Chaitanya R. Divgi
I. DEFINITIONS
A. Nuclear medicine is the use of radioactive tracers in the form of unsealed sources for the diagnosis, therapy, and laboratory testing of human diseases. The common radiopharmaceuticals include 25 forms for diagnostic imaging applications and 5 forms for therapy (Table 2.1).
Table 2.1 Some Diagnostic and Therapeutic Radiopharmaceuticals
Key: CEA, carcinoembryonic antigen; FDG, fluorodeoxyglucose; LVEF, left ventricular ejection fraction; MIBG, metaiodobenzylguanidine; MIBI, methoxyisobutyl isonitrile; MoAb, monoclonal antibody; PSMA, prostate-specific membrane antigen; TF, transferrin; WB, whole-body dose.
B. Radioactivity, radioisotopes, and radionuclides. The nucleus contains a variety of subatomic particles, such as protons and neutrons, which are held together by incredibly strong short-range forces. The atomic number(Z) of an atom is the number of protons in the nucleus and is characteristic of a particular element. The mass number of an atom is the sum of the protons and the neutrons (A); it is this number that we refer to in this section unless otherwise specified. For most of the common elements in the earth, the nucleus is completely stable and unchanging. Radioactive elements occur when the balance of subatomic particles in the nucleus is inherently unstable. Each radionuclide has specific radioactive decay characteristics in terms of half-life and radioactive emissions.
1. The half-life (t1/2) is the time required for one-half of the atoms to undergo radioactive decay.
a. The half-life of most of the radioisotopes is short, and they therefore do not exist in nature. Some naturally occurring elements are radioactive; for example, 40K accounts for 0.1% of the potassium found within the human body and has a half-life of 1.26 × 109 years. Other naturally occurring radioactive elements include radium, thorium, lead, and carbon. All elements with atomic weights greater than 209Bi are radioactive. The transuranium elements may also have half-lives of 10,000 years or more.
b. Most of the radioactivity used in nuclear medicine is artificially produced in a cyclotron or reactor (see Sections I.D.5 and I.D.6). 131I, for example, has a half-life of 8 days and emits a gamma ray of 364 keV, along with several beta particles, including one with a maximum energy of 0.606 MeV. These radioactive emissions can be detected externally and permit 131I to be useful as a tracer for the study of thyroid physiology.
2. Forms of radioactive emissions
a. Gamma rays: Photoelectric energy that is capable of penetrating a meter or more through human tissue
b. Beta rays: Particulate emissions with the mass of an electron and a negative charge that are capable of penetrating from a few millimeters to about a centimeter in tissue
c. Positrons: Particulate emissions with the mass of an electron and a positive charge that travel for a few millimeters in tissue and then interact with an electron, forming annihilation radiation
d. Annihilation radiation: Two gamma photons of 511-keV energy traveling at 180 degrees from each other that are created when a beta ray and a positron combine
e. Alpha particles: Two neutrons and two protons (a helium nucleus) that are capable of traveling for about 10 to 20 cell diameters in tissues
f. X-rays: Result from rearrangement of electrons in orbit around the nucleus
g. Auger electrons: Low-energy electrons that are emitted from the orbits around the nucleus and travel only a few microns in tissue
h. Applications. Gamma rays and annihilation radiation in particular are useful for various diagnostic imaging applications. The shorter range particles, such as alpha particles, beta rays, and Auger electrons, are used for therapeutic applications.
3. Quantity of radioactivity
a. Becquerel (Bq). One disintegration per second (dps) is defined as 1 Bq of radioactivity, in honor of the discoverer of radioactivity. Typical doses used for imaging are often 37 MegaBecquerels (MBq), which is 1 milliCurie (mCi).
b. Curies (Ci). The curie unit is based on the amount of radioactivity in 1 g of radium or 3.7 × 1010 dps. Typical diagnostic doses range from 1 mCi (37 MBq) to 30 mCi (1,110 MBq).
4. Quantity of absorbed radiation
a. Rads. When radioactive emissions interact with matter, a fraction of the total energy is absorbed. The rad is equivalent to 1 erg of energy absorbed per gram of tissue.
b. Gray (Gy) is the newer unit replacing the rad. One Gray is 100 rad; 1 centiGray (cGy) is 1 rad.
c. Rem (R), or roentgen equivalent man, was introduced as a unit because not all radiation emitted has equivalent potency for the biologic effects that it exerts for a given amount of radiation dose absorbed. For gamma photons and x-rays, the rad dose and the rem dose are the same. For larger particles (e.g., the alpha particle), the rem is the rad dose times a “quality factor.” For alpha particles, the quality factor is much higher, so that for a given rad dose, the rem for alpha-particle exposure is much greater than that for gamma exposure: The exact value is under debate but is typically assumed to be at least 20-fold higher.
d. Sieverts (Sv). One Sv is 100 rem.
C. How much radiation exposure is safe? The answer is the ALARA principle, which means “as low as reasonably achievable.”
1. In the workplace, a maximum of 5,000 milliRem (mRem) per year is permitted; 25% of this dose (1,250 mRem) is sought. Several decades of exposure of large populations of workers to the 5,000 mR/yr limit has demonstrated no adverse effects. The U.S. Food and Drug Administration (FDA) has used this definition for what could be considered “safe” levels of total-body radiation exposure. Directives for pregnant workers permit 500 mR per 9-month gestational period.
2. The general public in the United States receives an average of 290 mR/yr from naturally occurring radiation. Up to 10 times this exposure may occur at high altitudes, again with no discernible adverse effects. The mandated level for the general public is now set at 100 mR/yr.
3. Diagnostic exposure for the purpose of patient management has no limits because the doses involved are relatively low, and it is generally believed that the benefits outweigh the risks associated with indicated studies.
4. Therapeutic radioisotopes sometimes require admission to the hospital. In the United States, the Nuclear Regulatory Commission has established guidelines such that therapy may be administered on an outpatient basis provided the radiation dose to the general public is within acceptable limits (see above), usually calculated based on the amount and effective residence time of the administered radioactivity; if data are not available for such determination to be made, hospitalization with radiation isolation precautions needs to be carried out until the radiation levels fall to 5 to 7 mR/hr at 1 m from the treated subject. After that point, the patient is not subjected to special precautions.
