The use of positron emission tomography (PET) is increasing rapidly in the United States, with the most common use of PET scanning related to oncology. It is especially useful in the staging and management of lymphoma, lung cancer, and colorectal cancer, according to a panel of expert radiologists, surgeons, radiation oncologists, nuclear medicine physicians, medical oncologists, and general internists convened in November 2006 by the National Comprehensive Cancer Network. The Task Force was charged with reviewing existing data and developing clinical recommendations for the use of PET scans in the evaluation and management of breast cancer, colon cancer, non-small cell lung cancer, and lymphoma. This report summarizes the proceedings of this meeting, including discussions of the background of PET, possible future developments, and the role of PET in oncology. (JNCCN 2007;5(Suppl 1):S1–S22) The use of positron emission tomography (PET scanning) is increasing rapidly in the United States. The most common use of PET scanning is related to oncology, especially in staging and managing lymphoma, lung cancer, and colorectal cancer (Figure 1). In November 2006, the National Comprehensive Cancer Network (NCCN) gathered a panel of expert radiologists, surgeons, radiation oncologists, nuclear medicine physicians, medical oncologists, and general internists to review the existing data and develop clinical recommendations for using PET scans in evaluating and managing breast cancer, colon cancer, nonsmall cell lung cancer (NSCLC), and lymphoma. Because of time constraints, the PET Task force limited its review to these four most common oncologic indications. However, PET scan has a role in most other types of cancers, which are reviewed on an annual basis by the NCCN Guideline Panels for individual malignancies. (For further information, please go on-line to the NCCN Clinical Practice Guidelines in Oncology at www.nccn.org.) This supplement summarizes the proceedings of this meeting. The term PET scan refers to either a PET scan or PET/computed tomography (CT) scan, unless otherwise specified. In addition, the PET radiotracer used is F-fluorodeoxyglucose (F-FDG), unless otherwise specified. What is PET and How Does It Work? Imaging can be broadly subdivided into anatomic and molecular, with molecular imaging defined as the “in vivo characterization and measurement of biologic processes at the cellular and molecular level.” PET is considered the prototypical molecular imaging technique, with PET/CT providing combined anatomic and molecular imaging. PET imaging is based on a unique chemical process involving the collision between an electron and a positron arising from a positron-emitting radioisotope, leading to a process known as annihilation that produces two 511-KeV photons emitted at 180°. These photons can be simultaneously detected with a PET scanner, which consists of multiple stationary detectors that encircle the body. Fluorine-18 (F) incorporated into fluorodeoxyglucose (FDG) is the most common tracer used clinically, with a half-life of approximately 110 minutes. Substitution of fluorine for a hydroxyl group blocks metabolism of the tracer. The level of FDG uptake reflects the rate of trapping of phosphorylated FDG (FDG-6P) and thus the rate of glycolysis (Figure 2). PET scans can be performed with multiple tracers (Table 1) to provide information on blood flow, receptor expression, and metabolism. FDG uptake is increased in most malignant tissue and in various benign pathologies, such as inflammatory conditions, trauma, infection, and granulomatous diseases. For example, sarcoidosis causes false-positive PET scans. Benign neoplasms and hyperplastic and dysplastic tissue may also accumulate FDG. Because of the variability of FDG in normal tissue and benign conditions, physicians interpreting the scans must be familiar with the normal pattern of distribution and the benign causes of FDG accumulation to accurately interpret the data. Patient preparation is critical, with the major goals of minimizing tracer uptake in normal issues (e.g., myocardium and skeletal muscle) while maintaining uptake in target tissues (neoplastic disease). The preparation should include, but not be limited to: 1. Pregnancy testing when appropriate. 2. Fasting instruction and no oral or intravenous fluids containing sugar or dextrose (4–6 hours) to maintain normal glycemia and insulinemia. 3. Hydration to reduce accumulated urinary tracer activity in the collecting system and bladder. 