably smaller in the CTC group. CT colonography also was much less expensive than optical colonoscopy.[59]

Interestingly, the detection rate for polyps requiring biopsy was statistically identical between the two groups of patients. A large multicenter study is being performed in the United States to compare the two methods. A concern with the virtual colonoscopy method (CT colonography) is that it is highly interpreter-dependent. Before it can be recommended routinely, certainty of its performance across various medical centers will be highly desirable, though in expert hands it currently appears to be a viable alternative to colonoscopy and is considerably less expensive. It is probable that CT colonography methodology will assume a growing role in cancer screening in the coming years.

Regardless of means of detection, the extent of preoperative imaging performed before resection of primary colon cancer is variable, based on the institution. In general, the larger the primary tumor is, the more aggressive is the staging procedure required. In most instances, the primary tumor must be surgically resected for palliation (or cure), even if metastatic tumor is present. For staging, the most common studies include CT scan with contrast of the abdomen and pelvis, CT scan of the thorax (or chest radiograph), and bowel imaging to exclude the presence of a second primary colon cancer. In institutions in which PET imaging is available, PET is used somewhat more frequently at presentation; however, it is much more commonly applied in the setting of suspected recurrence.

For colorectal cancer, many advocate regular imaging studies after surgery for “cure,” because isolated metastases or oligometastases of colorectal cancer can be resected from the liver or lungs; in some instances, the patient is disease-free for a long period. Thus, before such removal of a limited number of metastases is contemplated, a thorough imaging procedure is undertaken. This usually includes CT of the abdomen and pelvis with contrast and CT of the thorax without contrast. CT of the thorax may be replaced by a chest x-ray, but chest x-rays are less sensitive for pulmonary metastases.

PET is applied very often in this setting and in the setting of a rising carcinoembryonic antigen level after surgery. The precise timing of follow-up studies can be variable, but they often are done every 6 to 12 months in the early years after surgery. Considerable evidence supports the idea that PET can detect more metastatic foci than CT in the setting of a rising carcinoembryonic antigen level.[60] An example of a patient initially believed to have only a limited number of liver metastases is shown in Figure 21-10 ; however, more extensive disease was identified ( Fig. 21-10B ). PET/CT has been shown to offer higher accuracy than PET alone in recurrent colorectal cancer.[61]

 
 

Figure 21-10  Colon cancer. A, PET and CT image display of a patient with two 18FDG-avid lesions in the liver. These are seen on the CT scan (upper left), the attenuation-corrected PET scan (upper right), the non–attenuation-corrected PET scan (lower right), and fused images (lower left). B, PET and CT images of the pelvis, oriented as in part A, show increased FDG uptake in a left external iliac lymph node metastasis.

 

 

Although immunoscintigraphy has been used, it has been rendered essentially obsolete due to the availability of FDG-PET. FDG-PET often does not detect small (<5 mm) tumors, however, and is known to be less sensitive for tumors of mucinous histology, so opportunities for improvement remain.

Ultrasound can detect many liver lesions, and is a very useful technique for guiding biopsies of the liver.[24] For liver metastases, CT is still the most commonly used procedure, but in a meta-analysis, PET was a more robust test to identify the presence and location of hepatic metastases of colorectal cancer compared with CT, MRI, or ultrasound methods.[62]

Gynecologic Neoplasms

Screening for gynecologic neoplasms usually is not performed by imaging, except for very limited programs that have evaluated the use of either transabdominal or, more commonly, transvaginal ultrasound of the pelvis to detect masses that may represent ovarian cancer. These programs have been combined with serum biomarkers. Such programs have not been proven cost-effective and are not widely applied, but they warrant further study, because this is a very important health problem. In women with high genetic risk of ovarian cancer, such as those with the BRCA mutation, screening may have greater value.

In cervical carcinoma, screening using the Pap smear has a large effect in terms of lowering mortality rates by detecting premalignant changes and early-stage disease. Although much of the staging of cervical carcinoma is performed by physical examination, for larger primary tumors, imaging has an important role. Both CT and MRI are used in the pelvis; however, the use of PET for tumor staging is increasing. As in other tumors, PET appears to be more sensitive than anatomic imaging methods. Emerging data show that PET provides better prognostic value than anatomic imaging in cervical cancer.[63] [64] [65]

In ovarian cancer, no technique is able to detect microscopic metastatic disease. Ultrasound is the main method by which ovarian tumors are identified at their earliest stages; however, the unfortunate fact is that these tumors are usually diagnosed at an advanced stage. Imaging can be used in an attempt to determine the extent of the surgical procedure that will be required. Both CT and MRI are used to assess the extent of ovarian cancer, with CT the preferred method ( Fig. 21-11 ). PET is not sensitive to tumor foci smaller than 8 mm to 1 cm, but it is reasonably reliable in detecting larger tumor foci. For this reason, some advocate the use of PET to determine whether tumor debulking should be performed. PET has a role in the setting of a rising CA125 level in patients with normal CT findings.[66]

 
 

Figure 21-11  Axial CT image shows a dense, calcified mass in the left pelvis, compatible with a metastatic implant from ovarian cancer.

