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Progress and Promise of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development

Authors' Affiliations: ¹ Cancer Imaging Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland; ² Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; ³ Memorial Sloan-Kettering Cancer Center, New York, New York; ⁴ Division of Nuclear Medicine, Mallinckrodt Institute of Radiology, St. Louis, Missouri; ⁵ Department of Orthopaedic Surgery, University of Minnesota and Orthopaedic Surgery Service, Fairview University Medical Center, Minneapolis, Minnesota; ⁶ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia; ⁷ Baylor Charles A. Sammons Cancer Center, Dallas, Texas; ⁸ CCS Associates, Mountain View, California; ⁹ Division of Nuclear Medicine, Department of Radiology, University of Washington, Seattle, Washington; and ¹⁰ Section of Hematology/Oncology, University of Chicago Pritzker School of Medicine, Chicago, Illinois

Requests for reprints: Gary J. Kelloff, Cancer Imaging Program, Division of Cancer Treatment and Diagnostics, National Cancer Institute, NIH, EPN 6130 Executive Boulevard, Suite 6058, Bethesda, MD 20892. Fax: 301-480-3507; E-mail: kelloffg{at}mail.nih.gov.

	Abstract

Top Abstract Cellular and Molecular Biology... The History and Science... FDG-PET Validated for Staging... Current Therapeutics for... Clinical Data of FDG-PET... The Developmental Path for... Conclusions and Recommendations References

 
2-[¹⁸F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non–small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.

Key Words: FDG-PET • molecular imaging • oncology • drug development

FDG-PET is based on the reliance of tumor cells on glycolysis for energy even under aerobic conditions. The sections that follow address:

• the cellular and molecular biology of neoplasia pertaining to glucose metabolism, hypoxia, and the Warburg effect;
  
• the development of FDG-PET as an imaging technique;
  
• the application of FDG-PET in cancer diagnosis, staging, and restaging;
  
• the rationale for using FDG-PET to assess the response to cytotoxic as well as molecularly targeted therapeutics;
  
• the existing clinical data on use of FDG-PET to measure therapeutic response;
  
• the development path for FDG-PET as a surrogate of clinical benefit, and its value in oncologic drug development, in seven case studies.
  
• a summary of the development and current utility of FDG-PET and recommendations for further evaluation and validation in oncologic drug development and patient management.
  

	Cellular and Molecular Biology of Neoplasia: Glucose Metabolism and the Warburg Effect

Top Abstract Cellular and Molecular Biology... The History and Science... FDG-PET Validated for Staging... Current Therapeutics for... Clinical Data of FDG-PET... The Developmental Path for... Conclusions and Recommendations References

 
In the early 1920s, Otto Warburg et al. observed that cancer cells exhibit an increased rate of glycolysis (1). In most living cells, oxidative phosphorylation predominates over simple glycolysis for energy production in the presence of oxygen. Tumor hypoxia may drive, at least in part, the metabolic switch from oxidative phosphorylation to glycolysis as a means of energy generation (2). However, as observed by Warburg et al., cancer cells use glycolysis for energy production regardless of the availability of oxygen. Indeed, not all cancers with high glycolysis are hypoxic (3). Thus, the effect does not necessarily arise as a consequence of hypoxia and may independently provide a growth advantage to cancer cells. This can occur because glycolysis produces energy much faster than oxidative phosphorylation despite the loss in efficiency (glycolysis yields only 2 versus 32 mol ATP per mol glucose). By exploiting rate over yield, cancer cells can more effectively compete for limited fuel resources (4). Normal cells share the consequences of more rapid resource utilization without benefiting from the higher ATP production rate. The growth advantage of cancer cells is yet more pronounced in the oxygen-poor conditions that exist in many solid tumors, which render oxidative phosphorylation less efficient (5).

One of the key alterations associated with the high glycolytic rate of cancer cells is increased cellular glucose uptake. Facilitative hexose uptake is mediated by transmembrane transporters, termed GLUT-1-5. GLUT-1, in particular, is highly expressed in several cancers (6), including breast, NSCLC, thyroid, head and neck, colon, and esophagus. Some studies suggest a correlation with tumor grade and prognosis. Other prominent changes include increased expression of hexokinases (predominantly HK-1 and HK-2), which catalyze the first phosphorylation step in glycolysis (7). In addition to their up-regulation, up to 80% of HK-1 and HK-2 are redistributed in cancer cells (other than brain) to the outer mitochondrial membrane, where the enzymes are bound via a NH₂-terminal hydrophobic tail (8). This binding is thought to provide access to intramitochondrial ATP stores, limit inhibition by glucose-6-phosphate, and improve coordination among glycolysis, oxidation of glucose to lactate, and protein synthesis (7). Also modulated during carcinogenesis are other enzymes comprising the glycolytic pathway (e.g., aldolase and enolase; ref. 9) as well as regulators of glycolytic flux (e.g., 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; ref. 10). A related change is the activation of the hexose monophosphate shunt through which glucose provides the carbon skeletons to meet the high needs of tumor cells for biosynthesis of nucleic acids and other molecules (11).

Oncogenic signal transduction pathways seem to directly stimulate glycolysis. The genes encoding glucose transporters and hexokinases are up-regulated on transfection with oncogenes, including src, ras, and c-myc, and stimulation with growth factors (12–15) independent of hypoxia. Although the molecular regulatory mechanisms are not fully elucidated, the multifunctional protein kinase Akt is postulated to play a central role in transducing these signals to metabolic as well as cell survival and proliferation pathways. Akt is activated by phosphatidylinositol 3-kinase (P13 kinase), is negatively regulated by the dual-specificity phosphatase and tensin homologue (PTEN), and phosphorylates mammalian target of rapamycin (mTOR). P13 kinase–dependent Akt stimulation regulates glucose metabolism in response to certain growth factor stimuli (16). In addition, activated Akt can maintain the mitochondrial membrane potential and induce hexokinase activity in cultured leukemic cells (17). Constitutive activation of Akt in human glioblastoma cells was sufficient to stimulate glucose uptake and aerobic glycolysis independent of influencing proliferation; a P13 kinase inhibitor blocked the effect (18). Thus, Akt seems to be a key mediator of the establishment and maintenance of glycolysis in cancer cells.