4. A focused history regarding diabetes, recent exercise, dates of diagnosis and treatments, medications, and recent trauma or infections. The oncologic applications of PET scanning are based on increased FDG uptake by tumor tissue. Glucose metabolism is the culmination of many different molecular pathways, and interrupting any of these components can result in glycolysis interruption and a change in the PET scan. Although genetic arrays can be considered multiple biomarkers of the myriad underlying metabolic pathways and may identify targets for intervention, PET scans can be considered a type of downstream imaging from biomarkers, reflecting the final common pathway of glucose metabolism, and they can provide real-time monitoring of treatment response. Cyclotrons that produce F and PET scanners have evolved over the past several decades, and current equipment is smaller and easier to use. Mini cyclotrons now available are highly computerized and can be operated by radiopharmacists or technicians. Minicyclotrons can make short-lived isotopes, such as fluorine, carbon, oxygen, or nitrogen. These radionuclides can be incorporated into metabolically important substrates through automated synthesis devices. In the United States, an estimated 55% of PET scanners are PET/CT scanners, and approximately 100% of scanners purchased in the past year have been PET/CT. The original impetus for combining PET/CT scans was to improve attenuation correction and throughput associated with the CT scan. However, PET/CT scans provide more specific anatomic correlation than PET alone, S-2 Supplement NCCN Task Force Report © Journal of the National Comprehensive Cancer Network | Volume 5 | Supplement 1 | May 2007 Figure 1 Growth of clinical PET. Figure 2 FDG uptake in a cancer cell. Source: Data from Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 2005;202:654–662; and Bos R, van Diest PJ, de Jong JS, et al. Hypoxia-inducible factor-1alpha is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology 2005;46:31–36. and this technology has been widely adopted. A rapid conversion to PET/CT has clearly occurred, and this technique is emerging as the new standard. Most literature has focused on PET rather than PET/CT scans, and the incremental value of the combined scan is only now being rigorously tested. Nevertheless, most clinicians feel comfortable extrapolating data from PET scans to PET/CT scans. Studies have shown that, in some specific clinical situations, the combined image can further clarify the anatomic location of the PET tracer, improve specificity, and thus reduce false-positive results. The CT portion of a PET/CT scan is used for attenuation correction and anatomic localization. A diagnostic quality CT scan similar to that obtained for diagnostic CT-only scans is not necessary to accomplish these tasks, and the CT component of a PET/CT scan is often a low-dose CT scan to minimize patient radiation exposure. Additionally, contrast is not used because it complicates the use of the CT scan for attenuation correction of the PET scan if appropriate algorithms are not used to correct for the high density of some contrast material. Sometimes patients have already undergone a diagnostic CT scan before being referred for a PET/CT. For example, patients who are potential candidates for liver resection will typically undergo an initial diagnostic CT to evaluate the vascular anatomy of the liver, and then be referred for PET/CT to evaluate for extrahepatic metastases. Another common situation is a patient with a history of malignancy who is being followed up with serial CT scans and is undergoing a PET scan to follow-up the CT scan findings. In these situations, the low-dose CT incorporated into the PET/CT is adequate. This implies that if a diagnostic CT scan is indicated, patients must undergo a separate scan. In most current PET/CT scanners, the CT component is comparable to stand-alone CT devices and capable of providing a high-quality diagnostic CT. Therefore, in some institutions, when patients require a diagnostic CT at the same time as PET/CT, it can be performed immediately after the PET/CT with the same CT scanner using normal CT scan technique and contrast. Standardized Uptake Value Aberrant glucose metabolism FDG uptake in malignant tissues and therefore alterations in glucose metabolism may reflect response to treatment. In this sense, FDG can be construed as a biomarker. Various different techniques for assessing the uptake of the tracer attempt to control for background uptake in the blood pool and surrounding tissues, including very sophisticated kinetic studies providing a quantitative analysis. However, a semiquantitative technique, the standardized uptake value (SUV), is most commonly used because of its relative simplicity. The SUV is calculated using the following formula: Activity per unit volume Injected Activity/Body Weight The use of SUV is an area of active research, with the number of citations rapidly increasing for many different tumor types; currently more than 1000 citations are available for SUV values and tumor response. The SUV is most useful if it reflects the uptake localized to the tumor and not the surrounding tissues. Maximum SUV is a better parameter than the average SUV because of the heterogeneity of th

