Nuclear Medicine

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Chapter 10 Nuclear Medicine

Amir H. Khandani, Arif Sheikh

Positron Emission Tomography

Despite the exquisite resolution of computed tomography (CT) and magnetic resonance imaging (MRI), some disease processes may go undetected by these anatomically based modalities. The anatomic modalities also have shortcomings in assessing the response to treatment and in distinguishing responders from nonresponders.

Over the past half-century, a variety of nuclear medicine probes have been used to evaluate disease processes at the cellular level. Nuclear medicine is the only clinical discipline using intracellular contrast agents in imaging, and it is therefore more sensitive than anatomic modalities in detecting certain disease processes. Some of these probes, such as radioiodine, have been very successful and are heavily used. Nevertheless, most nuclear medicine imaging techniques have suffered from low specificity and low spatial resolution; the latter problem is associated with the physics of single-photon-emitting radiotracers. Synthesis of biologically important radiopharmaceuticals with single-photon-emitting radiotracers has been a major challenge.

Positron emission tomography (PET) is a nuclear medicine modality that uses positron emitters such as fluorine-18, oxygen-15, nitrogen-13, and carbon-11. The fact that these nuclides are components of common biologic molecules makes PET particularly suitable for visually capturing various biologic pathways. Although PET has been used for several decades in the research setting, its clinical use has grown substantially in the past decade. PET with 18F-fluorodeoxyglucose (FDG), or “radioactive sugar,” as its workhorse has substantially influenced clinical oncology practice by refining the processes of diagnosis, staging, and restaging. Although many of the strengths and limitations of FDG-PET in diagnosing cancer are well known, its role in staging and restaging is evolving. The data indicate that FDG-PET will likely play an important role in monitoring therapy and predicting the course of the disease.

Basic Physics of Positron Emission Tomography

The radioisotope portion of the molecule used in PET imaging emits a positron (i.e., positively charged electron), which travels a distance of a few millimeters in tissue before it collides with a negatively charged electron. This collision annihilates the entire mass of the positron and electron, generating two photons with energy of 511 KeV each. These two photons travel at the speed of light in exactly opposite directions (i.e., 180 degrees apart). Coincident detection of these two photons by two oppositely positioned detectors in the PET scanner results in images with a much higher resolution compared with the conventional, single-photon nuclear medicine studies and produces the possibility of quantitative measurement of the tracer uptake in a volume of interest.

PET/CT allows the fusion of the metabolic information from PET with the anatomic information from CT and thus increases the diagnostic accuracy compared with stand-alone PET. In PET/CT, the patient undergoes a CT scan, followed by a PET scan, without changing the patient’s position. PET scans for most oncologic indications (whole-body PET scans) are acquired from the base of the skull through the upper thighs. In some instances, as in patients with melanoma, PET scans are acquired from the vertex of the skull through the toes. The CT portion (i.e., transmission scan) of PET/CT is acquired within seconds to minutes, whereas the PET acquisition time for each bed position (about 15 cm) is several minutes; the total PET acquisition time in newer machines is 15 to 25 minutes.

In addition to delivering anatomic information, the CT portion of PET/CT is used to measure the attenuation of the x-ray photons traveling through the patient to produce the so-called attenuation map and correct the PET data for tissue attenuation. During PET acquisition, photons from structures deep in the abdomen or pelvis are more strongly attenuated than those from superficial structures and the chest. The intensity of uptake in deeper structures is underestimated on non–attenuation-corrected PET images; the intensity of uptake in the deeper structures is normalized to the intensity of uptake in the superficial structures on the attenuation-corrected PET images (Fig. 10-1). Although correction of the PET data for tissue attenuation is indispensable, misalignment between PET and CT can cause mislocalization of lesions on the fused PET/CT images. This may be caused by the changed position of a body part (e.g., neck, legs) or physiologic changes in the position of an organ (e.g., respiratory movement) between the transmission scan (CT) and the emission scan (non–attenuation-corrected PET). Because the degree of misalignment and resulting mislocalization can be significant, the physician must be cautious when interpreting the attenuation-corrected PET/CT images or using PET/CT images for radiation therapy planning. The magnitude of this misalignment can be assessed by fusing the non–attenuation-corrected PET images with the CT images; this can be performed on any PET review station. In case of significant misalignment, the non–attenuation-corrected PET images should be reviewed without fusion with the CT images, and the metabolic findings of PET should be correlated side by side with the anatomic findings of CT (Fig. 10-2).

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Figure 10-1 Computed tomography (CT) (A) is used for anatomic localization and as an “attenuation map” to normalize the intensity of uptake in the deeper structures compared with that of the superficial structures. The metastatic liver lesion (arrow) is better appreciated on the attenuation-corrected positron emission tomography (PET) image (C) or fused attenuation-corrected PET/CT image (D) than on the non–attenuation-corrected PET image (B).

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Figure 10-2 Lesions can be mislocalized because of movement of the head between computed tomography (CT) and positron emission tomography (PET) acquisition. In a patient with recurrent squamous cell cancer of the left cheek, PET was requested for staging. Fused attenuation-corrected PET/CT images indicated an abnormal focus in the left external auditory canal (A). Review of the fused non–attenuation-corrected PET/CT images (B) revealed misalignment between CT and PET. Side-by-side review of the non–attenuation-corrected PET scans (C) and CT scans (D) was most useful and could localize the area of abnormal uptake anterior to the left ear (arrowhead).