Although it can also be controlled by other signaling pathways, the hypoxia-inducible factor-1 (HIF-1) is one downstream mediator of Akt that contributes to the regulation of glycolysis. A subunit of the basic-helix-loop-helix transcription factor HIF-1, HIF-1, is a known regulator of more than a dozen genes involved in glucose transport and metabolism (9, 19). Well known to mediate the response to hypoxia, the translation and stability of HIF-1 and other transcription factors can also be stimulated under normoxic conditions by growth factors, cytokines, and other oncogenic signals (e.g., activating ras or src mutations or p53, von Hippel Lindau, or PTEN loss) via the P13 kinase/Akt and mitogen-activated protein kinase pathways (20–23). For example, under normoxic conditions, growth factor–mediated synthesis of HIF-1 can be blocked by rapamycin (24) and mTOR overexpression stabilizes and transactivates HIF-1 (25). In a mouse prostate model overexpressing human Akt (26), mTOR inhibition reversed the neoplastic phenotype and blocked up-regulation of HIF-1 target genes (including glycolytic enzymes; ref. 27). Interestingly, HIF-1 did not play a role in the stimulation of aerobic glycolysis by Akt observed in the recent study by Elstrom et al. (18), suggesting a role for other effectors of Akt. Indeed, multiple and perhaps redundant signaling molecules may control distinct steps in the activation of genes controlling glycolysis (23).

	The History and Science of FDG-PET Development as an Imaging Probe

Top Abstract Cellular and Molecular Biology... The History and Science... FDG-PET Validated for Staging... Current Therapeutics for... Clinical Data of FDG-PET... The Developmental Path for... Conclusions and Recommendations References

 
Development of 2-[¹⁸F]fluoro-2-deoxyglucose imaging. Deoxyglucose was initially developed as a chemotherapeutic agent to block the accelerated glycolysis of tumor cells, but its central nervous system toxicity was prohibitive. The current technique for FDG assessments (28, 29) was adapted from the [¹⁴C]deoxyglucose method for measuring local glucose utilization in the brain described by Sokoloff et al. (30). FDG initially follows the same metabolic pathway as glucose. Like glucose, 2-deoxyglucose is carried into the cell by glucose transporters, where it is phosphorylated by hexokinase to yield 2-deoxyglucose-6-phosphate. Whereas glucose-6-phosphate subsequently undergoes isomerization to fructose-6-phosphate, further catabolism of 2-deoxyglucose-6-phosphate is not possible because it lacks an oxygen atom at the C-2 position. As 2-deoxyglucose-6-phosphate is unable to diffuse out of cells and the dephosphorylation reaction occurs slowly, it becomes trapped and in fact accumulates at a rate proportional to glucose utilization (Fig. 1). Because of these properties, FDG can be exploited to assess glucose uptake and metabolism.

View larger version (25K): [in this window] [in a new window]   Fig. 1. Transport and metabolism of FDG. Following facilitated transport by GLUT-1 (k1), FDG is phosphorylated by hexokinase (k3). FDG-6-phosphate can neither undergo further metabolism nor diffuse out of cells. As the dephosphorylation (k4) reaction also occurs slowly, FDG-6-phosphate is trapped intracellularly and accumulates.

Analyses of 2-[¹⁸F]fluoro-2-deoxyglucose data. The utility of FDG is further enhanced by the high specific activity of the labeled compound and the sensitivity of the PET scanner(s). These features allow injection of a tracer dose (e.g., nanomole), so that the underlying biological processes remain undisturbed. Thus, clinical FDG-PET studies are conducted as tracer kinetic experiments. The most accurate method to analyze these data is to quantitatively assess the FDG uptake rate over time, for example, by using kinetic modeling together with nonlinear regression techniques (33). The metabolic rate for glucose is calculated from the time course of radiotracer concentration in tissue and in arterial blood. Although metabolic rate for glucose is not dependent on uptake time, dynamic scanning following injection as well as an arterial input function are required. For thoracic studies, the latter can be derived from vascular structures within the field of view, but arterial catheterization and frequent sampling are otherwise usually required. The method enables evaluation of GLUT and hexokinase activity and accounts for dephosphorylation. The primary limitations are that tissue compartments are assumed to be homogenous and that nonlinear regression is sensitive to noise leading to less accurate results for smaller regions. Metabolic rate for glucose is calculated based on the assumption that the lumped constant is known and does not change over time. The lumped constant describes differences in transport and phosphorylation between glucose and FDG in a specific tissue or tumor type. The metabolic rate for glucose is thus estimated according to the following formula:

where MR_glc is the metabolic rate for glucose; C_glc is the circulating glucose level; LC is the lumped constant; K₁ and k₂ are the forward and reverse rate constants for FDG capillary transport, respectively; k₃ is the FDG phosphorylation rate constant; and K_i is the net rate of FDG influx (see also Fig. 1).

One simplified quantitative technique is the linearized Patlak analysis, which still requires dynamic scanning but fewer frames (34, 35). Patlak analysis essentially simplifies the computation of the influx rate constant, K_i, assuming equilibrium between FDG in tissue and plasma and negligible dephosphorylation. Importantly, the method is less sensitive to noise and it is thus possible to perform calculations at the pixel level. Automation is possible, reducing observer variability. Other quantitative methods include the two regions of interest/six-variable model, correlative imaging, the total lesion evaluation method, and the simplified kinetic method (reviewed in ref. 33).

Other methodologies for analyzing these data include visual and semiquantitative evaluations of the accumulated FDG since the net accumulation is proportional to the rate of glycolysis. These approaches assume that FDG uptake is virtually complete and that dephosphorylation of FDG-6-phosphate is negligible (see Fig. 1). The simplest approach is subjective, qualitative visual evaluation of static images (corrected for attenuation) or of whole-body images acquired at multiple axial positions. Alternatively, the radiotracer concentration can be estimated from attenuation-corrected images of the region of interest with semiquantitative analyses. The standardized uptake value (SUV) is a semiquantitative index of tumor uptake normalized to the injected dose and some measure of the total volume of distribution, such as the patient's body weight. The following formula is one example of how SUV can be calculated:

The SUV is dependent on patient size, time between injection and scan (uptake period, usually 60 minutes), plasma glucose levels, and method of image reconstruction (36–38). Normalizing SUV to body surface area or lean body mass reduces dependency on body weight, which can decrease during cancer therapy (39). It may also be appropriate to use lean body mass in heavier patients with a higher fraction of total body fat. Although the SUV can be normalized to the blood glucose concentration if it is expected to change with treatment, one study found no improvement in reproducibility between scans in treated cancer patients with correction for blood glucose (40).