The skeleton is the most frequent site of metastatic disease in breast cancer, involving cortical and trabecular bone with or without extension into adjacent bone marrow. A subset of breast cancer patients develop bone dominant disease without metastases to other organs over a prolonged period of time. An attractive strategy is to utilize bone targeted radiotherapy to address this site of disease with minimal systemic toxicity. This study was designed to determine the safety and preliminary efficacy of 166Ho-DOTMP, which localizes to bone providing radiation to adjacent marrow and malignant cells. The limiting toxicity is myelosuppression, which can be overcome by autologous stem cell transplantation. We studied this strategy in subjects with breast cancer metastatic to confined to the bone.

UNLABELLED Gastrointestinal stromal tumors (GISTs) are gaining the interest of researchers because of impressive metabolic response to the targeted molecular therapeutic drug imatinib mesylate. Initial reports suggest an impressive role for (18)F-FDG PET in follow-up of therapy for these tumors. However, the role of (18)F-FDG PET versus that of CT has not been established. Therefore, we compared the roles of (18)F-FDG PET and CT in staging and evaluation of early response to imatinib mesylate therapy in recurrent or metastatic GIST. METHODS The study included 54 patients who underwent (18)F-FDG PET and CT scans within 3 wk before initiation of imatinib mesylate therapy. Forty-nine of these patients underwent repeat scans 2 mo after therapy. The numbers of sites or organs containing lesions on (18)F-FDG PET and CT scans were compared. Corresponding lesions on (18)F-FDG PET and CT scans or those confirmed to be malignant in appearance by other imaging modalities or on follow-up were considered true positives. Lesions seen on (18)F-FDG PET or CT scans but not seen or confirmed to be of benign appearance with other imaging modalities or on follow-up were considered false positives. Measurements of the maximum standard uptake value (SUV) on (18)F-FDG PET scans and tumor size on CT scans were used for quantitative evaluation of early tumor response to therapy. RESULTS A total of 122 and 114 sites and/or organs were involved on pretherapy (18)F-FDG PET and CT scans, respectively. The sensitivity and positive predictive values (PPVs) for CT were 93% and 100%; whereas these values for (18)F-FDG PET were 86% and 98%. However, the differences between these values for CT and (18)F-FDG PET were not statistically significant (P = 0.27 for sensitivity and 0.25 for PPV). This suggests comparable performance of (18)F-FDG PET and CT in staging GISTs. Repeat scans at 2 mo after therapy showed agreement between (18)F-FDG PET and CT scans in 71.4% of patients (57.1% having a good response to therapy and 14.3% lacking a response). Discrepant results between (18)F-FDG PET and CT were recorded for 28.6% of the patients. (18)F-FDG PET predicted response to therapy earlier than did CT in 22.5% of patients during a longer follow-up interval (4-16 mo), whereas CT predicted lack of response to therapy earlier than (18)F-FDG PET in 4.1%. One patient did not undergo long-term follow-up. These findings suggest that (18)F-FDG PET is superior to CT in predicting early response to therapy in recurrent or metastatic GIST patients. CONCLUSION The performances of (18)F-FDG PET and CT are comparable in staging GISTs before initiation of imatinib mesylate therapy. However, (18)F-FDG PET is superior to CT in predicting early response to therapy. Thus, (18)F-FDG PET is a better guide for imatinib mesylate therapy.

BACKGROUND:Factors affecting the accuracy of left ventricular ejection fraction (LVEF) quantification using automated quantitative gated SPECT have not been adequately investigated in patients in the clinical setting. Therefore, the authors studied the effect of defect size and Tc-99m tetrofosmin dose on the accuracy of LVEF calculation using the automated QGS program. MATERIALS AND METHODS:Thirty-two consecutive patients underwent gated rest and stress myocardial perfusion SPECT after administration of 8 and 27 mCi Tc-99m tetrofosmin, respectively. The LVEF was obtained for both the rest and stress studies using the QGS program and compared with the LVEF obtained using quantitative echocardiography performed within 2 weeks. Myocardial perfusion defects were recorded as scarring, ischemia, or mixed scarring and ischemia in 12 left ventricular segments. The defect size was evaluated by adding the number of affected segments. RESULTS:The mean LVEF calculated using high-dose stress QGS, low-dose rest QGS, and echocardiography was 49.2% +/- 15%, 46.2% +/- 17% and 48.7% +/- 16.9% respectively, with no statistically significant differences. The LVEF obtained using high-dose stress QGS correlated better with echocardiography than did that obtained using low-dose rest QGS (r = 0.86 versus 0.76). In addition, when the high-dose stress LVEF in the 14 patients with normal myocardial perfusion was compared with that in 11 patients who had one- or two-segment perfusion defects, and 7 patients who had perfusion defects in > or = three segments, there was good correlation with echocardiography in the three patient groups (r = 0.85, 0.88, and 0.91, respectively). CONCLUSIONS:Myocardial perfusion defects do not affect the accuracy of LVEF calculation using automated QGS. High-dose gated myocardial SPECT demonstrated better correlation with quantitative echocardiography LVEF results.

Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation.