Photons can set off radiation detectors, increasingly in use in the United States after September 11, 2001. Thus, the patient needs to be advised about the potential for activation of such detectors—most institutions now provide patients with written directives including amount and type of radioactivity received.
D. Instrumentation
1. Well counters. A radiation-sensitive crystal (usually sodium iodide) is fashioned so that a small test tube containing a body fluid can be placed in a well. For each decay, the energy from the emitted radiation is deposited in the crystal, and the crystal is induced to emit a pulse of light. This light pulse is converted to a weak electrical signal by a photoelectric tube. Further amplification results in a signal that can be read as an individual “count.” Typical samples have 10,000 to 20,000 counts per minute (cpm). The amount of the radiotracer present is proportional to the total amount (cpm) detected. By reference to standards of known activity, the absolute amount of tracer can be detected.
2. Gamma camera devices are the most commonly used imaging device for the widely available radiopharmaceuticals, such as 99mTc, 111In, and 131I. The gamma camera is designed as a circular sheet of sodium iodide crystal, encased in a lead shield and directly coupled to 90 or more photoelectric tubes. A collimator device in front of the crystal serves to focus the radiation; it is a 1-in. thick lead shield with holes punched in the lead. Every disintegration in the patient that results in a gamma ray travels to the collimator and passes through the holes in the lead to strike the radiation-sensitive crystal. A light pulse is created in the crystal and is detected by several photomultiplier tubes simultaneously. A computer calculates where the photon hit the crystal, with the strongest signal being nearest the site where the photon struck the detector. Resolution is about 1 cm or so for most planar gamma cameras.
3. Single photon emission computerized tomography (SPECT). In this form of imaging, radioactivity within the patient is collected at 360 degrees around the patient, and the data are reconstructed into a three-dimensional representation. The data are collected by rotating a specialized gamma camera around a patient who has received an injection of radioactivity that is stable in distribution for the 45- to 60-minute collection times typically required. SPECT is commonly used for the imaging of 67Ga citrate in the mediastinum of patients with lymphoma, 201Tl in myocardial perfusion studies, hemangiomas within the liver, and radiolabeled antitumor antibodies.
The typical in-depth resolution is 16 mm, somewhat more coarse than for planar imaging. Planar gamma camera imaging provides better contrast resolution, whereas SPECT provides better images of small, deep lesions, especially when attenuation correction (whereby radioactivity emitted from deeper in the body is corrected based on the amount and type of tissue between the source and the detector) is carried out, using either assumptions or actual measurements of the density of tissue and nature of the attenuation.
4. Positron emission tomography (PET) has the highest resolution and is the most sensitive imaging device available for nuclear medicine. For reasons related to the physics of positron emission decay, the image can be converted into an accurate, quantitative three-dimensional distribution of radioactivity with a resolution of about 3 to 5 mm in depth within the body. The radiotracers used with PET are 18F, 15O, 13N, and 11C; these elements are readily incorporated into biologic molecules. Most of these radiotracers have half-lives that are too short for shipping. Thus, they must be produced in a hospital-based cyclotron. Nonetheless, clinical applications are emerging, especially using 18F-labeled tracers (which are now commonly being produced by commercial radiopharmaceutical manufacturers). 18F-fluorodeoxyglucose (18F-FDG) imaging of glycolysis by tumors has become the archetypal molecular imaging agent and is increasingly used to diagnose and stage cancer, as well as to demonstrate tumor viability after treatment with radiation or drugs.
5. Cyclotron. The cyclotron accelerates subatomic particles (e.g., protons, deuterons, helium nuclei, alpha particles) to speeds approaching the speed of light. The particle strikes a “target” atom and produces radioactivity. For example, by accelerating protons to about 11 MeV and striking a target that contains an enriched isotope of oxygen (18O), 18F in the form of fluoride ion is produced. These accelerator systemsproduce a large variety of the radio-tracers useful in nuclear medicine, including 11C, 15O, 13N, 67Ga, 111In, 123I, and 18F.
6. Reactors. The reactor is fueled by heavy elements, such as 238U and 235U, which undergo spontaneous fission. Neutrons are emitted from the nucleus and, when present in sufficient quantities, “split” the uranium atoms, with the consequent release of large amounts of energy. An entire cascade of radioactive elements is produced in this process; these elements, called fission products, include 99Mo (from which 99mTc is derived), 131I, 125I, 32P, and 35S. In some cases, a target element is bombarded with neutrons to produce the radioactive element used in medicine (e.g., 89Sr). In other cases, separation of fission products may produce the radioisotope as a by-product of reactor operation (131I, 125I).
II. TUMOR IMAGING STUDIES
A. Bone scanning
1. Indications for bone scanning are to determine the presence and extent of primary and metastatic tumor involving bone and to provide a baseline in early malignancy if the patient has a cancer that notoriously metastasizes to bone (e.g., prostate cancer, stage II or III breast cancer) or has significant bony abnormalities of a benign nature. Some cancers that metastasize to bone do not provoke increased hydroxyapatite turnover, and bone scans are not very useful in these cancers (multiple myeloma, thyroid cancer). Bone scans are frequently used for evaluation (not measurement) of bone metastases, most often in prostate and breast cancer, as well as in lung and colon cancer; bone scans are used less frequently in kidney cancer.
2. Radiopharmaceutical. A pyrophosphate or other phosphonate derivative is labeled with 99mTc.
3. Principle. Primary or metastatic tumor provokes a reaction in the adjacent bone that causes the bone crystal to remodel and in the process take up the 99mTc bone agent. Even small tumors can evoke a considerable response. (See Chapter 33, Section I.D.3.)
4. Procedural notes. Whole-body scans are ordinarily obtained using gamma cameras with large fields of view. SPECT imaging is performed on suspect regions and is particularly helpful in the spine.
5. Interpretation. Against a background of bone turnover, a metastatic site stands out as avid uptake. Bone scans are more sensitive than computed tomography (CT) and magnetic resonance imaging (MRI) for detection of metastases in cortical bone. MRI may detect metastases in the bone marrow before cortical bone is affected.