At its introduction, the CT portion of the PET/CT was acquired without contrast and used solely for attenuation correction and anatomic localization of the PET findings. However, with the development of multislice CT machines and their introduction to PET/CT scanners, an increasing number of institutions are performing the CT portion of the PET/CT studies with diagnostic-quality CT, using intravenous and oral contrast media as needed. However, because the density of intravenous and oral contrast media used in CT can produce artifacts, with overestimation of FDG uptake in areas of high-contrast density, the CT scanning protocol has to be modified with the general approach of dilution of the contrast medium.

General Aspects of Tumor Visualization on 18F-Fluorodeoxyglucose Positron Emission Tomography

FDG (2-[18F] fluoro-2-deoxy-D-glucose) is the most commonly used radiotracer in clinical PET imaging. Tumor imaging with FDG is based on the principle of increased glucose metabolism of cancer cells. Like glucose, FDG is taken up by the cancer cells through facilitative glucose transporters (GLUTs). GLUTs are glycoproteins; 12 isoforms have been identified. Once in the cell, glucose or FDG is phosphorylated by hexokinase to glucose-6-phospate or FDG-6-phosphate, respectively. Expression of GLUTs and hexokinase, as well as the affinity of hexokinase for phosphorylation of glucose or FDG, is generally higher in cancer cells than in normal cells. Glucose-6-phosphate travels farther down the glycolytic or oxidative pathways to be metabolized, in contrast to FDG-6-phosphate, which cannot be metabolized. In normal cells, glucose-6-phosphate or FDG-6-phosphate can be dephosphorylated and exit the cells. In cancer cells, however, expression of glucose-6-phosphatase is usually significantly decreased, and glucose-6-phosphate or FDG-6-phosphate therefore can become only minimally dephosphorylated and remains in large part within the cell. Because FDG-6-phosphate cannot be metabolized, it is trapped in the cancer cell as a polar metabolite, and it constitutes the basis for tumor visualization on PET.

The intensity of a malignant tumor on PET correlates with the number of malignant cells in the tumor mass. Although most malignant tumors are markedly intense on PET, tumors such as bronchoalveolar lung cancer may be only moderately or mildly intense or may not be visualized on PET at all. Likewise, the intensity of a tumor decreases as soon as only one cycle of effective chemotherapy has been completed, possibly because of a decreased number of viable cells or the decreasing metabolic activity of those cells. Although this constitutes the basis for monitoring therapy by PET, the effect can also cause false-negative PET findings.

The intensity of malignant lesions on PET also depends on their location in the body. For example, the FDG avidity of a lung or liver lesion may be underestimated, or the lesion may even go undetected on PET; because of the repetitive craniocaudal movement of the lung and liver lesions during PET acquisition, the effective acquisition time is decreased. Detectability of lung and liver lesions can be improved by respiratory gating, in which only emission data collected in certain parts of the respiratory cycle are used for image reconstruction, resulting in better visualization of small lesions with the disadvantage of longer acquisition time. A practical approach in systems not equipped with respiratory gating is to increase the PET acquisition time and view the non–attenuation-corrected images; the latter eliminate any underestimation of uptake due to misalignment between PET and CT.

18F-fluorodeoxyglucose is also taken up in benign processes such as infection and inflammation because white blood cells and fibroblasts are highly avid for FDG. This is probably the most common reason for false-positive findings on PET scans obtained for oncologic indications. A false-positive reading on PET can partly be avoided by obtaining the patient’s medical history and determining the pretest likelihood of an infectious or inflammatory process. There are no published data on the time interval after an invasive procedure or radiation therapy in which a PET scan can be falsely positive, and the inflammatory cell reaction after such a procedure varies among organs. For example, there is evidence that only minimal reactive cell accumulation occurs in the liver within the first 3 days after radiofrequency ablation and that the reactive cells do not cause false-positive PET findings at least in the first 7 days after radiofrequency ablation.1

To minimize FDG uptake in the muscle while maximizing its uptake in tumor, patients are instructed to fast for at least 4 hours and avoid excessive physical activity for 24 hours before the PET appointment. Glucose-containing drinks and intravenous glucose must be avoided at least 4 hours before FDG injection. The fasting state lowers the serum level of glucose so that FDG has less competition for uptake by the tumor, whereas muscle uptake is minimized by fasting (by lowering the serum insulin level) and by avoiding excessive physical activity; low FDG uptake in the muscles improves the tumor-to-background ratio and the image quality.

High glucose levels in patients with diabetes can decrease the image quality. Although a normal glucose level in a patient with diabetes is desirable before FDG injection, it often cannot be achieved. Most institutions perform PET for patients with diabetes after one or two attempts to reduce the serum glucose level below an empirically set level of 200 to 250 mg/dL. Although the positive predictive value of the findings on such a scan remains high, the negative predictive value may be reduced. In patients with diabetes, the image quality (i.e., muscle and soft tissue uptake) should be assessed before interpretation and mentioned in the report.

18F-fluorodeoxyglucose uptake in the brown fat in the neck and supraclavicular regions may obscure pathologic findings in these areas. FDG uptake in brown fat is even more extensive in pediatric patients, and it can be seen in the mediastinum, paraspinal region, and upper abdomen. Diazepam administration can reduce the FDG uptake in brown fat.

