PET for Sarcomas Other Than Gastrointestinal Stromal Tumors

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1 PET for Sarcomas Other Than Gastrointestinal Stromal Tumors Guy C. Toner, a,c Rodney J. Hicks b,c a Division of Haematology and Medical Oncology and b Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia; c Department of Medicine, St Vincent s Medical School, University of Melbourne, Melbourne, Australia Key Words. Sarcoma PET scanning Response assessment Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article. Abstract Positron emission tomography (PET) is increasingly used to diagnose, grade, and stage different types of tumors and to assess tumor response to therapy. Metabolic data acquired by fluorine--fluorodeoxyglucose ( FDG)-PET may facilitate accurate grading of sarcomas and have prognostic value when combined with other grading methods and various clinical/radiological features. In addition, FDG-PET is currently being evaluated in several cancer types for its utility in biopsy guidance. Whole-body FDG-PET also appears to be superior to other imaging modalities in detecting bone Introduction Positron emission tomography (PET) has wide-ranging utility in sarcoma, including staging, assessment of prognosis, monitoring response, and potentially to customize treatment regimens [1 4]. Fluorine--fluorodeoxyglucose ( FDG)-PET is well suited to detecting the inherent heterogeneity of these tumors. The utility of PET in tumor grading, biopsy guidance, staging and restaging, and response evaluation and monitoring in sarcoma patients is discussed. Utility of PET for Tumor Grading An association between FDG uptake and sarcoma tumor grade was first noted in 1988 [5]. FDG-PET avidity has been shown to increase with tumor grade in both bone and soft tissue sarcomas: the glycolytic metabolic activity of high-grade tumors is higher than that of low-grade or benign metastases in certain sarcoma patients. New PET tracers currently being investigated include F-fluorothymidine ( F-FLT) and F-misonidazole. F-FLT can help to determine tumor growth, rather than tumor shrinkage, which could be used to evaluate treatment response in sarcomas. PET imaging offers invaluable information to help maximize the clinical benefit of patients with sarcoma. This article reviews the use of PET in sarcoma management and its potential applications in the near future. The Oncologist 2008;13(suppl 2):22 26 tumors [6]. In addition to histopathological grade, FDG- PET standardized uptake value (SUV) was also demonstrated to be associated with cellularity, mitotic activity, MIB labeling index, and p53 overexpression in various bone and soft tissue sarcomas [6]. Thus, metabolic data acquired by FDG-PET may facilitate accurate grading and have prognostic value in the sarcoma setting. To a certain extent, FDG-PET may be used to differentiate benign from malignant sarcomas. Significant differences in the differential uptake ratio, a quantitative index of glucose metabolism, in benign masses and malignant sarcomas have been noted by several researchers [7, 8]. However, the definition of malignant has been problematic, as has the type of sarcoma being evaluated. Furthermore, different groups have obtained conflicting results using the metabolic rate of FDG (MRFDG) as a parameter to distinguish between benign and malignant sarcomas [9 11]. Downloaded from by guest on August 14, 20 Correspondence: Guy Toner, M.D., Peter MacCallum Cancer Institute, Medical Oncology, St. Andrews Place, East Melbourne, Australia Telephone: ; Fax: ; guy.toner@petermac.org Received August 20, 2007; accepted for publication December 11, AlphaMed Press /2008/$30.00/0 doi: /theoncologist.13-S2-22 The Oncologist 2008;13(suppl 2):

2 Toner, Hicks Figure 1. CT, FDG-PET, and fused FDG-PET/CT images of a patient with a large left thigh mass consistent with liposarcoma. FDG-PET was used during biopsy to target the region with highest metabolic activity. Abbreviations: FDG-PET, fluorine--fluorodeoxyglucose positron emission tomography; CT, computed tomography. Utility of PET for Biopsy Guidance Both PET and computed tomography (CT) are very useful for biopsy guidance. As an example, Figure 1 demonstrates combined PET/CT findings in a case with a large left thigh mass with features consistent with liposarcoma. FDGPET was used during biopsy to guide the treating physician to the highest metabolic region, which allowed confirmation that this was a high-grade tumor. In this patient, multiple s.c. metastases were also detected by PET. Thus, by guiding biopsy toward the most