B. 18F-FDG imaging with PET
1. Indications
a. To distinguish radiation necrosis from recurrent glioblastoma
b. To evaluate dedifferentiation of brain tumor from low grade to high grade
c. To evaluate the potential for recurrence of meningioma
d. To assess tumor viability and monitor treatment response
e. To differentiate benign from malignant pulmonary nodules
f. To evaluate staging, restaging, and response to therapy; local and distant metastasis; and response to treatment in patients with a variety of hematologic and solid cancers, including lymphoma, breast, GI, lung, melanoma, and others (note g and h below)
g. For the diagnosis, staging, and restaging of hormone-refractory prostate cancer
h. For restaging of recurrent or residual thyroid cancers, of follicular cell origin, that have been previously treated by thyroidectomy and radioiodine ablation with serum thyroglobulin levels >10 ng/mL and negative 131I whole-body scans
2. Radiopharmaceutical: [18F]-2-fluoro-2-deoxy-d-glucose (or FDG) is an analog of glucose.
3. Principle. Tumors have markedly accelerated glycolysis in comparison to the tissues from which they arise. FDG enters the tumor cell through the glucose transporter and is phosphorylated to FDG-6-phosphate (FDG-6P). FDG-6P, however, is not a suitable substrate for other glycolytic enzymes, is “metabolically trapped,” and accumulates in the tumor tissue in proportion to the rate of phosphorylation of FDG. Although FDG-6P can be dephosphorylated by glucose-6-phosphatase, this enzyme is not expressed in actively proliferating tumors. Most normal tissues, with the exception of brain and heart, do have glucose-6-phosphatase and rapidly clear the FDG. Thus, a gradient develops between tumor and background over time and can be readily detected by a PET scanner.
4. Procedural notes. 18FDG is injected into a fasting, euglycemic patient 45 to 60 minutes before PET scanning. Patients with blood glucose levels >200 mg/dL are typically not studied; patients who have received insulin immediately prior to study may also have altered biodistribution.
Increasingly, PET is carried out using a PET/CT instrument. The CT under such circumstances is carried out primarily to obtain a measure of tissue density for attenuation correction, and for anatomic localization. Frequently, oral contrast is administered (except when head and neck cancers are being evaluated), and an IV-contrast CT may also be carried out, usually after the PET/CT is completed.
5. Interpretation. 18FDG PET imaging is likely to be of great use in the scanning of many malignancies.
a. For primary brain tumors, a comparison is made to the “contralateral” white matter; a hyperactive tumor has a ratio of 1.4 times the concentration of FDG. Increased uptake is characteristic of high-grade primary and metastatic neoplasms. The more active the uptake, the more rapid the growth pattern. Areas of decreased uptake are seen with low-grade tumors and radiation necrosis.
b. Solitary pulmonary nodules are commonly managed with thoracotomy because of uncertainty about the benign or malignant nature of this finding. If the ratio of 18FDG PET uptake between a nodule and a normal control region is ≥2.5, the lesion is almost certainly malignant. The ratio varies between instruments and methodology; in general, the higher the cutoff value, the greater the specificity and the less the sensitivity.
c. False-negative studies are more common in those cancers that have a low metabolic rate; notably bronchioloalveolar carcinoma, well-differentiated (papillary or follicular) thyroid carcinomas particularly when the patient is on thyroid hormone, and hormone-sensitive, well-differentiated (Gleason ≤7) prostate carcinoma.
d. False-positive studies occur as a result of increased tracer concentration in nonmalignant regions with increased glucose metabolism. Infectious foci are the common false-positive abnormalities (for neoplasia); these may be acute infections, as well as chronic granulomatous diseases, notably tuberculosis and sarcoidosis. In most cases, the intensity of uptake is less than that noted in neoplasia. False-positive uptake has also been noted in muscle caused by tension or movement (especially of the vocalis muscles as a result of the patient talking after tracer injection) and in brown adipose tissue (the former may be decreased by encouraging the patient to relax, or by administration of short-acting benzodiazepines). To the trained interpreter, these latter appearances are usually distinguishable from neoplastic foci.
e. The concept of “metabolic response” is evolving. Most groups have accepted complete metabolic response (CMR) as representative of no viable tumor, and several studies have shown a correlation between CMR and survival in a variety of diseases, particularly lymphoma and breast cancer. Partial responses are being defined but currently utilize numerical criteria analogous to those used in response evaluation criteria in solid tumors (RECISTs) and other similar response sets.
f. Standardized uptake value (SUV) is a semiquantitative index of glycolytic rate. It is usually calculated based on the patient’s body weight, as follows:
Several studies have suggested that an SUV > 2.5 is representative of malignancy. SUVs are rarely >8 in infectious foci. It must be remembered that SUV is dependent on equipment and image reconstruction methodology as well as time after injection, among other factors, and therefore may be more useful for intrapatient comparison rather than group analyses.
C. 67Ga imaging
1. Indications. The use of radiogallium imaging has significantly decreased since the introduction of FDG PET. Positron-emitting isotopes of gallium (68Ga, 66Ga) are available and are currently being evaluated.
a. To evaluate response to treatment of patients with Hodgkin lymphoma and intermediate- or high-grade (but not low-grade) non-Hodgkin lymphoma (NHL). A baseline assessment is performed before therapy and repeated at the time of restaging procedures.
b. To evaluate viability selectively in other tumors (e.g., hepatoma, sarcoma, melanoma). These patients are studied as far from the completion of treatment as possible.
2. Radiopharmaceutical: 67Ga citrate
3. Principle. 67Ga is a transition element that shares a variety of properties with iron, including rapid binding to transferrin (TF) after intravenous injection. Thereafter, the 67Ga-TF is taken up by tumor cells through binding to the TF receptor on the membrane of tumor cells. The expression of the TF receptor is proportional to growth; the more rapidly proliferating the tumor, the more avid the uptake.
4. Procedural notes. The patient is imaged 48 to 72 hours after injection. A purgative may be administered the night before imaging. SPECT is significantly more sensitive than planar imaging for detecting active tumor sites. Anatomic correlation with CT or MRI helps greatly in interpretation. Where available, images from two different imaging modalities can be coregistered (“fused”) in the computer. The anatomic image is used as a template on which the 67Ga image is laid to identify the tumor-avid sites.