The standardized uptake value (SUV) is a semiquantitative measure of the tracer uptake in a region of interest that normalizes the lesion activity to the injected dose and body weight; SUV does not have a unit. Despite initial enthusiasm, it is generally accepted that SUV should not be used to differentiate malignant from benign processes, and that the visual interpretation of PET studies by an experienced reader provides the highest accuracy. There are many factors influencing the calculation of SUV, such as the body weight and composition, the time between tracer injection and image acquisition, the spatial resolution of the PET scanner, and the image reconstruction algorithm. Nonetheless, SUV may be useful as a measure to follow the metabolic activity of a tumor over time within the same patient and to compare different subjects within a research study under defined conditions. For example, the SUV of an individual tumor can be measured before and at different time points after therapy, and any change can be used as an index of therapeutic response. However, it is unclear whether this measure can be used for clinical decision making. Some indicate that the intensity of FDG uptake by itself can assess the aggressiveness of a tumor and therefore correlate with prognosis, regardless of the treatment modality. However, there is no firm evidence that patient management should be modified on the basis of intensity of uptake.2

Most Common Indications for 18F-Fluorodeoxyglucose Positron Emission Tomography in Oncology

Lung Cancer

Positron emission tomography has an overall sensitivity of more than 90% and a specificity of about 85% for diagnosing malignancy in primary and metastatic lung lesions; the sensitivity and specificity of PET for small cell lung cancer are similar. The sensitivity of PET for bronchoalveolar lung cancer and carcinoid of the lung is about 60%, and the specificity of PET for lung cancer is lower in areas with a high prevalence of granulomatous lung disease. PET is particularly useful in patients with a low (5% to 20%) or intermediate (20% to 70%) risk of lung cancer, as determined by an evaluation of symptoms, risk factors, and radiographic appearance. In these cases, PET is helpful in moving the patient to the very-low-risk (<5%) or high-risk (>70%) category.3 It is expected that the use of PET for diagnosing malignancy in indeterminate lung nodules will continue to grow as more patients are diagnosed with nodules on CT performed for other indications or as a screening test. Most current PET scanners are capable of detecting lung lesions as small as 6 mm, and the resolution of PET is likely to improve. Most of the literature in this regard is based on data from the 1990s, when the resolution of PET was above 1 cm; studies are being conducted to systematically assess the sensitivity and specificity of PET for detecting malignancy in subcentimeter lung lesions.

In mediastinal staging of non–small cell lung cancer (NSCLC), patients with clinical stage I and II disease have by definition a radiographically negative mediastinum. However, in patients with central tumors, adenocarcinoma, or N1 lymph node enlargement, the false-negative rate of CT for mediastinal involvement is 20% to 25%. It is unclear whether PET should be used instead of mediastinoscopy in staging the disease of these patients. In mediastinal staging of clinical stage III tumors, positive results of PET need to be confirmed by tissue diagnosis because of a relatively high false-positive rate (15% to 20%). The false-negative rate of PET and mediastinoscopy in assessing enlarged mediastinal lymph nodes is 5% to 10%, and some authorities therefore do not pursue biopsy in the case of a negative PET result for disease in the mediastinum, whereas others argue that mediastinoscopy can detect microscopic metastases, and they are not comfortable accepting a negative PET result.4 Practically, in larger centers, patients with stage III tumors undergo both PET to assess for distant metastases and mediastinoscopy, but a strong argument for staging of the mediastinum with PET can be made in communities without an experienced mediastinoscopy service.

For patients with clinical stage I peripheral tumors, most authorities do not request mediastinoscopy before surgery, because the rate of mediastinal or systemic involvement is very low (about 5%); however, this detection rate is based on investigations before implementation of PET, and PET may increase the detection rate. Among patients with clinical stage II tumors, the rate of metastatic disease is higher, and PET may be warranted in these patients to assess for systemic disease. For stage III tumors, the false-negative rate of clinical evaluation for systemic disease is 15% to 30%, and PET is justified instead of a battery of other tests (e.g., bone scan, CT, MRI) to assess for distant metastases.4 PET is more sensitive (90% vs. 80%) and more specific (90% vs. 70%) than bone scan in detecting bone metastases from NSCLC; PET has a sensitivity and specificity of greater than 90% in detecting adrenal metastases from NSCLC. Brain CT or MRI is still needed because PET cannot reliably detect brain metastases because of physiologically intense brain uptake of FDG. For patients with stage IV tumors, PET may be able to indicate the most accessible site for biopsy.

PET is also useful in restaging NSCLC. In particular, PET appears to be more sensitive than CT in differentiating postirradiation change from local recurrence, although differentiating these two entities remains a challenge. The postirradiation change in the chest can remain intense on PET for up to several years. In differentiating local recurrence from postirradiation change, the intensity of uptake and its shape should be taken into account (Fig. 10-3).

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Figure 10-3 Postirradiation change versus active tumor. A, An elongated area of mild uptake strongly suggests postirradiation change. B, A focal area of intense uptake (arrow) indicates cancer. C, The elongated area suggests postirradiation change, but the more focal area anteriorly (arrowhead) may be cancer, and biopsy or imaging follow-up is warranted.

Head and Neck Cancer

Most patients with head and neck cancer present for PET with a known diagnosis. However, cervical lymph node metastases from an unknown primary tumor constitute about 2% of newly diagnosed head and neck cancer cases; CT and MRI can identify up to 50% of the primary tumors in patients with no findings on physical examination. The overall PET detection rate in patients with negative results of physical examination, CT or MRI, and endoscopy is about 25%. This detection rate is based on studies in which stand-alone PET was used, and it is expected to be higher with fused PET/CT. PET/CT should probably be performed instead of CT or MRI before endoscopy.5 Knowledge of the variable physiologic uptake patterns in the head and neck region is essential to minimize false-positive interpretations.