 

 

The use of serum markers and imaging is recommended for surveillance after surgery for ovarian carcinoma. The aggressiveness of imaging follow-up depends on the treatments available. PET has an emerging role in this setting, although practice patterns vary widely. PET also has been shown to provide information related to treatment response in preliminary studies. [67] [68]

Lymphoma

For both Hodgkin's and non-Hodgkin's lymphomas, accurate staging is important. For both types of lymphoma, accurate definition of the tumor burden is needed for effective treatment planning, especially treatment with external beam radiation. CT is the historically accepted method for noninvasive staging of lymphoma, with PET being used increasingly because many studies have shown it to be capable of locating more tumor foci than CT.[69] An example of CT imaging of abdominopelvic lymphoma is shown in Figure 21-12 . In most lymphoma histologies, FDG-PET is more sensitive than CT, often detecting 20% more lesions than are seen on CT alone.[70] PET can detect disease in the bone marrow and spleen in some instances. In fact, marrow involvement seen on FDG-PET often is associated with a negative CT scan.[71]

 
 

Figure 21-12  A, Axial CT image with oral and IV contrast shows para-aortic adenopathy and infiltration of the left kidney by lymphoma. B, Image of the lower abdomen in the same patient shows enlarged mesenteric nodes. C, PET-only images (left to right: coronal, sagittal, transverse, and anterior projections) show focal areas of increased 18FDG uptake in multiple lymph node groups, including the axillary, inguinal, and iliac regions, consistent with disseminated lymphoma.

 

 

CT is traditionally used for follow-up of lymphoma, and there are clear response criteria in place to follow lymphoma therapy. One of the challenges in lymphoma is that large masses often do not normalize in size after treatment, leading to questions in interpretation of a residual mass lesion. Determining whether these lesions contain a viable tumor is important, because it defines whether more treatment is needed. Data indicate that gallium (Ga)-67 scintigraphy can be effective for assessing the viability of residual Hodgkin's lymphoma and intermediate- and high-grade non-Hodgkin's lymphoma. However, multiple studies now have been published on FDG-PET in this setting, and this imaging modality has essentially replaced Ga-67 scintigraphy in assessing the viability of residual masses of lymphoma. If a residual mass of lymphoma shows increased FDG uptake, that usually is indicative of residual viable tumor; however, scans also can be falsely negative, because some tumor foci may be smaller than the resolution of PET imaging.[72] False-positive results have been described in patients with Hodgkin's lymphoma, however.[73]

Positive midtreatment Ga-67 and PET scans predict a poor outcome from therapy, and positive PET scans at the conclusion of a therapeutic regimen also indicate a poor prognosis. It is increasingly appreciated that PET findings soon after treatment is initiated can be highly predictive of ultimate outcome of the therapy. [74] [75]

Challenges associated with PET include reactive lymph nodes and nodes involved with inflammatory processes such as sarcoidosis, which can be very FDG-avid. Similarly, uptake of FDG in brown fat in the neck and thymus can be confusing.[76]

Although anatomic imaging has been the key for lymphoma assessment, there is a growing trend to greater use of PET. PET imaging and PET/CT imaging, providing additional functional information, are of growing utility. A limitation of PET-only methods had been the lack of a standardized set of response criteria. Tracer activity in PET images generally decreases more rapidly than tumor shrinkage occurs (i.e., anatomic changes of treatment lag behind metabolic changes detectable by PET). For these reasons, PET scans may appear normal before CT scans do. A concern is that there is not strong evidence showing that a negative PET scan should be used to truncate the duration of lymphoma therapy. For example, if a PET scan became negative after two cycles of treatment, this would not justify, based on current data, discontinuing treatment. However, if a treatment involved a standard of four possible courses of treatment and PET became negative after these courses were completed, available data suggest that this portends a very good prognosis vs. a positive PET scan. Recently, new criteria for response including PET were developed for lymphoma. For FDG-avid lymphomas, a negative PET scan is required to determine a complete response. [77] [78] [79]

It can be argued that PET is not essential in all patients with lymphoma. However, the use of PET and PET/CT is becoming increasingly the norm in centers where this technology is available. Because PET can find some lymphomatous tumors that cannot be detected by CT, this method is increasingly finding routine application in the care of patients with lymphoma ( Fig. 21-12C ).