SUVs are strongly correlated with the FDG metabolic rate, particularly when body surface area rather than body weight is used to calculate SUV. For example, Minn et al. found a highly significant correlation (P < 0.0001) between FDG metabolic rate and SUV adjusted for injected dose and weight (r = 0.91) or dose and body surface area (r = 0.94). Absolute SUV values also correlated with Patlak slope in a comparative study of 13 patients (r = 0.97, P < 0.0001), although differences across serial scans were noted for the two methods (41). Nonetheless, serial assessments have established the reproducibility of FDG-PET scans, with several studies finding an 10% variability (refs. 40, 42; reviewed in ref. 33). Thus, regardless of analytic technique, the assessment of FDG in clinical oncology applications has been proven reliable and robust. Because it does not require dynamic data acquisition or arterial blood sampling, the SUV has frequently been used as a measure of FDG uptake to assess differences between scans.

Weaknesses of FDG-PET for cancer imaging include its limited reconstructed spatial resolution of 4 to 10 mm in commercially available scanners. Therefore, a negative scan cannot exclude the presence of a small tumor, and precise anatomic localization of the signal can be problematic in some settings (e.g., in the head and neck). Dual PET/computed tomography (PET/CT) scanners can often resolve indeterminate findings on FDG-PET alone. FDG-PET also cannot distinguish diseases of different histogenic origin (e.g., carcinoma versus lymphoma of the breast) because glycolysis is a general property of malignancy. Some tumors (e.g., mucinous carcinomas and most prostate carcinomas) have relatively low FDG uptake and may not be detected by FDG-PET. In addition, nonspecific signals can arise from normal glucose uptake (e.g., in the brain or bowel) as well as inflammation and other conditions. A dynamic imaging approach, or two-point or delayed imaging, may discriminate cancer from inflammation, because FDG uptake in inflammatory sites is initially rapid and then tapers gradually after 60 minutes, whereas tumor FDG uptake continues to increase with time. In a retrospective study of 76 patients with either malignant or benign conditions, the SUVs of malignant lesions (lung cancer, mesothelioma, non–Hodgkin's lymphoma, and esophageal cancer) increased (mean, 19.2%), whereas those of benign processes (pulmonary nodules, tubercular lesions, radiation-induced inflammation, and periprosthetic infection) tended to decrease (mean, –6.3%) over the interval between scans (mean time, 52 minutes; range, 41-65 minutes; ref. 43). Nonspecific FDG-PET signals can also arise from fat (e.g., brown fat depots in the neck and pericardial fat) or dense muscle activity (e.g., head and neck muscles and diaphragm), but these can usually be distinguished from true malignancies by combining conventional imaging technologies with FDG-PET (e.g., PET/CT), an increasingly common approach (44). Finally, variability can be also be reduced by using patients as their own controls when quantifying differences across serial scans (e.g., in response monitoring). As detailed in the section below, additional, cancer type–specific potential sources of false-positive and false-negative FDG-PET signals—and approaches for minimizing or avoiding them—should be considered during planning and interpretation of FDG-PET scans.

	FDG-PET Validated for Staging and Diagnosis: A Biomarker of Prognosis and Progression

Top Abstract Cellular and Molecular Biology... The History and Science... FDG-PET Validated for Staging... Current Therapeutics for... Clinical Data of FDG-PET... The Developmental Path for... Conclusions and Recommendations References

 
FDG-PET has been used in cancer patients for >25 years. In their review of the FDG-PET oncology literature from 1993 to 2000, Gambhir et al. estimated an overall average sensitivity of 84% (based on >18,402 patient studies) and a specificity of 88% (based on 14,264 patient studies) in cancer (45). As reviewed in detail by Gambhir et al. (45) and others, hundreds of publications have established a role for FDG-PET in the clinical management of cancer patients and as a biomarker of disease prognosis and progression. The Centers for Medicare and Medicaid Services (CMS) have now approved Medicare reimbursement for FDG-PET imaging in 10 oncologic settings (Table 1); in all other cancers, coverage applies only to FDG-PET scans conducted in certain prospective trials or patient registries. In most cancers, FDG-PET is approved for use in disease diagnosis, staging, and restaging. The modality is covered for diagnosis in those settings where FDG-PET results can replace invasive diagnostic procedures or can inform the anatomic location of procedures to be done. Because a tissue diagnosis is made before FDG-PET scanning in most solid tumors, FDG-PET is preferentially used to stage (rather than diagnose) melanoma, lymphoma, esophageal, and colorectal cancers. In these and other diseases, FDG-PET has had a significant impact because accurate staging is essential for appropriate clinical management of the identified cancer. One application where FDG-PET has found particular utility is in detecting distant metastases (e.g., in melanoma and colorectal cancer) and metastatic disease in lymph nodes that appear normal on CT scan (e.g., in lymphoma, lung, and esophageal cancer; ref. 46). After treatment, FDG-PET is valuable for restaging and is used in this setting to detect recurrent or residual disease or to determine the extent of a known recurrence. In locally advanced and metastatic breast cancer, FDG-PET is also employed to monitor therapy response when a change in therapy is anticipated. The following sections address the utility of FDG-PET in CMS-approved settings. Several other cancers, including those recently considered by CMS for approval, are also presented.