biologically significant regions of large masses, FDG-PET can reveal information about a lesion that cannot be obtained through other imaging modalities. The use of FDG-PET in biopsy is currently being investigated in several cancer types, and may prove invaluable in several settings, including sarcomas. Utility of PET for Staging and Restaging Two independent studies reported that the sensitivity and specificity of FDG-PET for the detection of pulmonary metastases from various types of sarcoma were 50% 86.7% and 98% 100%, respectively, while the sensitivity and specificity of spiral CT of the chest were 75% 100% and 96.4% 100%, respectively [14, 15]. However, FDGPET has a higher sensitivity than CT for soft tissue metastases, and it can also be used to identify false-positive CT masses. The two groups of researchers agreed that CT and FDG-PET are both needed to accurately define the extent of disease during initial staging as well as during follow-up. Our own experience with combined PET/CT scanning over the past 3 years suggests that CT scanning is particularly helpful in localizing small lung metastases wherein partial volume effects lead to insufficient signal on PET to allow a confident diagnosis of malignancy. Conversely, for larger nodules, the presence of high uptake at other sites of disease but not in the lung nodule makes a metastatic basis very unlikely. In contrast, whole-body FDG-PET appears to be superior to other imaging modalities for detection of bone metastases in certain sarcoma patients. Compared with bone scintigraphy, FDG-PET was associated with a higher sensitivity (100% versus 68%), specificity (96% versus 87%), and accuracy (97% versus 82%) in 38 patients with histologically proven malignant primary Ewing s sarcoma [16]. Interestingly, although FDG-PET also appeared to have some value in the detection of osseous masses from osteosarcomas, it appeared to be less sensitive than bone scintigraphy in these patients. FDG-PET is also very helpful in assessing possible local recurrence and performing restaging. Detection of local recurrence is often difficult because of disturbance of the normal anatomy by previous surgery and any subse- Downloaded from by guest on August 14, 20 MRFDG does not appear to be useful for grading certain bone tumors, such as giant cell tumors, which typically show a relatively high SUV. In contrast, this methodology has been successfully used to distinguish among grade I, II, and III soft tissue sarcomas [10]. While FDG-PET alone may not be sufficient for grading sarcomas, it does have the potential to provide complementary information when coupled with other grading modalities and with various clinical/radiological features. Evaluation of FDG uptake may also have potential prognostic value. In patients with gastrointestinal stromal tumors, reductions in the FDG-PET maximum SUV have been shown to correlate with longer time to progression [12]. In a study of 74 adult patients with soft tissue sarcoma who underwent preoperative FDG-PET imaging, SUV was found to be somewhat predictive of recurrencefree survival [13]. Patients with SUVs <1.59, 1.59 to <3.6, and 3.6 had 5-year recurrence-free survival rates of 66%, 24%, and 11%, respectively. While these results are promising, further studies are required to determine whether PET information can be used as an independent prognostic variable in this patient population. 23

3 24 quent radiotherapy. Unlike some other imaging modalities, FDG-PET is not disabled by the metal susceptibility or metal beam hardening artifacts that may result from previous treatments. Several studies have indicated the high accuracy of FDG-PET for detecting late local recurrence in sarcoma patients [17 21]. Utility of PET in Response Evaluation and Monitoring Figure 2. FDG-PET and merged FDG-PET/CT images of a patient with an osteosarcoma of the left femur that was treated with neoadjuvant chemotherapy. The scans demonstrate a dramatic reduction in metabolic activity in the tumor after chemotherapy. Abbreviations: FDG-PET, fluorine--fluorodeoxyglucose positron emission tomography; CT, computed tomography. The predictive value of PET scanning has been investigated for evaluating histological response following neoadjuvant chemotherapy in patients with osteosarcoma [24 26]. The case presented in Figure 2 shows that residual metabolic activity following neoadjuvant chemotherapeutic treatment of a leg osteosarcoma can be visualized using FDG-PET. In a prospective study that evaluated the utility of FDG-PET in assessing response to neoadjuvant