An exciting new opportunity for the use of PET in non-Hodgkin's lymphoma is in the setting of a “response adaptive” approach. In such treatment approaches, patients who are poorly responding can be identified by PET performed soon after treatment is initiated. This approach can allow segregation of responding from non-responding patients. In the responding patients, standard treatment is given, whereas in the poorly responding patients, alternative approaches such as stem cell transplants are used. This approach currently is investigational, but it is an area of great promise because it allows the potential for tailoring the therapy to the individual patient's responsiveness to the treatment algorithm.[80] Recently, use of such an approach has been shown feasible in a clinical comparative trial on Hodgkin's lymphoma.[81]

Melanoma

The imaging management of melanoma varies based on the stage of disease. Radiologic imaging has no significant role in the diagnosis of primary melanomas. Lymphoscintigraphy—the injection of radiolabeled colloidal material, typically technetium 99mTc sulfur colloid, into the subcutaneous tissues or intradermally to locate lymphatic drainage routes, and thus lymph nodes with the potential for metastatic involvement—commonly is performed for primary melanomas of intermediate thickness. Although practice patterns vary, this method typically is used for melanomas that are more than 1 mm thick without other evidence of metastases. If the sentinel node identified by surgery (often using radionuclide guidance) is involved with tumor, additional staging procedures often are done.[82] These procedures most commonly include CT of the chest and abdomen, and of the pelvis as well if the melanoma affected the lower extremities. If there are systemic metastases, brain imaging is performed, using MRI with and without gadolinium contrast enhancement.

PET and PET/CT with FDG also are potent methods for detecting metastatic melanoma, often detecting more tumor foci than CT. PET can detect nodal metastases, but is not as sensitive as sentinel node imaging and is not a replacement for sentinel node imaging and removal. PET is particularly good for soft tissue metastases, but cannot detect microscopic disease. Thus, sentinel lymph node biopsy is used in preference to PET for detecting early metastases. There is some evidence that ultrasound can detect small nodal metastases of melanoma, but it is not widely applied and is also less sensitive than sentinel node imaging.[1] However, PET can detect most tumor foci larger than 6 mm and sometimes can detect smaller tumor foci. CT is a more robust technique for small pulmonary nodules than is PET.[83]

Melanoma metastases, especially if they are localized, can be resected surgically. However, identifying whether only one or two vs. many metastases are present is a major challenge. Aggressive surgical procedures are not appropriate if there are disseminated metastases. For these reasons, staging imaging procedures are performed aggressively before major surgery is undertaken to resect melanoma metastases. PET commonly is part of such a staging evaluation. For systemically metastatic melanoma, PET has been reported to have sensitivity well over 90%. Thus, although anatomic imaging dominates, PET has a growing role in melanoma assessment.[84] For bone metastases, radionuclide bone scanning also is an important diagnostic procedure. Recently, it has been shown that the performance of FDG-PET in melanoma is significantly enhanced if the CT scan portion of PET/CT is analyzed very carefully. This appears to increase both sensitivity and specificity of the method.[85]

Bladder Carcinoma

Bladder carcinoma often presents at an early stage, and no imaging evaluation is performed to determine whether there are locoregional or systemic metastases. However, ultrasound has been used to determine the depth of penetration of primary bladder carcinomas. An important consideration in bladder carcinomas is that uroepithelial tumors are often multicentric. Thus, intravenous pyelogram examinations to evaluate the entire genitourinary system commonly are performed early in the diagnostic algorithm. Although ultrasound can detect many bladder cancers 5 mm and larger, transurethral sonography is more sensitive; obviously, however, it is invasive. MRI is used more commonly than CT for assessing primary bladder lesions because of its superior soft tissue contrast characterization abilities.[86]

For larger primary tumors that are invasive, imaging evaluation is important to help to determine whether surgery is appropriate. Metastatic disease to locoregional nodes or systemic metastases indicates disease with a poorer prognosis, and tumor invading local structures or metastatic either to nodes or systemically often is considered unresectable. CT is used most commonly for local nodal staging, but MRI also can be used. Small nodal metastases usually are not detected using CT, because they have not enlarged the lymph nodes sufficiently to allow the tumor-involved nodes to be detectable. CT has a reported sensitivity of 60% to 70%. Biopsy commonly is used to determine whether an enlarged node seen on CT truly contains tumor. MRI probably is more sensitive than CT in detecting nodal metastases, and new contrast agents that accumulate in normal nodes are potentially important for enhancing the diagnostic accuracy of MRI in detecting nodal metastases.[87] Initial data with MRI contrast agents support the accuracy of this approach, but also point out that the interpreter's experience is important.[88] Such agents are not yet routinely available or FDA-approved.