Evaluation of NSCLC is one of the primary clinical applications of FDG-PET. FDG-PET is widely used in diagnosing, staging, defining the treatment plan, and assessing recurrence for the disease (see refs. 50–53 for reviews). Several studies have found FDG-PET to be more accurate than conventional imaging in lung cancer. For example, in 100 lung cancer patients, the accuracy of FDG-PET for staging was 83% versus 65% by chest CT and bone scintigraphy (54). In their meta-analysis, Tozola et al. found FDG-PET to be 84% sensitive and 89% specific; the modality was more accurate than CT or endoscopic ultrasound for staging the mediastinum (55). FDG-PET is also superior to CT and magnetic resonance imaging (MRI) for detecting metastases, except for metastatic brain lesions where FDG-PET is clearly less sensitive than contrast-enhanced CT and MRI (52, 54) due to normal high rate of glucose metabolism in the brain. Compared with CT, FDG-PET improved detection of local and distant metastases, altering the clinical stage in 62 of 102 NSCLC patients studied (56). In a separate study, FDG-PET corrected the clinical stage in 27% and detected metastases in 13% of 97 patients (57). Similarly, FDG-PET upstaged 30% of 57 patients studied and improved selection for combined modality treatment by eliminating those with metastatic disease after induction therapy (58). Across series, a change in patient management occurred in up to half or more of patients (59). For example, Kalff et al. found that FDG-PET altered or influenced management in 70 of 105 (67%) patients studied (60). In the randomized, controlled PLUS trial, 39 (41%) of patients undergoing conventional imaging had thoracotomy that was determined to be futile compared with 19 (21%) in the patient group who also had FDG-PET imaging (61). The American College of Surgeons Oncology Group Z0050 trial also found that one in five patients could avoid unnecessary surgery based on FDG-PET data (62). The significant reduction in planned surgery with FDG-PET supports the cost-effectiveness and benefit to the patient of the approach. However, in a separate randomized, controlled trial in which advanced-stage cancer was rarely identified (2 cases among the 184 enrolled stage I-II patients), FDG-PET did not reduce unnecessary thoracotomies but did influence patient management (63). The prognostic significance of FDG-PET in NSCLC has also been established (64, 65). For example, FDG-PET-detected metastatic tumor burden was correlated with survival in a study of 42 NSCLC patients (66). Interestingly, a recent study of 178 NSCLC patients suggested an alternative basis, besides tumor grade, of the prognostic value of FDG-PET (67). Partial volume correction (for tumor size) abolished the significant correlation between SUV_max and surgical tumor stage; a longer follow-up is planned to assess the prognostic significance of the partial volume–corrected FDG-PET signal.

FDG-PET also has utility for restaging both local and metastatic recurrences of NSCLC. As in initial NSCLC staging, FDG-PET is highly specific for detecting metastatic disease (e.g., to lymph nodes, liver, bone, and adrenal glands). FDG-PET also offers improved sensitivity over CT imaging for differentiating new pulmonary nodules from scar tissue arising after surgical resection, radiation, and chemotherapy. For example, compared with CT, FDG-PET was 100% versus 71% sensitive and 92% versus 95% specific, respectively, in 126 NSCLC patients assessed before and after therapy (68). In a separate study of 63 NSCLC patients with suspected relapse, FDG-PET was 98% sensitive and had a negative predictive value of 93%; FDG-PET results stimulated a change in management of 40 (63%) patients (69). Similarly, in 156 NSCLC patients initially evaluated by CT and referred for restaging, FDG-PET downstaged 29% and upstaged 33%, with a resulting reclassification (from resectable to unresectable or vice versa) of 37% of patients (70). These and numerous other studies and clinical trials (see ref. 45 for a comprehensive review) provide the basis for the 1998 and 2001 CMS approvals for NSCLC.

Esophagus. Although relatively uncommon in the United States, esophageal cancer is associated with high mortality and thus accounts for >11,000 cancer deaths per year (71). FDG-PET can identify known primary esophageal tumors but lacks accuracy for regional nodal disease because of proximity to the primary lesion and the often microscopic nature of the neoplastic foci. In one study of 42 patients, FDG-PET was insensitive for regional nodes but superior to combined assessment with ultrasound and CT imaging for evaluating distant nodal metastases (72). In their recent meta-analysis, van Westreenen et al. found an overall sensitivity of 51% and specificity of 84% for locoregional metastases compared with a pooled sensitivity and specificity of 67% and 97%, respectively, for distant metastases (73). Because of its accuracy in identifying and characterizing metastatic disease, FDG-PET is primarily used in esophageal cancer to stage and plan treatment in patients being considered for resection (74). A combined modality approach (i.e., PET + CT) has been advocated as the most accurate method for staging such patients, clarifying clinical management decisions in 90% of 26 cases in one study (75); recent data from Bar-Shalom et al. support a greater accuracy of combined modality PET/CT imaging than FDG-PET alone or separately conducted FDG-PET and CT scans (76). FDG also has prognostic value in esophageal cancer. In a retrospective analysis of 32 patients, FDG uptake was significantly associated with depth of tumor invasion, presence of lymph node metastasis, and lymphatic invasion. Moreover, high FDG uptake in the primary tumor SUV (>3) significantly correlated with lower survival (77). Esophageal cancers commonly recur. Although FDG-PET is sensitive for local recurrence, specificity is limited by uptake due to inflammation, benign disease, and other conditions (e.g., following balloon dilation). However, FDG-PET is superior to conventional imaging for disease that recurs outside of the surgical field (75).

Head and neck. Outside of Asia, head and neck cancers are uncommon and comprise only 2% to 4% of U.S. cancers. Of these, most are oral and laryngeal cancers, which are accessible for diagnosis by visual and physical examination; FDG-PET evaluation does not usually provide additional diagnostic information. However, FDG-PET does have utility for initial diagnosis in those patients presenting with confirmed metastases in the cervical lymph nodes but unknown primary tumor. In studies comprising nearly 300 patients, FDG-PET determined the location of primary disease in 10% to 60% of cases (reviewed in refs. 49, 78). In addition, FDG-PET can define the extent of the primary disease before and after chemoradiotherapy; in contrast to estimates based on conventional imaging, the FDG-PET-defined extent of disease was a significant predictor of survival (P < 0.0001) in one recent study (79). FDG-PET is particularly accurate for staging local nodal spread, a key factor for prognosis and treatment planning. Although they can be readily detected by FDG-PET, distant metastases in head and neck cancer are uncommon, and second primaries are estimated to occur in 8% of cases (78, 80). In detection of recurrent disease, FDG-PET has greater sensitivity and specificity than conventional imaging; CT is limited by the anatomic distortion commonly seen following treatment due to inflammation and edema and typically requires serial examinations. In 53 patients with residual structural abnormalities following definitive treatment, FDG-PET changed patient management in 40%; planned surgery was determined to be futile in 14 patients based on negative FDG-PET scan (79). Indeed, FDG-PET has a high negative predictive value (89% in one study of 75 patients; ref. 81), whereas positive results are less reliable. Because FDG-PET abnormalities are also imprecisely localized, combined modality imaging (PET/CT) is advocated (82).