chemotherapy in patients with osteosarcoma, Schulte and colleagues demonstrated a strong correlation between a reduction in tumor glucose metabolism following therapy and the histologic grade of tumor regression [24]. In 25 of 27 patients, pre- and post-treatment tumor-to-background ratios (TBRs) of FDG uptake could be used to discriminate responders from nonresponders. Thus, FDG-PET provides a promising tool for noninvasive evaluation of neoadjuvant chemotherapy response in osteosarcoma. Ideally, PET scanning will be used in the near future to detect differential responses to different neoadjuvant chemotherapeutic compounds, which might facilitate patient-specific tailoring of neoadjuvant treatment and postoperative therapy. However, this type of information must be obtained through the cooperation of several research groups through well-designed clinical trials. In contrast to the current use of PET immediately before and after completion of treatment only, there is potential value in performing PET scans several times throughout treatment, as illustrated in Figure 3. This approach might allow individual assessment of response to Figure 3. Proposed clinical trial model for evaluating the utility of FDG-PET in predicting response in osteosarcoma. (A): Use of FDG-PET during a neoadjuvant sarcoma treatment regimen would allow correlation of PET response with histologic response. (B): Proposed use of FDG-PET during neoadjuvant sarcoma treatment regimen. More frequent use of FDG-PET might allow assessment of response to individual components of the treatment regimen. Abbreviations: FDG-PET, fluorine--fluorodeoxyglucose positron emission tomography; CDDP/ADM, cisplatin and doxorubicin; MTX, methotrexate. OTncologist he Downloaded from by guest on August 14, 20 The utility of FDG-PET in monitoring response has been recently demonstrated to be superior to that of CT for predicting outcome in patients with non-small cell lung cancer (NSCLC) [22]. CT and other structural imaging modalities have substantial limitations in the lung and pleura, such as irregular tumor shapes that are difficult to measure, poor contrast at the interface between tumor and normal tissue, and obstruction by radiation pneumonitis [22, 23]. In a direct head-to-head comparison, the utility of FDGPET and CT in assessing response and thereby survival in patients with NSCLC who received either radical radiotherapy or chemotherapy was evaluated. The study authors concluded that a single, early, post-treatment PET scan could significantly (p <.0001) predict survival, while CT results failed to do so [22]. FDG-PET may have similar response evaluation potential in other cancers, including sarcomas. PET for Other Sarcomas

4 Toner, Hicks 25 the different chemotherapy components of treatment. As a result, information obtained through PET scanning during therapy might potentially change a patient s treatment, ultimately affecting his or her chances of remission and survival. Future Directions: New PET Tracers While FDG PET can be used along with CT to reveal the location and malignant potential of abnormal tissue masses, PET imaging has the potential to yield additional information about tumors that could further improve diagnosis and individually tailor cancer treatment. Several alternative PET radiopharmaceuticals are currently being investigated, both preclinically and in early clinical trials, which have the potential to reveal the growth rate, oxygen use, drug resistance properties, and blood supply of tumors. Examples of new PET tracers being investigated for use in sarcoma as well as other cancers include F-fluorothymidine ( F- FLT) and F-misonidazole ( F-MISO). F-FLT is an analogue of the nucleotide thymidine, and is therefore used as a marker of DNA synthesis. When used before treatment and soon after treatment begins, F-FLT may help determine the extent to which a tumor s growth is being slowed in response to therapy. This is particularly relevant for sarcoma, in which the use of newer cytostatic agents leads to a References 1 Hicks RJ, Toner GC, Choong PF. Clinical applications of molecular imaging in sarcoma evaluation. Cancer Imaging 2005;5: Eary JF, O Sullivan F, Powitan Y et al. Sarcoma tumor FDG uptake measured by PET and patient outcome: A retrospective analysis. Eur J Nucl Med Mol Imaging 2002;29: Feldman F, van Heertum R, Manos C. FDG PET scanning of benign and malignant musculoskeletal lesions. Skeletal Radiol 2003;32: Schulte M, Brecht-Krauss D, Heymer B et al. Grading of tumors and tumorlike lesions of bone: Evaluation by FDG PET. J Nucl