FDG-PET has been used and is promising in bladder carcinoma; however, images of the pelvis can be degraded by intense F18 activity in the bladder. The use of PET in bladder cancer is enhanced by PET/CT and iterative reconstruction methods that make for better assessments of the pelvis with less degradation due to the bladder radiotracer activity. For bone metastases, radionuclide bone scan remains the procedure of choice, and MRI also can be sensitive. PET/CT is quite sensitive for metastatic disease beyond the pelvis and is being applied to a greater extent due to the availability of the CMS registry in the United States.[89]

Follow-up of bladder carcinoma usually involves the use of CT scans. Follow-up for new or recurrent bladder carcinoma within the bladder usually requires direct visualization of the bladder by cystoscopy.

Head and Neck Cancer

Head and neck cancers often are associated with cigarette smoking and alcohol use or abuse. Human papillomavirus also has been linked to head and neck cancers as well, especially in younger women. Most malignancies in the head and neck (except for lymphomas, as discussed earlier) are of squamous cell etiology. A key issue in these lesions is determining whether the disease is localized to the head and neck or whether metastatic disease or a second primary lesion is present. Thus, imaging of the lungs usually is done to exclude a primary or metastatic lung tumor. The physical examination is very important in assessing a primary lesion in the head and neck, but both CT and MRI are very potent methods. MRI typically is performed before and after gadolinium contrast is administered; CT scanning usually is performed after contrast enhancement ( Fig. 21-13A ). Because MRI is subject to respiratory and motion artifacts, CT is used somewhat more commonly in the initial staging of these tumors.[90]

 
 

Figure 21-13  Head and neck tumors. A, Axial CT image of the neck with IV contrast shows a mass in the left piriform sinus. B, PET and PET/CT images show right vocal cord cancer with intense tracer uptake. C, PET and PET/CT images from the lower level of the neck show nodal tracer uptake consistent with metastases.  (Courtesy of Dr. David Yousem, Johns Hopkins University.)

 



CT and MRI can characterize the extent of primary tumors; however, CT is more effective than MRI in assessing the extent of involvement of cartilage or bone. For nodal metastases, current diagnostic schemes are based mainly on nodal size. Nodal size is an imperfect indicator of tumor involvement, however.

Increasingly, FDG-PET is being applied to the assessment of head and neck cancers. Although several studies have suggested that PET, MRI, and CT have similar sensitivity, more recent studies have suggested that PET is more accurate in staging ( Fig. 21-13B and C ). However, PET can detect increased glucose uptake in nonmalignantly involved inflamed nodes (false-positive findings). These can occur in patients with head and neck or gingival infection or the common cold. Defining the precise extent of tumor is important to determine whether surgery or radiation therapy should be performed, because more extensive tumors are less amenable to surgical resection.

Occasionally, head and neck cancers present as isolated nodal metastases without the location of the primary tumor being evident. Imaging has a role in such cases. Often MRI is performed as well as extensive inspection and biopsies; however, FDG-PET also has been applied. This method can detect as many as 15% to 30% of primary tumors.

For recurrent tumors, PET appears to be a more robust test than MRI or CT, especially when timed properly, probably because contrast enhancement can be seen in both postoperative changes (and postradiation tissue) and tumors. In general, FDG uptake is a more reliable predictor of tumor than the anatomic methods. PET is useful in surveillance for the recurrence of these tumors, but it is not yet considered the standard of care.