Colorectum. In colorectal cancer, the primary utility of FDG-PET is in combination with standard CT imaging to detect distant metastases. The modality has low specificity (40-60%) for colorectal cancer because FDG accumulation occurs physiologically in the bowel wall and is enhanced when inflammation and colon polyps are present. FDG-PET also has limited utility for local and regional staging, with sensitivity for regional lymph node involvement of only 29% (83). Combined modality PET/CT offers improved specificity for the primary neoplasm (84). FDG-PET is a valuable addition to CT imaging for characterizing hepatic metastases (particularly those >1 cm) and for detecting extrahepatic metastases (85–89). In their meta-analysis, Huebner et al. found an overall sensitivity and specificity of 97% and 76%, respectively, of FDG-PET for detecting colorectal metastases throughout the body (90). FDG-PET is thus a particularly important staging tool in patients with metastatic disease considered for curative hepatic resection (91, 92). FDG-PET detected additional extrahepatic disease in 25% of 43 patients studied and thereby disqualified them for hepatic resection (93); survival after surgery was increased in this and a later study of 100 patients because of the improved selection of patients for the procedure (93, 94).

Melanoma. Melanoma is another setting in which FDG-PET is highly sensitive and specific for metastatic disease and is therefore an important tool for surgical planning (95). FDG-PET is inferior to sentinel lymph node mapping for characterizing spread to regional lymph nodes because only microscopic disease is present in the sentinel node in most cases (96, 97). However, malignant melanoma can spread to unusual and various sites (e.g., gallbladder, adrenal glands, and bone) that can be easily missed by conventional imaging (98). FDG-PET thus has particular utility for evaluating patients in whom distant metastases are suspected and is used in surveillance of high-risk stage III and IV patients after treatment (99). Post-treatment FDG-PET imaging is especially useful because aggressive resection of metastatic loci is a typical surgical approach. In one study, FDG-PET altered the therapeutic plan in 90% of 34 enrolled patients (100).

Lymphoma. Lymphomas comprise 30 distinct diseases, which are broadly divided into Hodgkin's disease and non–Hodgkin's lymphoma types. Classification (using the REAL or WHO systems) based on morphology, cell surface markers, genetic abnormalities, and clinical features of the disease is essential for guiding treatment and anticipating outcome. Accurate staging also directs treatment selection and thereby improves outcome. FDG-PET is not used for diagnosis in lymphoma because excisional lymph node biopsy with histopathology and immunophenotyping with immunohistochemistry and flow cytometry is the standard. Small series suggest that FDG uptake is correlated with tumor grade at biopsy (e.g., ref. 101), but discordant results may occur (e.g., in nodal large-cell non–Hodgkin's lymphoma with follicular involvement in the bone marrow). Assessing bone marrow involvement by biopsy is also an essential part of patient evaluation and was superior to FDG-PET in a retrospective study of 172 patients (102). However, noninvasive imaging with FDG-PET can play an important role in staging, and several studies have shown its superiority to anatomic imaging modalities (e.g., refs. 103–106; reviewed in refs. 107, 108). For example, compared with staging by CT, FDG-PET was equally sensitive but significantly more specific for Hodgkin's disease (96% versus 41%) as well as non–Hodgkin's lymphoma (100% versus 67%) in a retrospective study of 50 patients (104). Similarly, FDG-PET gave a lower (28%) or higher (12%) stage in 81 Hodgkin's disease patients (106). FDG-PET is also superior to, and has largely replaced, ⁶⁷Ga scintigraphy for staging (109. Hypermetabolic conditions (sarcoidosis, tuberculosis, fungal infections, etc.) are a source of false-positive findings in lymphoma; low-grade tumors and certain lymphomas (e.g., peripheral T-cell and marginal zone, including mucosal-associated lymphoid tissue) have low FDG uptake that can result in false-negative scans (102). Conventional imaging has low specificity for distinguishing residual tumor from fibrosis or scar tissue following therapy (104). Thus, FDG-PET is being increasingly used to restage lymphoma and has particular utility in assessing malignancy in residual masses post-treatment.

Breast. Accurate staging and restaging is essential for optimal management of invasive breast cancer. FDG-PET has utility for initial staging, defining the extent of disease, and treatment planning, particularly for patients with recurrent or metastatic disease. FDG-PET is approved for these uses as an adjunct to conventional imaging approaches. In small tumors and certain low-grade cancers (e.g., tubular and lobular carcinomas and ductal carcinoma in situ), limited FDG accumulation can cause false-negative results, whereas false-positive results can arise due to inflammation (49, 110). FDG-PET is specific (79-100%) for detecting axillary nodal disease, but the sensitivity of FDG-PET is low in cases when the involved nodes or metastases are small (5 mm; refs. 111–114). Sentinel lymph node mapping is superior overall; although FDG-PET has the advantage of being noninvasive (115), most cancers present as stage I or II disease with no or small volume disease in the axilla and thus the clinical utility of FDG-PET as an axillary staging tool is low. Nonetheless, FDG-PET is 2-fold more sensitive than CT for mediastinal or internal mammary nodes and is helpful in planning treatment (e.g., nodal radiation) for advanced axillary disease (116, 117). Further, in settings where breast cancer has metastasized beyond the axillary lymph nodes, FDG-PET has equal (bone and lung) or superior (liver) specificity and sensitivity relative to CT (118–122). As for restaging of other cancers, FDG-PET is useful for differentiating locally recurrent disease from scar tissue and fibrosis and for detecting systemic metastases following definitive treatment. FDG-PET correctly confirmed suspected recurrent or metastatic disease in 25 of 27 patients (123). In a recent retrospective study of 125 recurrent or metastatic breast cancer patients, FDG-PET had a significant impact in defining the extent of disease and, consequently, the planned therapeutic approach. The treatment plan was altered in 32% and supported in 27% of patients. A change was most likely in patients with suspected locoregional recurrence (124).

Thyroid. CMS has approved the use of FDG-PET in thyroid cancer patients with elevated serum thyroglobulin but negative ¹³¹I whole-body scan. Several studies have confirmed the high sensitivity and specificity of FDG-PET in these patients in whom FDG-PET can localize metastatic disease and thereby guide management (see refs. 49, 78 for reviews). For example, FDG-PET changed the surgical approach in 9 of 24 patients in one study (125) and in 19 of 24 in another study (126). Several studies also support the prognostic value of FDG-PET in thyroid cancer; a high volume of FDG-avid disease was associated with reduced survival in one study of 125 thyroid cancer patients followed for 41 months (127). Therefore, FDG-PET is highly useful in clinical decision-making regarding how aggressively to treat thyroid cancer, a disease that can range from rather indolent to highly aggressive. Emerging data suggest that FDG-PET may also have utility in certain rare but aggressive thyroid cancers (particularly Hürthle cell carcinoma and anaplastic thyroid cancer; reviewed in ref. 78). In addition, incidentally discovered focal FDG uptake in the thyroid gland has been associated with malignancy in up to 50% of cases, whereas diffuse uptake is indicative of thyroiditis (128, 129).