5. Interpretation
a. 67Ga citrate imaging is not normally used for staging purposes, but a baseline scan is helpful for later comparisons to help determine tumor response, particularly in patients with lymphomatous mediastinal involvement. Tumor sites may take up 67Ga with strong avidity, which is greatly reduced when the tumor has responded to treatment. Persistence of 67Ga is a sign of poor prognosis.
b. 67Ga imaging is nonspecific; the isotope is avidly taken up in inflammatory lesions (e.g., diffusely in the lungs with Pneumocystis carinii and other pneumonitides). 201Tl has been found to be useful when the cause of uptake on a 67Ga scan is questioned. 201Tl is normally concentrated in viable tumor and is rarely positive in lymphatic inflammation.
D. Lymphoscintigraphy
1. Indications: To determine the direction of lymph node drainage from truncal skin lesions (e.g., for melanoma) or the status of lymph ducts in regions of lymphedema
2. Radiopharmaceutical: 99mTc-labeled albumin or sulfur colloid
3. Procedural notes. Typically, injections are made into the webbing between the toes or fingers to assess the lower limbs or arms, respectively. Gamma camera imaging is performed to assess the direction of drainage as a guide to determining what lymph node–bearing region should undergo surgical exploration.
4. Interpretation. Careful attention to detailed imaging in the early images may show the sites of interruption of draining lymphatic ducts, which in some patients can be used as a basis for correcting the problem.
E. Lymphoscintigraphy: sentinel node detection
1. Indication: Detection of the sentinel lymph node in patients scheduled to undergo surgical resection of primary breast carcinoma or melanoma
2. Radiopharmaceutical: 99mTc sulfur colloid (in many cases, particularly for melanoma, passed through a 0.22-μm filter to decrease particle size). When filtered radiopharmaceutical is used, lymphatic channels are seen more frequently, and sentinel nodes are seen earlier. Several groups in the United States use unfiltered 99mTc sulfur colloid; this may permit greater flexibility from injection time to intraoperative detection, but may result in a lower proportion of sentinel nodes being visualized by imaging up to 2 hours after injection, though detection at surgery by intraoperative gamma probes remains feasible.
3. Procedural notes. After perilesional intradermal injection (or other site optimized for delineation of draining nodes) of the radiocolloid, serial gamma camera imaging (anterior and lateral views) is carried out to determine the lymphatic drainage and identify the first node that concentrates tracer. This is usually supplemented by intraoperative detection of nodal radioactivity using a gamma probe.
4. Interpretation. Serial images permit detection of the first node to concentrate radioactivity. It has been proposed that disease status of this node is representative of overall nodal status.
F. Metaiodobenzylguanidine (MIBG) imaging for catecholamines
1. Indication: To identify metastatic and primary tumor sites for pheochromocytoma and neuroblastoma
2. Radiopharmaceutical: Iobenguane sulfate, 131I-(MIBG sulfate), or 123I-(MIBG sulfate)
3. Principle. MIBG is normally concentrated by adrenergic tissues in cytoplasmic storage granules that also contain other catecholamines. Anything that blocks uptake or promotes release of these storage granules can potentially lead to false-negative results (see Section II.F.6).
4. Procedural notes
a. The typical dose for an adult is 0.5 mCi of 131I and 10 mCi of 123I. For children under 18 years of age, a body surface area adjustment is made assuming the adult dose is for a 1.7 m2 individual. Patients are pretreated with stable iodide (for adults, 10 drops daily of a 1 g/mL solution starting just before injection and continuing until the last day of imaging).
b. Technique: When 131I is administered, the patient is imaged with the whole-body camera at 24 hours, and at 48 hours if necessary, with special attention to the retroperitoneum and adrenal region. SPECT of regions of interest is possible in most instances the day after 123I-MIBG injection.
c. Warning. Hypertensive crises have occurred after injection of MIBG, especially in patients with pheochromocytoma. Pregnancy is not an absolute contraindication, but the potential risk to the fetus should be carefully assessed.
5. Interpretation. MIBG is cleared by glomerular filtration from the plasma and is rapidly taken up in catecholamine storage granules in tissue sites containing sympathetic nerves or adrenergic storage sites. Thus, uptake occurs in the heart, kidneys, liver, and adrenals at most imaging times. Tumors show up as areas of increased uptake.
6. Drug interactions. The following drugs have the potential to interfere with the uptake of MIBG by neuroblastoma and pheochromocytoma and should be stopped a few days to weeks before beginning the imaging, depending on the pharmacology of the drug.
a. Antihypertensives: Labetalol, reserpine, calcium-channel blockers
b. Amytriptyline, imipramine, and derivatives
c. Doxepin
d. Sympathetic amines (pseudoephedrine, ephedrine, phenylpropanolamine, phenylephrine)
e. Cocaine
7. MIBG as treatment. Several groups, notably in Canada and Europe, have used 131I-MIBG as therapy for the neuroendocrine tumors listed above. Typical doses range up to 200 mCi 131I. Dose-limiting toxicity is hematopoietic; most patients recover their blood counts completely and are eligible to be retreated in the absence of disease progression at 3- to 6-month intervals. For therapy studies, saturation with saturated solution of potassium iodide (SSKI) is carried out typically for a week after therapy.
G. Pentetreotide (octreotide) imaging
1. Indication: For diagnostic workup of neuroendocrine tumors that bear somatostatin receptors
2. Radiopharmaceutical. Pentetreotide is a diethylenetriaminepentaacetic acid (DPTA) conjugate of octreotide, which is a long-acting analog of human somatostatin. 111In is bound to the agent.
3. Principle. 111In-pentetreotide binds to somatostatin receptors throughout the body. Neuroendocrine tumors highly express these receptors and thus concentrate sufficient amounts of the radioactive agent to be seen by scintigraphy.
4. Procedural notes. The patient undergoes daily planar and SPECT imaging until it is determined whether the agent is helpful. Typical imaging times are 4, 24, and 48 hours after injection. Because the agent is excreted into the bowel, the patient should be given a mild laxative the evening before the 24-and 48-hour imaging times.
a. False-negative results may occur in patients who are concurrently taking octreotide acetate (Sandostatin®) for control of symptoms related to neuroendocrine tumors. If possible, patients should stop taking this medication 2 weeks before the scan. Also, corticosteroids by prescription should be stopped before scanning, as these and adrenocorticotropic hormone–producing tumors can reduce the expression of somatostatin receptors.
b. Warnings and adverse reactions. Transient symptoms are occasionally seen, including dizziness, hypotension, and headache. Patients with known or suspected insulinomas should have an intravenous line running with 5% dextrose in normal saline before and during administration to avoid possible hypoglycemia.