Thus, for head and neck cancers, MRI offers excellent contrast resolution for soft tissues, but can be degraded substantially by motion. For this reason, CT with contrast is much more commonly performed. FDG-PET is assuming a growing role in cancer management, especially for recurrence and for assessment of response to treatment. PET with CT is being used more often to stage and monitor these tumors during and after treatment, and may become the standard of care.[91] A recent comparison of PET/CT to MRI and PET alone showed superior accuracy of PET/CT versus the other methods.[92]

Pancreatic Carcinoma

The standard of care for the imaging diagnosis of pancreatic cancers is CT scanning. Although MRI can be useful, CT, including CT angiography, is the main method used for staging and assessing tumor invasion of vessels ( Fig. 21-14 ). Some studies have shown FDG-PET to be somewhat more sensitive for detecting tumors and to have moderately high accuracy—approximately 85%—in characterizing pancreatic lesions as malignant or benign. [93] [94] [95] Ultrasound is used to assess cystic lesions. After treatment, salvage therapy is ineffective, and these patients often are less aggressively monitored than those with other, more treatable cancers. Neuroendocrine tumors of the pancreas often can be detected using 111n-pentetreotide (Octreoscan), a SPECT procedure. Recently, positron emitter-labeled analogs of somatostatin have been developed and show encouraging biological characteristics compared with single photon agents.[96]

 
 

Figure 21-14  Pancreatic cancer. A, Axial CT image shows a mass in the pancreatic body, encasing the splenic artery. B, Coronal volume-rendered three-dimensional CT image shows tumor encasing the splenic and left gastric arteries. C, Coronal volume-rendered maximum-intensity projection. D, Sagittal volume-rendered three-dimensional CT images show a mass in the pancreatic head without invasion of the superior mesenteric artery or vein. A common bile duct stent also is seen.

 

 

Liver Cancer

Hepatic malignancies, especially hepatomas, are common worldwide. Both CT and MRI can be very effective in detecting these lesions. They sometimes are challenging to assess, because the appearance of cirrhosis with regenerating nodules and tumors can overlap. Multiphase CT imaging, CT angiography, and MRI with and without gadolinium contrast are commonly used in hepatomas. PET is less reliable, because approximately half—and sometimes more—of hepatomas are not FDG-avid. There has been some use of alternative PET tracers such as C-11 acetate to image some pancreatic cancers, because some FDG-negative tumors are C-11 acetate avid.[97] Ultrasound also can be used to assess the liver and guide biopsies.

Metastatic lesions to the liver also are common, especially in the United States. For most tumors, CT is the initial method used for assessing whether tumor is present. However, FDG-PET is more sensitive than CT in detecting liver metastases in common cancers such as colorectal cancer. [60] [62] Thus, PET is seeing greater application in assessing suspected liver metastases, although ultrasound, CT, and MRI also are important methods and still are more commonly applied in many centers ( Fig. 21-15 ).

 
 

Figure 21-15  A, Carcinoid metastases to the liver. Axial MR image with gadolinium shows multiple enhancing masses in both lobes of the liver. B, Hepatoma. Axial MR image with gadolinium shows a solid mass in the left lobe of the liver. C, Intraductal papillary mucinous tumor of the pancreas. Axial T1-weighted MR image of the abdomen shows a low-signal-intensity cystic mass in the head of the pancreas.  (Courtesy of Dr. Ihab Kamel, Johns Hopkins University.)

 



Kidney Cancer

In the past, renal cancers were detected by intravenous pyelograms; currently, however, the most common method for detection is CT. Renal cell cancer commonly is detected incidentally because of the widespread use of cross-sectional imaging. Between 25% and 50% of surgically treated renal cell cancers are discovered incidentally.[98] Renal lesions are classified as cysts or solid masses, depending on their characteristics as shown by imaging. Renal cysts are fluid-filled and appear anechoic with increased through-transmission on ultrasound. They show water density without enhancement on CT, and appear hyperintense on T2-weighted images, also without enhancement, on MRI. Renal masses typically are evaluated by CT because of its short examination times and ease of evaluation, even in patients with a large body habitus, which can make ultrasound difficult. MRI typically is used for problem-solving. Multiphasic scanning is performed on CT to evaluate the density of lesions before contrast and as contrast filters from the cortex into the medulla and collecting system. An increase in density by greater than 20 HU corresponds to lesion enhancement and confirms the presence of a solid mass. CT is used to stage the tumor by determining the presence of renal vein invasion, adenopathy, local extension, and distant metastases. CT's accuracy for staging is 91%.[98] For resectable lesions, CT can provide information on whether the lesion is amenable to nephron-sparing surgery or partial nephrectomy. Lesions that are smaller than 4 cm, polar, and cortical, and do not involve the renal hilum or collecting system may be candidates for partial nephrectomy. Although CT, MRI, and ultrasound can all be used to assess renal lesions, CT with contrast is the dominant method ( Fig. 21-16 ). PET is useful only when the tumor is FDG-avid. However, the normal excretion of FDG by the kidneys makes evaluation of the kidneys more challenging than other tissues, and some renal masses are not very FDG-avid. Thus, FDG-PET is not currently recommended for renal cancers, at least not for reliably characterizing renal masses as malignant or benign. Metastatic renal cancer is more accurately imaged on FDG-PET than is primary renal cancer. [99] [100]

 
 

Figure 21-16  Axial CT images of the abdomen with IV contrast show enhancing renal cell carcinoma in the right kidney. Enhancing tumor invades the right renal vein.