In initial staging of head and neck tumors, PET has a sensitivity and specificity of about 90% for nodal staging, and PET therefore is more sensitive and specific than CT or MRI. A weakness of PET is its low sensitivity (30%) for nodal disease in patients with disease in the neck at clinical stage N0. Given the high specificity of PET in nodal staging, it appears reasonable to perform neck dissection in patients with a positive PET result, whereas those with a negative PET result may be able to undergo sentinel node localization and biopsy.5 In addition to local staging, PET can detect synchronous cancers and distant metastases. In initial staging of head and neck cancers, a PET scan is overall most helpful in patients with locally advanced disease because these patients have a risk of 10% or greater for distant disease.

For restaging of head and neck tumors after radiation therapy, PET is highly sensitive; however, the optimal time to perform PET is a matter of debate. There is a higher likelihood of false-positive findings when PET is performed earlier than 3 months after irradiation. Based on recommendations from large institutions in the United States, PET should be performed 3 months after radiation therapy; patients with a negative scan can be followed without intervention (i.e., high negative predictive value), but those with a positive scan need to undergo further evaluation.5

Lymphoma

Positron emission tomography (especially fused PET/CT) is superior to conventional CT in staging of Hodgkin’s disease and non-Hodgkin’s lymphoma; however, there is no definite evidence that PET changes the initial management of lymphoma patients. Nonetheless, because most recurrences occur at the sites of the primary disease, pretreatment PET appears helpful in identifying recurrence.

Hodgkin’s disease and high-grade non-Hodgkin’s lymphoma are mostly markedly avid for FDG and almost always visible on PET, whereas low-grade non-Hodgkin’s lymphoma can be only mildly intense and, in rare cases, completely invisible on PET. The normal spleen shows mild uptake, whereas the uptake of the normal bone marrow can be variably intense. Intense spleen uptake (i.e., more intense than the liver) before chemotherapy is a reliable indicator of its involvement, but spleen involvement by lymphoma cannot be excluded with normal uptake. PET cannot be used to reliably evaluate bone marrow involvement. Activation of hematopoiesis after chemotherapy or by bone marrow–stimulating factors can cause intense uptake in the bone marrow, spleen, or thymus, which can persist after the termination of the chemotherapy or stimulating factors.

The most promising role of PET in lymphoma management appears to be in therapy monitoring: early prediction of response to chemotherapy (i.e., interim or midway PET) and evaluation of a residual mass for active lymphoma at the completion of chemotherapy (i.e., end-of-treatment PET). The decrease of uptake associated with effective chemotherapy seen on interim PET precedes the anatomic changes seen on CT by weeks to months. Overall, metabolic changes on interim PET after one or a few cycles of chemotherapy are reliable predictors of response, progression-free survival rates, and overall survival rates. However, it is unclear how the findings on interim PET should be used in patient care.

End-of-treatment PET has proven impact in patient care. At the completion of chemotherapy, CT demonstrates a residual mass at the initial site of disease in as many as 50% of patients. On the end-of-treatment PET, these patients demonstrate increased FDG uptake in the area of residual lymphoma in contrast to those without active lymphoma. The positive predictive value of residual uptake at the completion of chemotherapy is more than 90%. The negative predictive value is likely lower and associated with microscopic remnant disease. Generally, patients with non-Hodgkin’s lymphoma and stages III and IV Hodgkin’s disease who have negative PET results at the completion of chemotherapy should undergo repeat PET at least once at about 6 weeks after the last cycle of chemotherapy.

In follow-up of patients in remission, PET is more sensitive than CT in detecting recurrent disease. There are no clear guidelines about how often follow-up PET scans should be performed; they often are performed as frequently as every 3 months. PET (especially PET/CT) is superior to gallium scan in all of the previous indications.

Colorectal Cancer

PET plays no role in the screening or diagnosing of colorectal cancer, and neither the depth of the tumor nor the status of local lymph nodes can be assessed by PET. However, PET is highly sensitive in detecting distant hepatic and extrahepatic metastases. A meta-analysis of the literature on detection of hepatic metastases from colorectal, gastric, and esophageal cancers by ultrasound, CT, MRI, and PET found that in studies with a specificity higher than 85%, the mean weighted sensitivity was 55% for ultrasound, 72% for CT, 76% for MRI, and 90% for PET. Results of pairwise comparison between imaging modalities demonstrated a greater sensitivity of PET than ultrasound (p = .001), CT (p = .017), and MRI (p = .055). The conclusion was that at equivalent specificity, PET is the most sensitive noninvasive imaging modality for the diagnosis of hepatic metastases from colorectal, gastric, and esophageal cancers.6 Considering the higher sensitivity of PET in detecting distant metastases and the introduction of intravenous contrast media to the CT portion of fused PET/CT, it is conceivable that PET/CT will be increasingly employed in preoperative staging of colorectal cancer; the contrast-enhanced CT portion of PET/CT can be used instead of conventional CT or MRI for evaluation of anatomic resectability of liver metastases. PET plays an important role in restaging of colorectal cancer and is even more important now that it is known that treatment of limited metastatic disease can be curative. PET can visualize the site of the local and distant disease when recurrence is suspected based on the clinical findings, findings on other imaging modalities, or an increasing carcinoembryonic antigen level with sensitivity and specificity higher than 90% (Fig. 10-4).