5. Interpretation. The normal pituitary gland, thyroid gland, and liver are seen. To a lesser extent, the gall bladder, kidney, and bladder are also visible. Uptake in tumors bearing somatostatin receptors is apparent beginning at 4 hours, with the 24- and 48-hour images showing the greatest tissue contrast. The sensitivity for detecting tumor types depends on the frequency of somatostatin receptor. Those patients with strongly positive scans may be most likely to benefit from treatment with octreotide.
a. New lesions that were previously occult, despite extensive workup, were identified in nearly 30% of patients studied with 111In-pentetreotide. Carcinoid tumors, neuroblastomas, pheochromocytoma, paragangliomas, small cell lung cancer, and meningiomas were detected in about 90% of cases. Lymphomas, pituitary tumors, and medullary tumors were detected in high but more variable percentages.
b. Granulomatous lesions and other types of inflammatory lesions were also positive, including tuberculosis, sarcoidosis, rheumatoid arthritis, and Graves disease ophthalmopathy.
H. Prostascint for prostate tumor imaging
1. Indications: Detection of prostate cancer outside the prostatic bed or recurrent prostate cancer in the prostatic bed
2. Radiopharmaceutical. 111In-capromab pendetide (Prostascint) consists of a monoclonal antibody, to which 111In is attached by a chelate, against the prostate-specific membrane antigen (PSMA).
3. Principle. The antibody reacts with an antigen specifically found in prostate cancer cells. After intravenous administration, the antibody is gradually cleared from the circulation while localizing in tumor tissue.
4. Procedural notes. Anterior and posterior whole-body images are obtained starting about 30 minutes after injection, followed by SPECT of the infrahepatic abdomen and pelvis. Comparable images are obtained typically 4 days after injection. Because the radioactivity may be concentrated in the liver and is usually excreted through the bowel, it is important to prepare the bowel with an oral laxative the night before.
5. Interpretation. The whole-body images are searched for areas of increased uptake in the region of the aortic and iliac nodal groups, as well as for recurrence in the prostate bed. The SPECT images are important for the region of the prostate bed and the obturator nodes. Because the antibody remains in circulation and because the increased uptake in diseased areas is sometimes difficult to distinguish from normal vascular activity, it is important to compare the early and delayed image sets to ensure that the area of uptake seen in the delayed imaging is not in a vascular region. Some groups do not carry out the early image sets and instead carry out “dual-isotope” imaging using 99mTc-labeled red cells to delineate the vascular structures. Increasingly, groups are beginning to use SPECT/CT so that the CT component can provide anatomic localization of radioactivity distribution. It is also important to ensure that the patient voids urine as completely as possible before imaging and to image comparable areas of the body.
I. Tumor viability imaging: 201Tl chloride and 99mTc sestaMIBI
1. Indications. FDG PET/CT is increasingly used in place of these agents, particularly in areas outside the brain.
a. Differential diagnosis of breast masses
b. Viability assessment of primary bone tumors after chemotherapy
c. Monitoring viability of well-differentiated thyroid cancer
d. Imaging of parathyroid adenomas
e. Imaging of brain tumors (SPECT)
2. Radiopharmaceutical
a. 99mTc methoxyisobutyl isonitrile (MIBI) is a monovalent cationic form of 99mTc that is highly lipid soluble. The agent is formed as a central 99mTc atom surrounded by six isobutyl nitrile molecules; for this reason, it is sometimes referred to as sestaMIBI.
b. 201Tl (thallous) chloride is a radioisotope of thallium, which is in the actinide series of elements and behaves in vivo as an analog of potassium.
3. Principle. 201Tl chloride is a widely used cardiac perfusion agent that is taken up by most viable cells as a potassium analog and transported by the Na+–K+ pump. 99mTc sestaMIBI is also used to monitor cardiac perfusion. In addition, when taken up into the cell by a different mechanism, it can be used as a marker for cellular viability. After introduction into the bloodstream, both of these agents are rapidly cleared from the circulation in proportion to cardiac output.
4. Procedural notes. The tracer is injected intravenously, and imaging is begun over the region of interest within 20 minutes of injection, frequently at an early and a late time after injection (e.g., 5 and 60 minutes after injection). For breast imaging, a special breast apparatus permits planar lateral views of the breast in the prone position. This appears to be a technical advance. For brain and other imaging, SPECT scanning is performed.
5. Interpretation
a. Breast masses. About 25% of patients who are subjected to screening mammography have “dense” breasts that obfuscate interpretation. If these patients also have palpable breast masses, there may be a clinical dilemma in regard to biopsy of these lesions. It has been reported that uptake of 201Tl is negative in fibrocystic disease and positive in 96% of breast cancer nodules. Similar results have been observed in patients with breast masses imaged with MIBI. The negative predictive value for breast cancer with these studies is likely to improve the specificity of breast mammography and is applicable to both dense breasts and normal breasts.
b. Primary bone tumors are frequently treated with chemotherapy before surgery. 201Tl and 99mTc sestaMIBI are both taken up with high sensitivity into primary bone tumors and extremity sarcomas. Chondrosarcoma is an exception. MIBI uptake is lost in tumors responding to chemotherapy and has also been shown to correlate well with response to therapy.
c. Brain tumors. 201Tl chloride appears to be the agent of choice for evaluating supratentorial primary brain tumors when FDG PET is not available. SPECT imaging is accurate for assessing the viability of brain tumors. In our experience, 201Tl is preferred over 99mTc sestaMIBI because uptake in the choroid plexus is not as marked.
d. Thyroid cancer imaging. 201Tl whole-body imaging is a good way to monitor the activity of well-differentiated thyroid cancer during the interval when the patient is fully suppressed on thyroid hormone. The total uptake, as a percentage of the total-body uptake, is a monitor of the cellular viability of the tumor and can be used to assess the effectiveness of primary cancer treatment.
e. Parathyroid imaging. With careful comparisons of 201Tl or 99mTc sesta-MIBI imaging, it is sometimes possible to detect parathyroid adenomas in the neck or upper mediastinum when other modalities are negative. Still, the sensitivity of these techniques is disappointingly low (about 50%) in patients with intact parathyroid glands and considerably higher (about 80%) for the detection of recurrence. FDG PET has not been found to be useful for parathyroid imaging.