Other settings. Accumulating evidence suggests that FDG-PET is a promising imaging modality for other malignancies as well. For example, the utility of FDG-PET has been shown in grading of sarcomas (130–133). Emerging data in testicular cancer support the utility of FDG-PET in initial staging as well as for evaluating residual disease after chemotherapy or if serum markers are elevated but CT scans are negative (134–138). In cervical cancer, several investigations have shown the utility of FDG-PET for identifying occult metastases and for evaluating recurrence and therapy response (139–145). CMS recently considered Medicare approval in six additional cancer settings—small cell lung cancer as well as cancers of the brain, pancreas, cervix, ovary, and testes [see CMS Web site for detailed review of the evidence (146)]. In their January 2005 Decision Memorandum (147), CMS expanded Medicare approval to include FDG-PET scans for the detection of pretreatment metastases in newly diagnosed cervical cancer after negative conventional imaging. In addition, CMS coverage was expanded to include all cancer patients participating in a prospective clinical study of the following types:

• trial meeting requirements for Food and Drug Administration category B investigational device exemption or
  
• an appropriately designed and conducted FDG-PET clinical study to collect additional information at the time of the scan to assist in patient management.
  

	Current Therapeutics for Oncologic Disease: Mechanistic Rationale for FDG-PET as a Measure of Activity

Top Abstract Cellular and Molecular Biology... The History and Science... FDG-PET Validated for Staging... Current Therapeutics for... Clinical Data of FDG-PET... The Developmental Path for... Conclusions and Recommendations References

 
Oncologic treatment options typically include surgery and radiotherapy either alone or together with combination chemotherapy. Using gene expression arrays and other approaches, recent studies have sought to characterize the response to chemotherapeutic agents to elucidate their molecular effectors (148). As depicted in Fig. 2, emerging data suggest that cytotoxic and cytostatic agents affect, directly or indirectly, the pathways, glucose transporters, and metabolic enzymes controlling glycolysis. For example, cytotoxic agents, such as cisplatin and etoposide, dramatically down-regulate hexokinases as well as GLUT-1 and GLUT-3, and suppress glycolysis in vitro (149). Cyclophosphamide also inhibits glycolysis as shown in C3H mice with radiation-induced fibrosarcomas (150). Paclitaxel inhibits glycolysis by mediating detachment of phosphofructokinase from the cytoskeleton, resulting in decreases in two allosteric stimulators of glycolysis (151). Topotecan may affect transcription of the genes controlling glycolysis by decreasing the rate of HIF-1 protein translation (152). In human breast cancer xenografts, estrogen-stimulated growth is associated with a dramatic increase in tumor glycolytic activity and a concomitant elevation in GLUT-1 expression. Tamoxifen treatment induced growth arrest, halved the rate of glycolysis, and dramatically decreased GLUT-1 expression (153).

View larger version (22K): [in this window] [in a new window]   Fig. 2. Molecular targets of cytotoxic and cytostatic drugs in the pathways controlling glycolytic metabolism.

The correlation of molecular abnormalities in specific cancers with alterations in glucose metabolism, including transporters, which are concordantly modulated with several classes of chemotherapeutic drugs, suggests the utility of FDG-PET for therapy monitoring. One possible confounder is that agents targeting Akt or other molecular signals could theoretically affect glycolysis without chemotherapeutic efficacy on the disease or survival. Gene expression arrays or other assays may aid in interpretation of FDG-PET imaging data where the precise molecular target or mechanisms for affecting glycolysis are unknown. In addition, preclinical studies may help to clarify the expected FDG-PET outcome for certain therapies. Indeed, although the data are still emerging, validation of the association of the modulation of glycolysis with tumor response is actively being pursued in ever more relevant preclinical models and innovative small phase II neoadjuvant studies. Existing clinical data, reviewed in the next section, indicate the promise of FDG-PET as a measure of treatment efficacy. Further prospective studies will provide validation in many clinical cancer target organs.

	Clinical Data of FDG-PET as a Measure of Treatment Efficacy with Approved Therapies and Its Role in Patient Management

Top Abstract Cellular and Molecular Biology... The History and Science... FDG-PET Validated for Staging... Current Therapeutics for... Clinical Data of FDG-PET... The Developmental Path for... Conclusions and Recommendations References

 
Although CMS reimbursement for monitoring response to therapy is only approved in certain breast cancer settings, FDG-PET has shown encouraging results as an early predictor of tumor response, progression-free survival (PFS), and OS in a range of clinical settings. Table 2 highlights 25 studies involving nearly a thousand patients with lymphoma, lung, esophagus, head and neck, and other cancers that have correlated the FDG-PET response with clinical outcome. As a measure of treatment efficacy, FDG-PET has several potential applications that can significantly affect patient management. These include early assessment of response, so that ineffective therapy can be discontinued. This is particularly important in disease such as NSCLC, where response rates to existing toxic therapies are modest (20-40%) and expected OS is also low. An additional potential utility of FDG-PET is in monitoring the efficacy of neoadjuvant therapy. Response in the neoadjuvant setting is an important prognostic factor in many cancers. It predicts the benefit from surgery in esophageal cancer and chemosensitivity to the same breast cancer chemotherapeutic agents postsurgery. The sections below summarize the key data validating FDG-PET as a predictor of patient outcome. In many cases, SUV cut points were determined post hoc, and these values need to be further validated in prospective studies. The utility of the imaging modality for influencing patient management in these various clinical settings is highlighted.

Esophagus. In locally advanced esophageal cancer, histopathologic response to preoperative chemotherapy or chemoradiotherapy is one of the most important prognostic factors. Although responders may survive three to four times longer, neoadjuvant therapy does not confer an OS benefit because very few patients do respond (166, 167). Whereas responders should undergo esophagectomy, nonresponders have such a poor prognosis (median survival, 9 months) that the benefit of surgical resection is questionable. If nonresponding patients could be identified early, futile toxic therapies could be discontinued and alternatives considered. As detailed below and in Table 2, studies comprising >130 patients support the potential of FDG-PET to predict histopathologic response within weeks after initiating preoperative therapy. In contrast, endoscopic ultrasonography has an accuracy of <50%, and tumor size cannot be reliably measured with conventional imaging and may not reflect response (e.g., due to edema).