 

 

Endocrine Tumors

Imaging is used to study several types of endocrine tumors in a variety of locations. For adrenal tumors, CT is the procedure of choice, with metaiodobenzyl-guanidine 123I (MIBG) scanning and MRI scanning also proving useful for lesion characterization.[100] MIBG accumulates selectively in pheochromocytomas. Adrenal masses with low HU values (<10 HU) typically are adenomas, which are lipid-rich. For the thyroid gland, radioiodine imaging commonly is used. For non–radioiodine-avid thyroid cancers, FDG-PET is very useful for lesion detection and is recommended in the setting of a rising serum thyroglobulin level with a normal 131I or 23I scan, particularly when recombinant TSH stimulation is used ( Fig. 21-17 ).[101] For neuroendocrine tumors such as carcinoid tumors, CT and radiolabeled octreotide analogs are very useful. Several newer PET imaging agents are under study for endocrine imaging, but are not yet widely available or widely applied. [96] [102]

 
 

Figure 21-17  PET and CT image panel showing an intense 18FDG uptake focus near clips in the left thyroid bed, consistent with recurrent thyroid cancer.

 

 

Brain Tumors

The dominant method for the assessment of brain tumors is the MRI scan, which is the preferred method for initial detection, assessment of extent of disease, and assessment of efficacy of therapy. The superior soft tissue contrast provided by MRI places it ahead of CT for lesion characterization ( Fig. 21-18 ).

 
 

Figure 21-18  Coronal MR image with gadolinium of the brain shows a mass with peripheral enhancement (arrows), compatible with tumor, and a more hypointense necrotic area.

 

 

Unfortunately, even sophisticated MRI techniques, often relying on tumor enhancement using gadolinium, cannot detect microscopic disease. MRI findings, although fairly specific for tumor, are not completely specific. Thus, infarcts, infections, and foci of demyelination occasionally can mimic tumor foci on MRI. FDG-PET has a very limited role but can be useful in assessing residual tumor after radiation therapy and determining whether residual masses are caused by tumor or tumor necrosis. It is most accurate in highly aggressive tumors where brain tumor uptake of FDG is greater than that of normal brain tissue. Recently, other tracers, such as FDOPA and FLT, have shown results more promising than those for FDG. [103] [104]

MRS also can be useful in evaluating this issue because tumors typically have high levels of choline and low levels of N-acetyl-aspartate. Angiography, although a historically useful method, is performed less frequently for diagnostic purposes in brain tumors. MRI, CT, and PET can guide biopsies. Further, MRI can be used intraoperatively to guide therapy.[105]

Pediatric Tumors

CT usually is the method of choice for evaluation of pediatric tumors. For tumors of the central nervous system and for sarcomas, MRI is preferred. FDG has a growing role, especially for lymphomas and sarcomas. MIBG scanning often is used in neuroblastomas. CT scanning should be performed with a reduced tube current and energy to minimize the radiation dose while preserving the quality of the diagnostic image. Multiphase CT should be avoided in children unless it is clearly indicated to minimize the radiation dose to the child.[106] PET/CT has shown broad utility in pediatric cancers, although the available literature is quite modest at present.

Esophageal and Gastric Cancer

CT scanning is the method of choice for initial staging of esophageal and gastric cancer. Endoscopic ultrasound is the most sensitive and accurate method for determining whether tumor has invaded the wall of the esophagus or involved the periesophageal nodes. PET scanning is very sensitive in determining whether stage IV disease is present, and typically is performed as part of the initial staging evaluation, at least for esophageal cancer, to identify patients who are clearly not candidates for surgery.[107] FDG-PET also is being used with increasing frequency to assess treatment response in patients with esophageal cancer, as early changes in glycolysis after treatment appear related to treatment efficacy.[108]