A. This guideline is written specifically for lymphoscintigraphy in patients with primary melanomas that originate in the skin. Staging of these tumors is based on tumor thickness (Breslow measurement) and level of skin invasion (Clark’s level), both of which are determined by the pathologist from a biopsy sample. Ample data correlate patient survival with Breslow and Clark measurements. In the past, elective lymph node dissection (ELND) of the lymphatic bed believed most likely to drain the primary tumor site (based on Sappey’s classic anatomic description of cutaneous lymphatic flow) was used as part of the staging procedure for melanoma. ELND has been a controversial staging procedure for patients with intermediate (I and II)stage melanoma, because approximately 80% have tumor-negative lymph nodes and therefore do not need ELND, a procedure associated with significant morbidity and cost. The sentinel lymph node excisional biopsy procedure, in contrast, is simpler and not associated with significant morbidity, provides accurate information about lymphatic drainage patterns, and allows the surgeon to make a smaller incision directly over the node, based on the image and probe counts. Lymphoscintigraphy images readily demonstrate the unpredictability of lymphatic drainage patterns. Sentinel lymph node biopsy, after identification by lymphoscintigraphy and excision using the intraoperative gamma probe and/or blue dye technique, is frequently performed in patients without either clinically apparent metastases or early intermediate-stage melanoma (Clark level, 4; Breslow thickness, 0.76–4 mm) because of its significant diagnostic and prognostic information. B. Definitions 1. Lymphoscintigraphy: Imaging pathways of lymphatic flow and lymph nodes after injection of a radiopharmaceutical that is absorbed by the lymphatics. 2. Sentinel lymph node: The first lymph node in a lymph node bed to receive lymphatic drainage from a tumor. Often drainage to more than 1 lymph node group and sentinel node is identified. 3. Blue dye technique: Intraoperative injection (usually peritumoral) of isosulfan blue dye for the purpose of staining lymphatic vessels and sentinel lymph nodes so that they can be identified visually during surgery for excisional biopsy. 4. Gamma-detecting intraoperative probe: Small, hand-held radiation-detecting device that uses auditory signals and meter readouts of counts detected. The intraoperative gamma probe can be used effectively by the surgeon and nuclear medicine physician as a guide to find the radiolabeled sentinel lymph node(s). For correspondence or reprint requests contact: Naomi Alazraki, MD, Division of Nuclear Medicine, Emory University and Veterans Affairs Medical Center, 1670 Clairmont Rd., Decatur, GA 30033. E-mail: nalazra@emory.edu *Previously published in the Procedure Guidelines Manual. YOU CAN ACCESS THIS ARTICLE THROUGH THE SNM WEB SITE (http://www.snm.org/ policy/new_guidelines_1.html).

MM is largely confined to the bone and bone marrow. It has been shown to be responsive to alkylating agents and external radiation. High dose therapy (HDT) with ASCT has been shown to prolong remission and survival. The delivery of targeted radiation using a bone seeking radiopharmaceutical with HDT/ASCT could enhance cytoreduction, improving response rate and survival. 166Ho-DOTMP is a high energy, beta emitting, phosphonate chelate which localizes to bone and produces aplasia. 166Ho-DOTMP is eliminated through the urinary tract; with minimal extramedullary toxicity. Two phase I-II studies combined 166Ho-DOTMP, in escalating doses in combination with HDT have been completed. The HDT consisted of three arms of melphalan at the following doses: 1)140 mg/m2, 2)200 mg/m2 or 3)140 mg/m2 in combination with TBI (800cGy in 4 fractions), MM. Doses of 166Ho-DOTMP to bone marrow began at 20 Gy and escalated in 10 Gy increments up to 40 Gy. 31 pts have been evaluated to date for response and 59 for safety. 57/59 pts experienced rapid neutrophil and platelet engraftment. The complete response rate to date is 42%, with an overall response rate of 48%. These data demonstrate that a marrow dose as high as 40 Gy can be achieved with little toxicity using 166Ho-DOTMP. A phase III, multi-center, randomized trial will start in mid-2000 using a targeted dose of 40 Gy 166Ho-DOTMP in combination with melphalan (200 mg/m2) and ASCT.

PURPOSE:To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS:Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed. RESULTS:The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to < or = 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related. CONCLUSION:This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.

Gallium (67Ga) scan was performed in 29 CLL patients with chronic lymphocytic leukemia who were suspected on clinical grounds to have Richter's transformation (RT). Of 29 patients, nine had a positive 67Ga scan; seven of these had a subsequent biopsy that verified large-cell lymphoma or Hodgkin's disease. The other two patients underwent biopsies that revealed fungal infections, a known cause of 67Ga uptake. Two patients had biopsies that were consistent with RT but showed no affinity to 67Ga. One false negative resulted five days after chemotherapy, a known cause of diminished 67Ga uptake. The other occurred within a small infraorbital mass, containing only 10% centroblasts, which is below the level of detection for 67Ga scanning. Subsequent 67Ga scans in both patients revealed 67Ga avid lesions, which demonstrated RT upon biopsy. This technique was more strongly predictive of RT than was measurement of serum B-2 microglobulin or serum lactate dehydrogenase levels. 67Ga scanning is very useful in localizing an optimal site for biopsy to document RT; it may also have the potential to help assess response to treatment, predict recurrence, and contribute to long-term follow-up in this subset of patients.