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Figure 10-4 Positron emission tomography (PET) is used in differentiating local recurrence from scar in a patient with colon cancer after low anterior resection. Recurrent disease was suspected based on the increasing carcinoembryonic antigen level. CT could not differentiate between scar and local recurrence. A, PET indicated an intense focus (arrow) suspicious for cancer, and a second mild focus (arrowhead) was interpreted as scar. B, The diagnosis was confirmed surgically, and the recurrent tumor was removed.

Breast Cancer

PET can increase the detectability of small primary breast cancers and may be especially useful in evaluating patients with dense breast tissue. Its role in routine patient care is under investigation. In evaluating the axillary lymph nodes, PET does not play any role because of its low sensitivity (60%) despite relatively high specificity (80%).7 In contrast, PET is relatively sensitive (85%) and specific (90%), and it is superior to CT (sensitivity of 54%, specificity of 85%) in evaluation of the internal mammary chain lymph node for metastases. The main role of PET in breast cancer lies in the investigation of distant metastases and response monitoring. Compared with CT, PET has a higher sensitivity (90% vs. 40%) but lower specificity (80% vs. 95%) in detecting metastatic disease. Overall, PET has the same sensitivity as bone scan in detecting bone metastases (both about 90%), but PET appears to be somewhat more sensitive than bone scan for osteolytic lesions and somewhat less sensitive than bone scan for osteoblastic lesions. PET has a higher specificity than bone scan in detecting bone metastases (95% vs. 80%). This may be explained by the fact that PET captures the metabolic activity of the tumor cells independently of changes in the bone, whereas bone remodeling seen on bone scan can result from metastatic disease and benign causes.

In patients with advanced breast cancer undergoing neoadjuvant chemotherapy, PET may differentiate responders from nonresponders as soon as the first cycle of therapy has been completed. This may help improve patient management by avoiding ineffective chemotherapy and supporting the decision to continue dose-intensive preoperative chemotherapy in responding patients.

Positron Emission Tomography Applications in Other Malignancies

In esophageal and gastric cancers, PET is useful to assess for distant disease. PET is routinely used in the staging of esophageal cancer, and it has the potential to be used for monitoring the effect of neoadjuvant therapy. In ovarian, uterine, and cervical cancers, PET is used to assess for recurrent disease. In cervical cancer, PET plays an important role in nodal staging and can have a role in radiotherapy planning. In malignant melanoma, PET is used to evaluate the presence of distant metastases. In sarcoma, the most intense areas on PET have usually the highest grade and should be considered in planning the biopsy.

Targeted Imaging In Nuclear Medicine

From its inception, nuclear medicine has used specific physiologic and biophysical targets for imaging and therapy. Many of these targets hold promise for the future, but a few are being used routinely and are expanding the boundaries of research.

Because nuclear imaging techniques have had high sensitivities with known lesser specificities, other agents with greater specificity are being developed. Even though there may be some trade-off in sensitivity compared with other nuclear modalities, they have proved to be better than general radiologic modalities for many indications, and, in some cases, they can be used for targeted radionuclide therapies. Newer imaging technologies have been developed that greatly improve the ability to evaluate nuclear imaging.

Traditionally, nuclear imaging has used planar imaging with single-photon emitters such as technetium-99m (99mTc), indium-111 (111In), and iodine-123 (123I), amongst many others. However, it is possible to do tomographic—or single-photon emission computed tomography (SPECT)—imaging of radiotracers, providing overall greater accuracy of lesion diagnosis and detection. Compared with PET imaging, SPECT imaging has lower resolution, and it may be further limited in large patients because of attenuation. In the last few years, however, there has been substantial development using concurrent CT imaging—similar to PET/CT—for attenuation correction as well as anatomic localization. The result has been the development of SPECT/CT, which has provided a meaningful advance in disease evaluation, and the continued development of molecular imaging in addition to PET/CT.

Some radiopharmaceutical agents target by means of antibodies or their fragments, peptides, or are receptor- or even gene-specific. Although established procedures such as FDG-PET imaging are clearly superior to most of these newer methods, agents that focus on these specific targets remain clinically important in sites where PET may not be available. Nevertheless, radiopharmaceutical development in both PET and SPECT shows promise in the evaluation of disease and the advent of molecular imaging.

Bone Scanning

Bone scanning is the most basic oncologic imaging procedure in nuclear medicine. Its utility has long been proven in multiple diseases for both disease detection and follow-up. Traditionally, the study is done with planar whole body imaging using 99mTc-labeled bisphosphonates, most commonly MDP (methylene diphosphonate) and HDP (hydroxymethylene diphosphonate). Additional limited planar or SPECT views can be obtained that focus on the body part of interest. Essentially, the procedure allows a rapid skeletal survey and an overall assessment of disease.

There are drawbacks to this modality. Primarily, planar bone imaging is insensitive for the detection of lytic lesions, although these are not infrequently detected. SPECT imaging improves sensitivity of the study, as does imaging with SPECT/CT; however, a single SPECT acquisition can take 15 to 30 minutes but only show a single area of the body. Some have advocated whole-body SPECT studies, but this could easily take more than 90 minutes.