Sarcomas

MRI is the method of choice for detection and assessment of soft tissue sarcomas. Gadolinium contrast enhancement is commonly used as well. FDG-PET imaging has been useful in assessing primary sarcomas for aggressiveness and defining possible sites for biopsy as well as for defining prognosis and grade. [109] [110] It also has been used to assess and predict the response of sarcomas to therapy.[111]

Gastrointestinal Stromal Tumors

GI stromal tumors are relatively infrequent, but have been studied extensively with both CT and PET imaging in the past few years. These tumors often are responsive to imatinib and other tyrosine kinase inhibitors, in part due to their constituitive overactivity of a mutated KIT oncogene. These tumors have been shown to be typically FDG-avid. FDG accumulation declines very rapidly with effective treatments, earlier than changes in tumor size. Of interest is that recently revised CT criteria may allow CT to assess response more quickly to treatment in such tumors, with changes in tumor HU one of the characteristic findings of response. Both PET and CT thus have a role in this somewhat uncommon tumor, especially for the early assessment of treatment response.[112]

DEFINING NORMAL ORGAN FUNCTION FOR CANCER THERAPY

Several tests are used to determine whether a patient is a suitable candidate for aggressive therapy. These tests include myocardial perfusion imaging at stress to determine whether ischemia is present, because if present it could increase the risk for a major surgical procedure. Echocardiography also is used for this purpose. Myocardial function often is evaluated before chemotherapy is given. This may be done using a myocardial blood pool study or, less commonly, an echocardiogram to determine chamber size and ejection fraction.

Pulmonary function usually is determined by pulmonary ventilatory function tests; however, split lung function and regional function may be determined by pulmonary perfusion imaging with 99mTc MAA (macro-aggregated albumin; i.e., a quantitative lung scan). Regional ventilation also can be assessed quantitatively. Such determinations help to predict the level of pulmonary function expected after surgery. Split assessment of renal function sometimes is performed before removal of a renal cancer to ensure that the remaining kidney will be functional.

Functional imaging can identify the location of eloquent brain activity and evaluate motor cortex function. It also can help to guide brain tumor surgery by avoiding key areas of the brain.

GUIDANCE OF RADIATION THERAPY

Radiation therapy can be palliative, or it may be performed with curative intent. In general, the goal is to deliver maximum radiation to the tumor while minimizing radiation delivery to normal tissues. This delicate balance is achieved through increasingly sophisticated dose delivery systems. The anatomic location of a tumor most commonly is defined by treatment-planning CT. The CT data are used to define tumor and normal tissues with a therapy-planning system. The planning potentially can be enhanced by better definition of the gross tumor volume (or biologic tumor volume) versus anatomic tumor volume, which are not always the same. FDG-PET is beginning to be used to better define the biologic tumor volume, often with data from PET/CT. Although this procedure is hardly the norm, it is clear that imaging is key to the optimal planning of radiation therapy ports. Substantial potential exists to target areas of tumor that are not identified on CT (expand port size) or reduce ports to areas that are not involved with tumor, because the goal is to irradiate tumor while not irradiating normal tissues.[113] A substantial number of centers now include PET imaging as part of their radiation therapy planning in a broad range of diseases.[114] Treatment plans for radiation therapy are discussed in a separate chapter in this book.

INTERVENTIONAL PROCEDURES

Increasingly, imaging is being combined with a therapeutic procedure to provide minimally invasive therapeutics. Examples include the use of CT to guide thermal ablation of the liver or lung and the use of MRI to guide ablation of brain and prostate tumors (through heat and cold). The ability to locate tumors and follow, in near real time, the response to treatment is of tremendous potential.

Catheter-based delivery systems also are important. For example, angiographic catheters can be used to deliver regional chemotherapy, emboli, or radioactive or chemical microspheres to treat tumors. Radioactive microspheres also are assuming a growing role in interventional oncologic radiology.[115]

EMERGING OPPORTUNITIES IN IMAGING

Functional imaging methods such as PET and varying innovative MRI techniques are being used increasingly to assess treatment response early after treatment is begun.[25] Beyond this, a variety of imaging methods are being developed to image key aspects of tumor biology ( Table 21-3 ). An exciting area for both MRI and PET is in detection of hypoxia, which is common in a broad range of malignancies and which represents a possible target for cancer treatments.[116] In addition to hypoxia, tumor perfusion can be imaged with a variety of approaches.