III. OTHER IMAGING STUDIES USED IN ONCOLOGY
A. Cardiac functional studies. Equilibrium (gated) blood pool imaging is used to evaluate possible cardiac failure and to monitor changes after treatment with cardiotoxic drugs.
1. Radiopharmaceutical. Red blood cells (RBCs) may be labeled in vivo. Stannous pyrophosphate (1 mg) is administered 20 minutes before injecting 99mTc pertechnetate. The stannous pyrophosphate enters and is trapped in the RBCs. The 99mTc pertechnetate diffuses into the RBCs and is bound to the β chain of hemoglobin. About 75% of the dose is labeled to the RBCs. An electrocardiogram R-wave signal serves as a physiologic “gate” for collection of timed “frames” (often called gated blood pool imaging).
2. Interpretation. Images obtained during rest are interpreted qualitatively to determine areas of abnormal wall motion, size of cardiac chambers, presence of intrinsic or extrinsic compression of the cardiac contour, and size and shape of the outflow tracts. Images are interpreted quantitatively for a physiologic assessment of the quantity of blood ejected from the left ventricle with each beat (the left ventricular ejection fraction [LVEF]). A normal LVEF is usually >50%. LVEFs <30% are usually but not always associated with clinical congestive heart failure. A decrease of >10% in LVEF is highly significant. Cardiotoxic chemotherapeutic agents should be stopped when ejection fractions fall to below normal.
B. Vascular flow and bleeding studies can be used to detect the patency of venous access in the upper extremities (e.g., postsubclavian catheter-placement swelling, superior vena cava syndrome), to assess for the presence of hemangioma as a space-occupying lesion, or to determine a site for bleeding. 99mTc pertechnetate or 99mTc sulfur colloid can be used as transient labels of the vasculature. In vivo labeling of RBCs with 99mTc may be used as more long-term vascular labels (see Section III.A.1).
C. 99mTc-macroaggregated albumin for lung perfusion can be used to evaluate patients suspected of having pulmonary embolism and to determine the lung function capacity before pulmonary resection. 99mTc-labeled to macroaggregates of albumin (30 to 60 μm in diameter) are injected intravenously and are cleared in the first pass through the pulmonary circulation. The distribution of radioactivity is proportional to blood flow to the lungs.
D. Studies of pulmonary ventilation can be used to determine whether a ventilation-perfusion “mismatch” exists as an aid in the differential diagnosis of pulmonary embolism and to assess the ventilatory capacity of the human lung. 133Xe gas, 127Xe gas, 81mKr, and 99mTc-DPTA aerosol are used to label the inspiratory air. As the patient breathes, a gamma camera obtains an image of the distribution of radioactivity. Several minutes of breathing is required to achieve equilibrium with bullae and fistulous tracts.
E. Infection imaging
1. 67Ga citrate appears to be taken up by the cells near the region of the infection. 67Ga imaging requires several days to complete, and normal physiologic uptake (especially in the abdomen) interferes with interpretation. 67Ga citrate imaging is sensitive for making the diagnosis of P. carinii pneumonia at a relatively early stage. It is somewhat less sensitive than 111In-labeled white blood cells (WBCs) in the postsurgical setting; the normal excretion of 67Ga into the bowel is a drawback. Nevertheless, by using imaging methods that increase contrast, such as SPECT, satisfactory imaging can be obtained in most cases.
2. Radiolabeled (111In or 99mTc) WBCs progressively accumulate at the site of infection. The labeled WBC method requires external manipulation and labeling of the patient’s blood. WBC imaging with 111In shows uptake in the liver, spleen, and bone marrow, but not in other sites within the abdomen. Sensitivity for acute infection approaches 90%.
3. FDG PET has a high sensitivity rate for detection of infection. Its utility in patients with cancer is limited by its comparable sensitivity for viable cancer detection, with consequent inability to differentiate infection from recurrent cancer.
4. New directions for inflammation imaging. Radiolabeled monoclonal antibodies that label WBC in vivo, a variety of leukotropic peptides (that also label WBC in vivo), and a radiolabeled nonspecific immunoglobulin (with accuracy rates of close to 90%) are in various stages of development and approval.
IV. THERAPEUTIC RADIOISOTOPES
A. 131I for well-differentiated thyroid cancer
1. Radiopharmaceutical: Sodium iodide (131I), oral solution
2. Patient selection (see Chapter 15, Section III). Patients are selected for study after surgery has established the diagnosis of thyroid cancer. Patients considered for radioactive 131I are those at high risk for recurrence of well-differentiated thyroid cancer, either papillary or follicular, or one of the well-known variants to these tumors. Patients are considered at “high risk” if they are older than 40 years of age; if the primary tumor is large (>2 cm), locally invasive, or multicentric in the neck; or if there is metastatic tumor in the neck.
3. Procedural notes. There is considerable variation in the study and treatment protocol for thyroid carcinoma.
a. Some experts simply treat all high-risk patients after surgery with >100 mCi of 131I. A thyroid remnant, if present, is ablated with administered doses sufficient to deliver at least 300 Gy to the normal thyroid.
b. In most situations, some form of testing is performed for the ability of the tumor to concentrate radioactive iodine, and patients are treated if there is residual 131I-concentrating tissue in the neck. At the time of testing, patients are expected to be hypothyroid (thyroid-stimulating hormone level >30 IU/mL) and to have a low serum iodine concentration (<5 μg/dL). Patients are prepared by being off thyroid hormone (thyroxine for 6 weeks and tri-iodothyronine for 3 weeks) and on a low-iodide diet (for 3 weeks before treatment).
c. The recent approval of recombinant thyrotropin (rhTSH, Thyrogen) has enabled the evaluation of patients in the euthyroid state. The recommended dose of rhTSH is 0.9 mg IM daily for 2 days. Typically, diagnostic 131I is given on the third day, and imaging and thyroglobulin estimation are carried out on the fifth day.