An even older modality is now gaining a resurgence of interest. Several studies have shown that imaging with 18F-NaF using modern PET/CT systems is superior to 99mTc-labeled bisphosphonate imaging, including whole body SPECT.8 Furthermore, the imaging time involved in obtaining a tomographic whole body view with PET/CT is similar to the time it would take to obtain a whole-body planar scan with additional limited planar and/or SPECT views. Because 18F-NaF imaging can be started much earlier than traditional SPECT imaging, the procedure from injection time to the end of scan is a few hours shorter for the patient. Although 18F-NaF imaging has been approved by the U.S. Food and Drug Administration (FDA), it is currently being evaluated by the Centers for Medicare and Medicaid Services (CMS) for reimbursement as a routine clinical procedure.

Antibody-Based Imaging Agents

One of the more successful antibody imaging agents is ProstaScint (capromab pendetide), an antibody against prostate membrane surface antigen, a type II membrane glycoprotein strongly associated with prostate cancer. The usual indication is a rising level of prostate-specific antigen (PSA) in a patient who has had a prostatectomy but who has no obvious location for a metastatic focus as determined by CT or MRI. This modality has a sensitivity of disease detection of only 5% to 20%, although it has a much higher specificity. The overall accuracy for capromab imaging is about 70%, although it is much less sensitive than bone scan for skeletal metastases. Absence of extrapelvic disease on capromab and other studies may allow for radiotherapy to the pelvis in a patient at high risk for extensive disease. Because of the limited success of FDG-PET in detection of metastatic prostate cancer, capromab still has utility. It is unclear whether the development of positron-labeled agents such as choline or methionine will surpass its performance.

Carcinoembryonic antigen scans use a labeled murine antibody fragment (99mTc-arcitumomab) to detect recurrent colorectal carcinoma, and the modality can also be used for detecting breast cancer. OncoScint (111In-satumomab pendetide) is another antibody used for detection of recurrent colorectal and ovarian carcinomas. For colorectal malignancy, the sensitivity, specificity, and accuracy of extrahepatic disease recurrence detection for satumomab are 97%, 78%, and 92%, respectively, whereas those for CT scans are 72%, 89%, and 76%, respectively. For liver metastases, CT is better, with sensitivity, specificity, and accuracy values all about 92%; satumomab values are 85%, 92%, and 89%, respectively. When the two modalities are combined, the sensitivity is approximately 90%.9 Nevertheless, FDG-PET outperforms these modalities and is the scan of choice, although the antibodies have clinical value where FDG-PET is not available.

Cellular Imaging

Various agents being developed build on the newer understanding of cellular physiology, including angiogenesis, apoptosis, and other ideas. Some are routinely used clinically, but others show potential for future development and may revolutionize the way cancer is approached.

18F-fluorothymidine (18F-FLT) is a thymidine analog and a PET tracer that is phosphorylated by thymidine kinase-1 (TK1) to FLT-monophosphate. FLT uptake correlates with TK1 activity and cellular proliferation. FLT may be more suitable than FDG to monitor the effects of chemotherapy and radiation therapy. Another important area of PET tracer research concerns cell-cell and cell-matrix interaction. Tracers such as 18F-galacto-GRD (glycosylated Arg-Gly-Asp) enable the noninvasive determination of integrin αvβ3 expression and may be used in assessing angiogenesis and the metastatic potential of tumors.

Annexin-V shows promise for evaluating apoptosis and is available as a single-photon and PET agent. Highly apoptotic areas in tumors are likely to be sensitive to irradiation or chemotherapy, and there is the potential for evaluating therapy response or overall disease prognosis with such agents. Similarly, the field of tumor hypoxia is central to the understanding of tumor response to irradiation. PET agents such as 18F-fluoromisonidazole (18F-MISO) and Cu(II)-diacetyl-bis(N(4)-methylthiosemicarbazone) (Cu-ATSM) can be used to detect intratumoral hypoxia. Although these agents are still in the early evaluation phase, they could be used in the future to evaluate areas of hypoxia for targeting radiation delivery.

Neuroendocrine Tumor Imaging

111In-octreotide is a peptide that is routinely indicated for neuroendocrine tumors, including carcinoids, tumors associated with MEN (multiple endocrine neoplasia), meningiomas, and lymphomas (both Hodgkin’s disease and non-Hodgkin’s lymphoma). Increased activity can be seen in benign disease such as sarcoidosis and other inflammatory processes. 111In-octreotide has the highest affinity for somatostatin receptor (SSTR) subtypes 2 and 5, with weaker affinities for others. This agent is very relevant in the era of PET because many of the well-differentiated lesions do not take up FDG. However, many tumors do not have appropriate receptor expression and therefore have limited detection on such scans. A similar agent, 99mTc-depreotide, has greater affinity for SSTR 2, 3, and 5 and therefore has the potential for greater sensitivity for tumors with various SSTR expression and uptake in a broader number of cancers, including lung cancers. Nonetheless, 111In-octreotide is more widely used, and FDG-PET remains the modality of choice in detecting lung cancers where available.

Routine imaging of neuroblastomas and pheochromocytomas involves metaiodobenzylguanidine (MIBG), a norepinephrine analog taken up by the uptake 1 mechanism in receptors. Like octreotide, its uptake occurs in many similar cancers, although not with the same frequency. For imaging, MIBG may be labeled with 131I, 123I, or 124I, a positron emitter. The sensitivity for lesion detection can exceed 90%, and specificity approaches almost 100% for single-photon imaging.10 However, as tumors de-differentiate or metastasize to other sites, specifically the bones, MIBG becomes less sensitive, in which case a bone scan is useful. With the advent of 124I-MIBG used in PET/CT, it is possible that the increased resolution will allow better detection of disease, obviating the need for bone scans.