Table 21-3   -- Emerging Uses of Imaging

  

 

INDIVIDUAL PATIENT MANAGEMENT DECISIONS

  

 

Screening

  

 

Phenotyping of the tumor and host

  

 

TUMOR

  

 

Viability, proliferation, extent of necrosis or apoptosis, hypoxia, prognosis, type of treatment most likely to be effective based on receptors or presence of imageable pathways

  

 

HOST

  

 

Individualized assessment of pharmacokinetics of the drug and of organ function and pharmacodynamics

  

 

DRUG DEVELOPMENT

  

 

Does the tumor have a relevant target?

  

 

Does the drug reach the target?

  

 

Is the target pathway affected by treatment?

  

 

Is the proper dose of drug being given?

  

 

Does alteration of the target pathway alter the tumor biology?

 

 

Even though the process is difficult, interest remains in gene therapeutic approaches, which has led to attempts to determine, through imaging, whether genes, when delivered, actually reach tumors and, more importantly, whether they express in vivo the desired levels of gene product expected to be required to achieve a therapeutic effect. For example, dopamine receptors have been transfected into cells and imaged with radioligands capable of binding to the D2 dopamine receptor. Similarly, genes have been transfected that express varying thymidine kinase activities. This agent is suitable for gene therapy and can be imaged with radiolabeled substrates such as FMAU. [117] [118]

Similarly, a great deal of interest has been expressed in stem cell biology and the potential for stem cells to allow for regeneration of tissues. Tracking these stem cells in vivo and determining their biodistribution and ultimate proliferation are exceptional opportunities for imaging. These goals have been achieved with both nuclear medicine and MRI methods.

Small animal imaging devices of a variety of types are now being used to help in drug development. Small animal PET, SPECT, MRI, and CT scanners have been used to assess treatment response and aspects of tumor biology. Such methods are of critical importance for assessing the response of cancers to treatment with newer agents and understanding therapeutic effects. Even combined human PET/CT devices have been used for imaging and can provide useful information for drug development in cancer.

Some methods are of tremendous importance in preclinical studies, but will be more difficult to extend to human studies. One example is optical imaging. Such methods are capable of tremendous sensitivity and excellent resolution in vivo in small animals. A variety of approaches can be used, with emitted light, transmitted light, and reflected light. With bioluminescence approaches, a very small number of cancer cells can be identified in vivo in small animals. Such approaches, although very potent in vivo in small animals and capable of being combined with radionuclide and other methods, are not likely to be easily translated into humans, at least for broad applications, because of the limited penetration in tissue of light photons. However, in a broad range of detection issues the light can reach detectors, both intraoperatively and endoscopically for superficial structures, so this area is likely to be increasingly translated to practice. Thus, small animal imaging is a key element of progress allowing for proof of concept and refinement of tumor biological processes before translation to human use.

SUMMARY

Anatomic imaging of cancer using x-rays has been and remains extremely useful, and in the more modern form of CT is the dominant approach to imaging the patient with visceral cancer. Anatomic methods, although very potent, have clear limitations, but continue to improve, as evidenced by digital mammography and other techniques. Screening programs with mammography, CT of the thorax, and CT colonography are showing promise as methods to detect disease at earlier stages and potentially change outcomes. Anatomic methods can detect disease early, and such methods reliably show whether a mass is present. However, they provide limited information regarding the composition of the mass. In addition, they can be insensitive to small tumor foci, may be slow to change in response to therapy, are not predictive of response, and may be more challenging to apply in evaluating the postoperative patient. The functional information provided by MRI, including diffusion characteristics and, to a lesser extent, MR spectroscopy, adds to the anatomic signature of the lesions and continues to grow in application. Imaging additional phenotypic alterations of cancers with functional imaging methods such as PET adds information that often is clinically valuable for patient management in many common cancers.

Although many molecular alterations are present in cancer, the one that is by far most exploited in clinical practice and clinical research is the accelerated glucose metabolism present in most cancers. This process is well imaged with the radiotracer FDG. The ability to localize the molecular alterations of cancer spatially, through qualitative cognitive methods performed by the imaging specialist, computer fusion of image sets, or fused “anatomolecular” image sets using dedicated PET/CT, is key to optimal use of the imaging methods. Increasingly, the ability of PET imaging to quickly assess treatment response is allowing adaptation of treatments depending on the response of a specific patient's tumor to treatment. This response adaptive approach is expected to grow in the coming years. Functional imaging also is revising the approach to radiation therapy treatment planning. Functional “molecular” imaging methods such as PET, SPECT, and varying methods of MRI, in addition to optical and ultrasound imaging and technical improvements in CT and interventional techniques, are expected to enhance the care of the patient with cancer in the coming years and will likely continue to change the way oncology is practiced.

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