In a study of 40 patients, a decline in FDG uptake 14 days after preoperative cisplatin-based chemotherapy significantly differed among responders (–54%) and nonresponders (–15%; ref. 168). Using a –35% cutoff (defined in receiver operator characteristic analysis), FDG-PET predicted clinical response (>50% reduction in tumor length by standard imaging 3 months post-therapy) as well as recurrence-free survival (P = 0.01) and OS (P = 0.04). Similarly, in a study of 24 patients who went on to esophagectomy, a decreased SUV (52%) 3 weeks after 5-fluorouracil (5-FU) and radiotherapy correlated with both histopathologic response and survival (median, 22.5 versus 8.8 months, P = 0.0001; ref. 169). In a third study, FDG-PET strongly correlated with response to 5-FU/cisplatin and radiotherapy (with 71% sensitivity and 82% specificity) in 36 patients with locally advanced disease (170). In contrast to CT or endoscopic ultrasonography, FDG-PET was also predictive of OS (median, 16.3 versus 6.4 months; P = 0.002). A 60% reduction in SUV after induction paclitaxel/cisplatin chemotherapy (with or without radiation) predicted survival in a fourth study of 39 patients (171); 2-year disease-free survival (DFS) and OS were 63% and 89% compared with only 38% DFS and 67% OS in patients with >60% versus <60% SUV decrease (P = 0.055 and 0.089, respectively). Finally, in a recent study of 38 patients, a reduced SUV 3 to 4 weeks after 5-FU with radiation correlated with histologic response and survival (172). Using a –30% SUV cutoff, positive and negative predictive values were 93% and 88%, respectively. Survival was >38 versus only 18 months in patients with >30% versus <30% SUV decrease, respectively (P = 0.011).

Head and neck. Head and neck cancers are clinically heterogenous, comprising multiple anatomic sites of origin with distinct natural histories and prognoses. Cure rates are low (30-50%) in locally advanced disease. In such patients (stage III-IV), the accuracy of FDG-PET for detecting residual disease provides particular utility for assessing response to neoadjuvant or definitive treatment. Following treatment, prompt salvage surgery improves local control, but the procedure can be avoided or reduced (i.e., for organ preservation) in responding patients. It may also be possible to limit or avoid neck dissection if lymph nodes are shown to lack disease following treatment. Several studies have shown that FDG-PET can assess treatment response, influence patient management, and predict histopathologic control and outcome (reviewed in ref. 173). For example, in a Japanese study, 7 of 15 patients with reduced FDG-PET 4 weeks postchemoradiotherapy (SUV <4) lacked viable tumor cells and either avoided surgery or underwent a less extensive procedure (174). In four patients, positive FDG-PET scans were due to severe mucositis; an interval of 6 to 8 weeks following radiation seems necessary to reduce or avoid false-positive results (78, 175). FDG-PET was sensitive (90%) and specific (83%) for persistent cancer after neoadjuvant chemotherapy in a 28-patient study (176). In a recent study of 41 patients treated definitively by radiation (with or without chemotherapy), FDG-PET findings were highly correlated with lymph node pathology, suggesting that neck dissection could be avoided in patients with negative FDG-PET scan (SUV <3.0; ref. 177). Moreover, in a separate study of patients receiving radiation with or without chemotherapy, a post-therapy metabolic rate below versus above the median was associated with a 5-year OS of 72% versus 35%, respectively (P = 0.0042; ref. 178).

Lymphoma. Although 30% to 70% of patients with advanced or aggressive lymphomas can be cured with first-line therapy, many still die of their disease. As detailed in Table 2, considerable evidence supports the significant association of post-therapy FDG-PET results with outcome. In particular, FDG uptake has been a significant early predictor of residual or recurrent disease and disease progression as well as PFS and OS (179–185). FDG-PET is especially useful in differentiating tumor from fibrosis within residual radiographic masses (186, 187). Such masses are present in half (non–Hodgkin's lymphoma) to two-thirds (Hodgkin's disease) of patients, of whom only 25% (non–Hodgkin's lymphoma) to 30% (Hodgkin's disease) eventually relapse. In a prospective study of 58 patients (43 with Hodgkin's disease) with residual masses following treatment, FDG-PET (SUV 3) predicted recurrence (P = 0.004) and PFS (P < 0.00001; ref. 185). Disease progression was observed after 2 months in 16 of 19 versus 3 of 22 lymphoma patients with positive and negative FDG-PET results, respectively (P < 0.001; ref. 184). FDG-PET results obtained after the first cycle of chemotherapy in 30 non–Hodgkin's lymphoma and Hodgkin's disease patients predicted PFS at 18 months (P 0.001; ref. 188). A recent meta-analysis found that persistence of FDG-avid lesions after therapy predicted relapse, with up to 100% of patients with positive FDG-PET scans experiencing recurrence within 2 years (189). Conversely, absence of disease by FDG-PET scan is an indicator of a favorable prognosis. Indeed, the negative predictive value of FDG-PET was 96% in one study of 81 Hodgkin's disease patients (106), and several studies have also reported a higher positive predictive value for FDG-PET versus conventional imaging modalities (106, 190–192). Integrating FDG-PET into the International Workshop response criteria also seems to increase the predictability of outcome (193, 194).

Prognosis is usually poor in nonresponding and relapsed patients regardless of further conventional treatment, but early, intensive treatment (e.g., high-dose chemotherapy with autologous stem cell transplantation) may be of benefit to appropriately selected patients. Timely identification of nonresponders (e.g., during induction therapy) is important for planning additional treatment of these patients. FDG-PET results following one to four cycles of therapy seems to predict outcome in patients with Hodgkin's disease and aggressive non–Hodgkin's lymphoma; however, whether altering therapy based on those observations will improve outcome has yet to be shown (180).