There is growing interest in being able to use newer tracers such as 3,4-dihydroxy-6-18F-fluoro-phenylalanine (18F-FDOPA) and PET in neuroendocrine imaging. These agents use neurohumoral pathways of uptake and trapping, similar in concept to that of FDG, to concentrate in relevant areas. Many studies show that this tracer has far greater accuracy for disease detection than either octreotide analogs or MIBG.11 Unlike the SPECT counterparts, the PET imaging can be done within an hour after injection; images are of the same quality as PET images. 18F-FDOPA is most useful in well-differentiated to moderately differentiated tumors, with FDG being superior for the more poorly differentiated ones. Other octreotide-based positron tracers labeled with 68Ga, such as [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-1-Nal3-octreotide (68Ga-DOTANOC), are showing promise as imaging agents.

Renal Cell Carcinoma

Clear cell varieties of renal cell carcinomas can constitute a substantial percentage of incidentally discovered renal masses, and methods to identify this aggressive cancer early and preoperatively could be useful. A recently developed agent, 124I-girentuximab, a radiolabeled antibody against carbonic anhydrase IX (CA IX), is reactive in more than 95% of immunohistochemical assays on fresh-frozen tissues. A phase I trial for this agent showed accuracy of more than 90% for the detection of primary clear cell renal carcinoma, although the accuracy for metastatic disease detection was not studied.12 A phase III trial of this agent has been concluded and is undergoing data analysis.

Multimodality Imaging

An intriguing concept is imaging of multiple tracers simultaneously, allowing a wealth of information to be obtained concurrently in a single imaging session. Whereas this can be done with different isotopes in the SPECT arena, it is much more limited with PET because all the positron isotopes emit the same energy photons (511 keV) and, therefore, different PET tracers cannot be distinguished. Whereas acquisition of separate images, such as FDOPA and FDG, may provide a wealth of molecular information about a disease, as well as diagnostic information, it would entail obtaining two separate scans, one for each tracer. Conversely, performing a scan with simultaneous administration of tracers would provide optimal diagnostic imaging and would require only one scanning session, although molecular information provided by the separate tracers would not be obtained. Similarly, other theoretical combinations with FDG/124I-cG250, FDG/F-choline, FDG/NaF, and others can be used in a variety of diseases to improve the overall performance of PET as a diagnostic tool, if that is all that is needed.13

Targeted Radionuclide Therapy

Imaging agents are valued more for their sensitivity, but for targeted therapy, it is the specificity that is essential. Many imaging agents are specific enough for therapeutic purposes. Treatment of well-differentiated thyroid cancer, radioimmunotherapy, and pain palliation for bone metastases are discussed elsewhere in this book. The following sections provide examples of assorted therapies used in other clinical settings that show promise for development in the near future.

Benign Thyroid Disease

Thyroid diseases have the most successful application of targeted therapy that is clinically relevant. The thyroid’s unique ability to metabolize elemental iodine to synthesize thyroid hormones is fortuitous because it is a highly specific but easily targeted process with radioactive iodine. Treatment is effective, is virtually definitive, and has minimal side effects. There are practically no long-term sequelae from radioactive iodine administration for benign thyroid disease. Generally, radioactive iodine treatment in benign disease is reserved for hyperthyroid conditions, such as Graves’ disease or toxic and multinodular goiters. Radioactive iodine is used when the disease cannot be controlled medically, and it is often a first-line option in patients with clinical hyperthyroidism. Surgery is reserved for instances in which radioactive iodine may be contraindicated (e.g., pregnancy, marrow suppression) or when there may be compressive findings of the enlarged thyroid on critical structures such as the trachea.

Thyroid Cancer Evaluation and Treatment

Thyroid cancer patients have traditionally undergone 4 to 6 weeks of LSM-thyroxine withdrawal prior to radioiodine scanning and treatment to stimulate tumors to take up iodine. The introduction of recombinant human thyroid-stimulating hormone (rhTSH) has revolutionized thyroid cancer evaluation. TSH is injected intramuscularly to stimulate residual thyroid cells to take up radioiodine. Results are available within a few days, which means that patients need not endure a prolonged hypothyroid state before diagnostic studies can be obtained, as they once did. Although approved for therapeutic administration of radioiodine for postsurgical remnant ablation in low-risk disease groups (based on data showing equivalent efficacy in outcomes),14 rhTSH is still not approved for patients who have moderate-risk or high-risk disease. However, the option to use it in patients who would otherwise be unable to tolerate hormone withdrawal, or would do so with difficulty, is a great step forward for many patients. Use with caution in the moderate-risk to high-risk groups because there are no long-term outcome studies showing the efficacy of rhTSH compared with the hormone withdrawal method.

