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

Abstract

2-[ 18 F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamentalpropertyof neoplasia, theWarburgeffect.This molecularimaging technique offers acomplementary 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-PETalso has significant potential for assessing therapy response. In this regard, it canimprove patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reductioninthe FDG-PETsignal withindays 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 usedin drug approvals.These findings suggest that FDGPETcould facilitate drug development as an early surrogate of clinicalbenefit.This article reviews the scientificbasis ofFDG-PETandits development andapplicationasavaluableoncologyimagingtool. 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. FDG-PET (2-[18 F]Fluoro-2-deoxyglucose positron emission tomography) is an accepted and widely used clinical imaging tool in oncology. U.S. Medicare reimbursement of FDG-PET recently expanded to encompass all cancer patients participating in certain prospective studies or registries in addition to more general coverage in 10 defined oncologic settings. Primarily covered are disease diagnosis, staging, and restaging, but FDG-PET is also approved for monitoring response to therapy in locally advanced and metastatic breast cancers when a change in therapy is anticipated. Clinical trials in breast cancer and other settings [e.g., non -small cell lung cancer (NSCLC) and esophageal cancer] have shown that FDG-PET imaging can provide an early indication of therapeutic response that is well correlated with clinical outcome. FDG-PET thus has the potential to improve patient management, particularly by signaling the need for early therapeutic changes in nonresponders, thereby obviating the side effects and costs of ineffective treatment. As an early surrogate for clinical benefit, the modality also has the potential to facilitate oncologic drug development by shortening phase II trials and detecting clinical benefit earlier in phase III investigations. Studies to further explore and validate these approaches are needed and can be conducted in parallel with those employing end points now use...

PET/CT imaging in cancer: Current applications and future directions

“…The types of cancer that are most commonly imaged with FDG-PET include lymphoma, head and neck cancer, lung, colorectal cancer, breast cancer, esophageal cancer, melanoma, cervical cancer, thyroid cancer, and pancreatic cancer. [17][18][19] Some of these cancers, such as aggressive lymphoma, squamous cell carcinoma of the head and neck, and melanoma, are usually "hot" on FDG-PET. 20 Other cancers, such as prostate cancer, neuroendocrine cancer, and well differentiated hepatocellular carcinoma, are often "cold," which limits the utility of FDG-PET in those tumors.…”

“…23 False-positive findings are relatively common on FDG-PET, because elevated glycolysis is not limited to cancer cells. 17 Typical causes of increased FDG uptake unrelated to malignancy include infectious and inflammatory etiologies, muscular activity, metabolism in brown fat, and changes in response to bone marrow-stimulating cytokines. Thus, the modest specificity and low sensitivity of FDG-PET for early stage disease limit its utility for cancer screening.…”

Evolutionary dynamics of the Warburg effect: Glycolysis as a collective action problem among cancer cells

“…Tumors, however, consistently rely on glycolysis even in the presence of abundant oxygen (Beckner et al, 2005;Griguer et al, 2005;Kelloff et al, 2005;Rajendran et al, 2003). Since the anaerobic metabolism of glucose to lactic acid is substantially less efficient than oxidation to CO 2 and H 2 O, tumor cells must increase glucose flux in order to maintain sufficient ATP production.…”

Novel radiolabeled antibody conjugates

“…For example, in radioimmunodetection, these radiolabeled antibodies could differentiate tumor from nonspecific proliferation, such as in inflammation, when compared to FDG, or when FDG was not suitable (such as in prostate cancer) (Kelloff et al, 2005a, b;Jana and Blaufox, 2006;Zalutsky, 2006a). In radioimmunotherapy, evidence for efficacy could be shown in locoregional applications (Alvarez et al, 1997(Alvarez et al, , 2002Mahe et al, 1999;Riva et al, 1999;Meredith et al, 2001;Goetz et al, 2003;Paganelli et al, 2006;Reardon et al, 2006), in an adjuvant setting (Liersch et al, 2005;Zalutsky, 2006b) IgG Figure 1 Examples of molecularly re-engineered forms of antibody used for targeting radionuclides.…”