Sarcoma. The response to treatment in sarcoma is difficult to objectively measure and quantify anatomically as shown by the limited usefulness of the Response Evaluation Criteria in Solid Tumors in this setting (195, 196). Assessment of tumor dimensions in sites, such as bone, bowel, and peritoneal metastases, is problematic; in addition, tumor volume reductions that can be measured by standard criteria may occur slowly or not at all (e.g., due to persistence of necrotic or fibrotic tissue). Several studies now suggest that FDG-PET has significant potential for assessing response to treatment in sarcoma (197–204) as well as for detecting local relapse (200). In high-grade soft tissue sarcomas, chemotherapy remains controversial because response only approximates 40% (205). A meta-analysis of existing studies has not shown a definite benefit of FDG-PET imaging in the management of sarcomas (206); however, this is likely due to the inclusion of studies using poor methodologies as well as limited adherence to appropriate definitions of tumor response. FDG-PET has shown particular promise in monitoring sarcoma and gastrointestinal stromal tumor therapy with the targeted cytostatic agent imatinib (207, 208) and supported in part the demonstration of the agent's efficacy in gastrointestinal stromal tumor (209–211). Compared with standard CT imaging, early therapy monitoring with FDG-PET was a better predictor of long-term outcome. For instance, FDG-PET imaging accurately predicted 1-year tumor response to imatinib in 85% (1-month scan) or 100% (3- or 6-month scan) of 20 gastrointestinal stromal tumor patients compared with only 57% (at 6 months) by CT (207). In a separate study of 21 gastrointestinal stromal tumor and soft tissue sarcoma patients, response based on FDG-PET data and as defined by the European Organization for Research and Treatment of Cancer criteria (ref. 212; see Table 3) obtained 8 days after imatinib treatment correlated with symptom control as well as longer PFS (ref. 208; see Fig. 5). Furthermore, in a recent study of only high-grade or large intermediate-grade soft tissue sarcomas, a 40% reduction in SUV_max following neoadjuvant chemotherapy was a statistically significant independent predictor of both DFS and OS (213).

View larger version (13K): [in this window] [in a new window]   Fig. 5. FDG-PET response to imatinib predicts PFS in advanced soft tissue sarcomas. Kaplan-Meier survival curves for all patients (A) and FDG-PET responders versus nonresponders (B).Reprinted with permissionfrom ref. 208.

In several settings (e.g., colorectal and cervical), the utility of FDG-PET for initial staging and restaging disease, particularly when tumor volume is unchanged or changes slowly, also has advantages for assessing treatment response. For example, as noted in Table 2, FDG-PET is significantly predictive of response to therapy in cervical cancer. This is because FDG-PET is relatively accurate for assessing the extent of disease, particularly in lymph nodes that do not change in size following therapy. The extent of lymph node metastases determined by FDG-PET predicted 3-year cause-specific survival in 47 treated stage IIIb patients (223). Compared with a 73% survival at 45 months in patients negative for lymph node FDG uptake, those with increased FDG signal from pelvic, plus para-aortic, or plus para-aortic and supraclavicular nodes had reduced survival rates of 58%, 29%, and 0%, respectively (P = 0.0005). In a retrospective study of 76 newly diagnosed cervical cancer patients, OS was 30% and 70%, respectively, for those with any or no post-treatment FDG uptake in the cervix and lymph nodes (142). None of the patients who developed new sites of FDG uptake were alive at 2 years. As confirmed in a later report from the same investigators of an expanded population of 152 cervical cancer patients (143), post-treatment FDG-PET was the most significant prognostic factor for death from cervical cancer.

Accumulating evidence supports the utility of FDG-PET for assessing therapy response in colorectal cancer as a predictor of long-term outcomes. In rectal cancer, neoadjuvant therapy can enhance the length as well as the quality of life, the latter due to improved pelvic control and sphincter preservation. Emerging data indicate that, compared with anatomic imaging modalities, FDG-PET can better differentiate scar tissue from locally recurrent rectal cancer and thereby improve response assessment. For example, a recent study of 15 rectal cancer patients found a significantly larger mean change in SUV_max (69% versus 37%) for patients remaining free from recurrence following presurgical chemoradiation, with a larger change in SUV_max (62.5) correlated with increased disease-specific and recurrence-free survival (226). FDG-PET has high sensitivity for colorectal cancer recurrence (230) and has particular utility in assessing the response in colorectal patients with hepatic metastases. For example, response to 5-FU with or without IFN was associated with lower FDG-PET SUVs at 4 to 5 weeks or with lower tumor/liver ratios at 1 to 2 or 4 to 5 weeks (227). Similarly, FDG-PET identified patients responsive to combination therapy with 5-FU and folinic acid (231) or 5-FU, folinic acid, and oxaliplatin (the FOLFOX regimen; ref. 232). Finally, several studies have shown the utility of FDG-PET for monitoring response to local ablative therapy for colorectal liver metastases (233–236).

	The Developmental Path for Validation of FDG-PET as a Surrogate Marker for Clinical Benefit and Its Value in Oncologic Drug Development

Top Abstract Cellular and Molecular Biology... The History and Science... FDG-PET Validated for Staging... Current Therapeutics for... Clinical Data of FDG-PET... The Developmental Path for... Conclusions and Recommendations References

 
Taken together, studies to date establish a role for FDG-PET in assessing response to standard therapies and predicting outcome. These data suggest that FDG-PET has potential to be validated as a surrogate end point for clinical benefit. Once validated with approved therapies, FDG-PET could be employed as a trial end point both in phase III accelerated approval trials and to support go/no go decisions in phase II clinical trials. As such, FDG-PET has the potential to accelerate the drug development process by allowing dosing adjustments or early identification of responders. The paragraphs below present seven case studies, which highlight the outstanding issues and drug development opportunities of employing FDG-PET as a surrogate marker of clinical benefit. Based on existing data, European Organization for Research and Treatment of Cancer has published recommendations regarding the use of FDG-PET for disease assessment (see Table 3; ref. 212). It is anticipated that further insight into the appropriate target organ–specific cutoffs and application of FDG-PET will be defined using receiver operator characteristic analyses in specific cancer types. Once available, these data will guide the design of definitive prospective validation studies of FDG-PET for clinical benefit. As an example, Fig. 3 shows such a prospective validation study of FDG-PET with standard approved chemotherapy in NSCLC. Once validated, FDG-PET could then be incorporated into studies of new therapeutics to accelerate their development and ultimately facilitate progress in the management of cancer patients.

View larger version (47K): [in this window] [in a new window]   Fig. 3. Validation of FDG-PET metabolic response as an approvable surrogate end point in a randomized discontinuation study of a novel cytostatic for the treatment of NSCLC. The recent study by Weber et al. (161) established that a prospectively defined FDG-PET response predicts response to, and survival following, cytotoxic chemotherapy in NSCLC (see Fig. 4). Based on these data, prospective trial designs are possible to allow exploration of the further utility and evaluation of FDG-PET with existing and novel therapies.

View larger version (16K): [in this window] [in a new window]   Fig. 4. FDG-PET predicts response to chemotherapy in NSCLC. Median PFS and OS are significantly longer for responders than nonresponders (163 versus 54 days and 252 versus 151 days, respectively). Reprinted with permission from ref. 161.