4. Dose selection. Several authorities treat with standard doses after uptake in thyroid cancer is demonstrated. If lymph nodal metastases are demonstrated in the neck only, a dose of 150 mCi is sometimes used. For pulmonary, bone, or central nervous system metastases, a dose of 200 mCi may be used.
At Memorial Sloan Kettering Cancer Center (MSKCC), a higher dose protocol has been developed, which depends on more careful dosimetry and is called the highest safe dose approach. Dosimetry testing for 3 to 5 days in the well-prepared patient is used to select a dose that delivers at least 2 Gy (200 cGy) to the blood, not >140 mCi retained in the whole body at 48 hours, and, in patients with metastatic lung disease, <80 mCi retained in the lungs at 48 hours. With this set of dosing rules, several hundred patients have been treated with good treatment response and without major complications.
5. Treatment response. Patients respond best to treatment when the tumor is small (total tumor burden <200 g) and confined to local or regional areas of the body. The cure rate at MSKCC was >95% for patients younger than 40 years of age and 50% for those older than 40 years of age. Even when cure is not achieved, significant palliation can be obtained with 131I treatment.
6. Follow-up. Patients are normally evaluated at yearly intervals. Consideration for retreatment requires taking the patient off thyroid hormone, allowing hypothyroidism to develop, and treating with high-dose 131I until no appreciable 131I tissue is present (“clean slate”). Elevation of thyroglobulin levels indicates a high likelihood of recurrence of thyroid cancer at some time in the next 5 years in patients with well-differentiated thyroid cancer. In patients with unusually aggressive thyroid cancers, retreatment at a shorter interval can be considered (usually at about 6 months). We usually require tumor doses of at least 20 Gy. Ablation of known metastases has occurred with doses as low as 35 Gy, but 100 Gy is usually required for lymph nodes containing tumor.
7. Treatment complications. The most common complication of high-dose 131I treatment is sialadenitis, which occurs in about 20% of patients at doses >200 mCi; a few patients develop chronic sialadenitis.
With any exposure to whole-body irradiation, there is always the concern that an increase in malignancies may occur, particularly leukemias. However, no increase in leukemia was seen in a large group of Swedish patients treated with an average dose of 160 mCi. At higher average doses in more than 500 patients at Memorial Sloan-Kettering Cancer Center, no leukemias have occurred in the treatment group. These data suggest that 131I does not significantly increase the risk for leukemia.
B. Bone pain palliation with radioisotopes
1. Radiopharmaceuticals: 89Sr chloride (Metastron), 4 mCi; or 153Sm-EDTMP (Lexidronam), 1 mCi/kg. 153Sm emits gamma rays and thus can be evaluated for radioactivity distribution.
2. Principle. Various human tumors produce a strong osteoblastic reaction that results in the deposition of bone-seeking radionuclides in the hydroxyapatite crystal in the region of the tumor. When given in sufficient quantity, the radionuclide radiates the active bony regions near the metastases sufficiently to relieve pain. It is unclear whether the benefits of treatment are due to the irradiation of the bone or of the tumor itself. The usual dose is thought to be about 7 to 10 Gys.
3. Procedural notes. Patients should have platelet counts >60,000/μL and WBC counts >2,400/μL, and painful bone lesions should be demonstrated as being positive on bone scan preferably carried out within 3 weeks of the treatment. Patients should not be treated with 89Sr unless their life expectancy is at least 3 months. Patients with platelet counts >150,000/μL, may be treated at the recommended dose; those with lower platelet counts should be treated at lower doses and monitored carefully for hematopoietic toxicity.
a. Complete blood counts should be repeated every 2 weeks for 4 months. Platelet and WBC counts are typically decreased by about 30%, and the nadir counts occur 12 to 16 weeks after injection.
b. Because the radioactivity is primarily excreted in the urine, the patient should be continent or catheterized to minimize contamination of clothing and the patient’s home environment.
4. Treatment response. Patients with cancers of the prostate, breast, and lung have been treated with these radiopharmaceuticals, but, in principle, any tumor with an osteoblastic component on bone scan could be treated. The usual onset of pain relief occurs within 7 to 21 days after administration (earlier for Lexidronam). Patients should be counseled about the possibility of a “flare response,” in which pain is increased for a period of days to weeks after the treatment. A significant proportion of patients (75% to 80%) do get significant pain relief, and the typical duration of response is 3 to 4 months.
5. Contraindications and precautions. Pregnancy is an absolute contraindication, and women of childbearing age should have a pregnancy test the day before administration of a radiopharmaceutical. Patients may be considered for retreatment, usually after 90 days, if they have responded well to initial therapy and provided that hematopoietic toxicity was not excessively severe. Most patients tolerate multiple injections without major side effects.
C. 32P for polycythemia vera (PV)
1. Radiopharmaceutical: Buffered sodium 32P-phosphate solution
2. Dosage. Intravenous doses of 2.3 mCi/m2 (dose not to exceed 5.0 mCi) are administered at 3-month intervals to induce remission or to control excessive cellular proliferation. The dose may be repeated twice if a remission is not achieved and is increased by 25% each dose (not to exceed 7 mCi as a single dose).
3. Treatment response. About 80% of patients with PV achieve remission after one injection of 32P. In comparison with phlebotomy alone, patients treated with 32P survive longer and have fewer thrombotic complications but have a significantly increased incidence of acute myelogenous leukemia.
4. Contraindications. Pregnancy is an absolute contraindication because of the possibility of teratogenic effects. In PV, the drug should not be administered when the WBC count is <5,000/μL or platelets are <150,000/μL.
D. Colloidal 32P for malignant effusions
1. Radiopharmaceutical: Chromic 32P-phosphate colloidal suspension
2. Dosage. In a 70-kg patient, 6 to 12 mCi is used for intrapleural administration and 10 to 20 mCi for intraperitoneal administration. Great care should be taken to ensure that all radioactivity is deposited in the intended body cavity. Large tumor masses or loculation of fluid is a relative contraindication to treatment.