Med 2000;41: Kern KA, Brunetti A, Norton JA et al. Metabolic imaging of human extremity musculoskeletal tumors by PET. J Nucl Med 1988;29: Folpe AL, Lyles RH, Sprouse JT et al. (F-) fluorodeoxyglucose positron emission tomography as a predictor of pathologic grade and other prognostic variables in bone and soft tissue sarcoma. Clin Cancer Res 2000;6: Adler LP, Blair HF, Makley JT et al. Noninvasive grading of musculoskeletal tumors using PET. J Nucl Med 1991;32: Griffeth LK, Dehdashti F, McGuire AH et al. PET evaluation of softtissue masses with fluorine- fluoro-2-deoxy-d-glucose. Radiology 1992;2: Nieweg OE, Pruim J, van Ginkel RJ et al. Fluorine--fluorodeoxyglucose PET imaging of soft-tissue sarcoma. J Nucl Med 1996;37: Eary JF, Conrad EU, Bruckner JD et al. Quantitative [F-]fluorodeoxyglucose positron emission tomography in pretreatment and grading of sarcoma. Clin Cancer Res 1998;4: slower rate of tumor growth rather than tumor shrinkage. F-FLT-PET may allow changes in cell proliferation to be observed much earlier and to a much greater extent than FDG-PET. F-MISO is a marker of tumor hypoxia, which can lead to cellular responses that can potentially raise a tumor s resistance to therapy. Recent results have shown that F-MISO-PET may be useful for predicting survival in patients with head and neck cancer [27]. Conclusions In sarcoma, PET scans provide useful complementary information that must be interpreted in the overall context of the patient s imaging and other evaluations. PET can be used for grading of disease and differentiating between benign and malignant disease, biopsy evaluation, staging and restaging, assessing local recurrence, and therapeutic monitoring. However, further studies are required to improve quantitation of response, because SUVs and TBRs are at best semiquantitative, and comparison among different sites and use in clinical trials will require additional study. Finally, the potential advantages of identifying new radiopharmaceuticals such as FLT and F-MISO suggest that PET scanning will play an even larger role in the diagnosis and treatment of sarcomas in the future. 11 Kole AC, Nieweg OE, Hoekstra HJ et al. Fluorine--fluorodeoxyglucose assessment of glucose metabolism in bone tumors. J Nucl Med 1998;39: Holdsworth CH, Manola J, Badawi RD et al. Use of computerized tomography (CT) as an early prognostic indicator of response to imatinib mesylate (IM) in patients with gastrointestinal stromal tumors (GIST). J Clin Oncol 2004;22(suppl 14):197s. 13 Schwarzbach MH, Hinz U, Dimitrakopoulou-Strauss A et al. Prognostic significance of preoperative [-F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging in patients with resectable soft tissue sarcomas. Ann Surg 2005;241: Lucas JD, O Doherty MJ, Wong JC et al. Evaluation of fluorodeoxyglucose positron emission tomography in the management of soft-tissue sarcomas. 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5 26 PET for Other Sarcomas 19 el-zeftawy H, Heiba SI, Jana S et al. Role of repeated F- fluorodeoxyglucose imaging in management of patients with bone and soft tissue sarcoma. Cancer Biother Radiopharm 2001;16: Bredella MA, Caputo GR, Steinbach LS. Value of FDG positron emission tomography in conjunction with MR imaging for evaluating therapy response in patients with musculoskeletal sarcomas. AJR Am J Roentgenol 2002;179: Johnson GR, Zhuang H, Khan J et al. Roles of positron emission tomography with fluorine--deoxyglucose in the detection of local recurrent and distant metastatic sarcoma. Clin Nucl Med 2003;28: MacManus MP, Hicks RJ, Matthews JP et al. Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 2003;21: Werner-Wasik M, Xiao Y, Pequignot E et al. Assessment of lung cancer response after nonoperative therapy: Tumor diameter, bidimensional product, and volume. A serial CT scan-based study. Int J Radiat Oncol Biol Phys 2001; Schulte M, Brecht-Krauss D, Werner M et al. Evaluation of neoadjuvant therapy response of osteogenic sarcoma using FDG PET. J Nucl Med 1999;40: Franzius C, Sciuk J, Brinkschmidt C et al. Evaluation of chemotherapy response in primary bone tumors with F- FDG positron emission tomography compared with histologically assessed tumor necrosis. Clin Nucl Med 2000;25: Nair N, Ali A, Green AA et al. Response of osteosarcoma to chemotherapy. Evaluation with F- FDG-PET scans. Clin Positron Imaging 2000;3: Schwartz DL, Rajendran J, Yueh B et al. FDG-PET prediction of head and neck squamous cell cancer outcomes. Arch Otolaryngol Head Neck Surg 2004;130: Downloaded from by guest on August 14, 20 The Oncologist