Octreotide Derivatives in Neuroendocrine Cancers

A novel application is the use of octreotide in targeted radionuclide therapy. 111In-octreotide has been used in clinical trials, and initial results were encouraging, although objective response rates were a meager 0% to 8%, with 42% to 81% of patients having stable disease and 12% to 38% showing disease progression. The octreotide molecule has subsequently been modified to increase its specificity for tumor targeting, to decrease its affinity for nontargeting areas in other organs, and to try to improve its toxicity profile. 111In-octreotide has been altered to create [90Y-DOTA0]-Tyr3-octreotide (DOTATOC) and [177Lu-DOTA0]-Tyr3-otreotate (DOTATATE), with some improvement in their target-to-nontarget ratios. The DOTATOC trials showed improved objective responses ranging from 7% to 33%, with stable disease in 52% to 81% of patients and disease progression in 9% to 19%. Trials with DOTATATE showed similar objective response rates. Aside from marrow toxicity and myelodysplasia, nephrotoxicity was the other most significant long-term sequela; it could be decreased with infusion of amino acids before therapy. As in all radionuclide targeted therapies for solid tumors, hematotoxicity was seen.15

The success of DOTATOC and DOTATATE likely results from their better targeting of tumor compared with octreotide. The radiobiology of the beta emitters 90Y and 177Lu appears to be superior to that of the Auger emitter 111In. The newer trifunctional, somatostatin-based derivatives have prolonged cell retention, and they are internalized into the cell nucleus, making them optimal for Auger therapy, as 111In.16 Future trials with such compounds are of great interest in developing targeted radionuclide modalities.

Metaiodobenzylguanidine Therapy in Neuroendocrine Cancers

Metaiodobenzylguanidine (MIBG) has been used therapeutically as 131I-MIBG in neuroblastomas in children and in pheochromocytomas. Objective responses have ranged from 47% to 80% when MIBG is used as a single agent in neuroblastoma. The main toxicity is hematologic, and trials are being conducted with autologous stem cell reconstitution. Studies have also been conducted combining MIBG with chemoradiotherapy, with various responses.17

Other Uses of Targeted Radionuclide Therapies

Polycythemia vera was frequently treated with phosphorus-32 (32P) in the past, but with the advent of modern chemotherapy, this has become uncommon. Although the median survival rate was improved, there was an increase in the incidence of secondary blood dyscrasias. This therapy is used in patients who cannot tolerate hydroxyurea and other treatments or who have symptoms that do not respond to other therapeutic maneuvers.

Radiocolloids such as gold-198 (198Au) colloid or chromic phosphates labeled with 32P or 90Y have been used as palliative regimens in malignant ascites in ovarian carcinoma, for pleurodesis for pleural effusions, as intracavitary injections for cystic brain tumors, and even for radiosynovectomies in benign inflammatory arthritic diseases. Other therapies have included using 35S-thiouracil for ocular melanoma. Despite being effective treatments, they have been replaced by modern medical management, although they are still rarely used when other therapies fail. Interest in radiosynovectomy is growing as an alternative to surgical management or as a means of delaying surgery when medical management is no longer adequate.

Another therapy involves using microspheres embedded with 90Y for palliation in hepatocellular carcinoma, as well as other cancers such as colorectal carcinoma and neuroendocrine tumors that have metastasized to the liver. Microspheres are injected into the hepatic artery directly to the site of diseased liver, where they reside in the vascular space as the nuclides decay, delivering high local radiation doses. Because the product is not systemically delivered (although shunting can occur), side effects are well tolerated and may be less severe than with other therapeutic options. The data suggest palliative benefits, and initial evidence suggests promising survival times compared with systemic options.18 Similarly, 131I-lipiodol is emerging as a candidate for similar indications and has undergone trials with cisplatin showing a well-tolerated toxicity profile.19 On the horizon, newer therapies may use liposomes to deliver therapeutic radionuclides to micrometastases in various cancers to complement antibody-mediated therapies.20

Therapy-Enhancing Strategies

Therapy enhancement basically relies on trying to boost radionuclide uptake and prolong its cellular retention to improve tumor kill from the targeted radiation. In thyroid cancer, lithium has been shown to produce a modest increase in free iodine retention and to increase dose delivery to tissue.21 There is evidence to suggest that medications such as rosiglitazone, suberoylanilide hydroxamic acid (SAHA), and others may improve radioiodine uptake in selected tumors, but no clear clinical benefit has yet been demonstrated.22

The addition of gemcitabine to the 90Y-radiolabeled antibody 90YcPAM4 has shown some promise in pancreatic cancer in improving the efficacy of targeted therapy, presumably because of its action as a radiosensitizer to the effects of 90YcPAM4. Currently, phase I/II trials are under way for evaluation of this combination, but they use a humanized version of the antibody (90Y-hPAM4).23

Some of the newer antibody therapies use genetically engineered antibodies or altered pharmaceuticals and attach radionuclides with more favorable characteristics to improve tumor-specific targeting and, possibly, therapeutic efficacy. Other methods employ multistep targeting; all of the methods are experimental, but they hold promise. Such results have prompted their use in conjunction with external beam radiation therapy and chemotherapy. This could help to develop targeted radionuclide therapy into a clinically relevant option.

References

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18 Stuart JE, Tan B, Myerson RJ, et al. Salvage radioembolization of liver-dominant metastases with a resin-based microsphere. Initial outcomes. J Vasc Interv Radial. 2008;19(10):1427-1433.

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20 Emfietzoglou D, Kostarelos K, Papakostas A, et al. Liposome-mediated radiotherapeutics within avascular tumor spheroids. Comparative dosimetry study for various radionuclides, liposome systems, and a targeting antibody. J Nucl Med. 2005;46(1):89-97.

21 Koong SS, Reynolds JC, Movius EG, et al. Lithium as a potential adjuvant to 131I therapy of metastatic, well differentiated thyroid carcinoma. J Clin Endocrinol Metab. 1999;84(3):912-916.

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