3. Treatment response. Most patients receive some benefit from treatment in terms of control of effusions. There is a growing interest in the use of 32P in the treatment of low-volume ovarian cancer.
E. 90Y-labeled anti-CD20 antibody for lymphoma
1. Radiopharmaceutical: 90Y-labeled ibritumomab tiuxetan (Zevalin)
2. Indications. Zevalin, as part of the Zevalin therapeutic regimen, is indicated for the treatment of patients with relapsed or refractory low-grade follicular or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL.
3. Dosage. Ibritumomab is a murine antibody that reacts with CD20, a cell-surface receptor found on most B-cell lymphomas. Tiuxetan is a proprietary chelate that binds radioactive metals to antibody. The dose of ibritumomab tiuxetan in patients with platelet counts >150,000/μL is 0.4 mCi/kg body weight, and in patients with platelets between 100,000 and 149,000/μL is 0.3 mCi/kg. In both instances, the maximum administered dose should not exceed 32 mCi 90Y. Patients with >25% lymphomatous involvement of marrow should not be treated with this agent.
a. Assessing biodistribution. The patient initially receives 250 mg/m2 of rituximab (Rituxan, Mabthera), a chimeric (Fv-grafted human IgG1) monoclonal antibody that recognizes the CD20 receptor (for details on rituximab administration, see Chapter 4, Section VII.G4.). The rituximab is followed by 5 mCi 111In-labeled ibritumomab tiuxetan. Whole-body 111In images are then carried out 2 to 24 hours and 48 to 72 hours after injection to assess biodistribution. Visual assessment of favorable biodistribution is defined by tumor uptake of radioactivity; easily detectable uptake in blood pool on the first-day image, decreasing subsequently; and moderate uptake in normal liver and spleen with low uptake in normal kidneys and normal bowel.
b. Treatment is carried out in an identical manner to the diagnostic infusion. The patient is treated between 7 and 9 days after this first infusion. The patient receives 250 mg/m2 of rituximab. This is followed by 90Y-labeled ibritumomab tiuxetan at a dose of 0.3 to 0.4 mCi/kg body weight (to a maximum of 32 mCi), usually given over 10 minutes.
4. Toxicity. Acute side effects following Zevalin are rare; nonspecific symptoms following rituximab are more common after the first treatment than after the second. Grade 3 or greater hematologic toxicity occurs in almost half of all treated patients and requires support (G-CSF for neutropenia, transfusions for thrombocytopenia) in about 10% to 30%. Toxicity nadirs occur between 7 and 9 weeks after treatment and last for about 3 weeks. Patients should be monitored closely for hematologic toxicity for at least 8 weeks or until recovery (usually 12 weeks).
5. Efficacy. Ibritumomab tiuxetan in combination with rituximab gives significantly higher overall response rates compared with rituximab alone (80% vs. 56%). The complete response rate with ibritumomab tiuxetan is also higher than with rituximab alone (30% to 34% vs. 16% to 20%). The secondary end points, duration of response and time to progression, are not significantly different between the two treatment arms; however, there is a trend toward longer time to progression in patients with follicular NHL (15 months in the ibritumomab tiuxetan arm vs. 10 months in the rituximab arm) and in patients who have achieved a complete response (25 months vs. 13 months, respectively).
F. 131I-labeled anti-CD20 antibody for lymphoma
1. Radiopharmaceutical: 131I-labeled tositumomab (Bexxar)
2. Indications: The Bexxar therapeutic regimen (tositumomab and 131 I-tositumomab) is indicated for the treatment of patients with CD20-positive, follicular NHL, with and without transformation, whose disease is refractory to rituximab and has relapsed following chemotherapy. The Bexxar therapeutic regimen, like the Zevalin regimen, is not indicated for the initial treatment of patients with CD20-positive NHL. Patients with >25% lymphomatous involvement of marrow should not be treated with this agent.
3. Dosage. Tositumomab is a murine antibody that reacts with CD20, a cell-surface receptor found on most B-cell lymphomas. In contrast to Zevalin, which is administered on an activity per unit weight basis, Bexxar is administered on a whole-body radiation absorbed dose calculation. The dose of 131I-tositumomab in patients with platelet counts >150,000/μL is 0.75 Gy to the whole body and 0.65 Gy in patients with platelets between 100,000 and 149,000/μL.
a. Preparation. A day prior to initiation of therapy, the patient starts oral iodide therapy for thyroid protection (typically 10 drops of SSKI solution daily), which continues until 2 weeks after the therapeutic dose.
b. Biodistribution and dosimetry. The patient initially receives 450 mg of tositumomab over an hour. Nonspecific symptoms are rare (fatigue, low-grade fever, and chills) and can be controlled if necessary with oral acetaminophen and diphenhydramine. This is followed by 5 mCi 131I-labeled tositumomab (35 mg), given over 20 minutes. Whole-body 131I images (dosimetry scans, carried out at speeds of about 30 cm/min) are carried out immediately on completion of infusion, and again 2 to 4 days and 6 to 7 days after injection. These images are used to calculate the amount of 131I that will deliver no >0.75 Gy radiation absorbed dose to the whole body. As with Zevalin, visual assessment of favorable biodistribution is defined by easily detectable uptake in the blood pool on the first-day image, decreasing subsequently, and by moderate uptake in normal liver and spleen, with low uptake in normal kidneys and normal bowel.
c. Treatment. The patient is treated between 7 and 14 days after this first infusion. Treatment is carried out in an identical manner to the diagnostic infusion. The patient receives 450 mg of tositumomab, followed by 131I-labeled tositumomab (mass 35 mg). The amount of 131I administered is calculated based on whole-body clearance of the dosimetric radioactivity.
4. Toxicity. The most common adverse reaction is hematopoietic, with most patients having grade 3 or 4 toxicity, with a time to nadir of 4 to 7 weeks, lasting for approximately a month. Due to the variable nature in the onset of cytopenias, complete blood counts should be obtained weekly for 10 to 12 weeks. Hematopoietic toxicity follows patterns comparable to those with Zevalin.
5. Efficacy. Bexxar therapy results in responses and response durations comparable to those with Zevalin. The overall response rates have ranged from 47% to 64% and the median durations of response from 12 to 18 months. These response rates have been comparable in patients refractory to rituximab.