Multiagent PET for Risk Characterization in Sarcoma

The pathobiologic process of cancer is dynamic and multifaceted. Contributions from clinical and biomedical research continue to add dimensions to this understanding. In clinical practice, risk assessment for cancer outcome is required for patient counseling and treatment planning. Currently, we assess risk with standard clinical methods including physical examination, clinical evaluation, imaging, and tumor biopsy. These evaluations provide information on cancer biologic process parameters but are limited by the discontinuous nature of the observations. These fragmented data likely lack specificity to suggest the most effective therapy for a patient’s treatment. Because of the ability of PET methods to noninvasively report on the rate of change of biologically specific processes, we designed an experimental protocol using sequentially administered 11C and 18F imaging agents to gauge multiple parameters for patient risk assessment in a single imaging session. The short half-life of 11C is advantageous for sequential radiotracer injection and imaging, as demonstrated by our previous experience (1–5). The soft-tissue sarcoma patient population under care in our institution comprises a group with highly diverse tumor biology. Despite this diversity, treatment protocols are the same for most soft-tissue sarcoma types. This fact points out the need for identification of tumors at high risk for poor outcome within this group. Sarcomas exhibit intralesional heterogeneity in cellular proliferation rates, making it difficult to predict treatment effectiveness. These differences led us to choose this tumor group to demonstrate that diverse tumors will show differences in specific imaging agent uptake parameters. For example, a high level of cellular proliferation is a feature of high-grade soft-tissue sarcomas, suggesting that treatment with cell cycle–active cytotoxic chemotherapy agents would be effective. Lower-grade tumors are less likely to have high cellular proliferation rates and are known to be less responsive to standard chemotherapy. Measurement of this parameter before and during therapy would be useful in planning individualized treatment and monitoring early response. Sarcomas also have intrinsic multiple-drug resistance, a significant problem for effectiveness of alkylator drugs, which form the basis of sarcoma chemotherapy. This resistance is thought to be induced as a consequence of therapy. Many sarcomas are also known to be hypoxic, which likely confers resistance to chemo- and radiotherapy and accelerated metastatic spread. Many patients experience tumor local recurrences, but pulmonary metastases are the principal cause of death. Consequently, neoadjuvant and adjuvant treatments in sarcoma are aimed primarily at decreasing pulmonary metastases or treating those metastases that present early in the patient’s disease course. Tumor biologic features may also directly influence the risk for pulmonary metastases and their progression. The multiagent PET protocol we developed was designed to demonstrate the use of multiple biologic measures for risk associated with tumor biologic characteristics. This PET tumor imaging methodology may be an effective tool for risk assessment in individual patients with many other types of cancer. Three PET agents provided the core of the imaging sequence in this study: 11C-thymidine, for tissue cellular proliferation; 11C-verapamil, a P-glycoprotein (P-gp) substrate, to assess multiple-drug resistance activity; and 18F-fluoromisonidazole (18F-FMISO), to identify tumor hypoxic volume (Table 1). This group of imaging agents was supported by additional imaging with 15O-water, an indicator of tumor blood flow, and 11C-CO2, the dominant labeled metabolite of thymidine. In this report, initial experience in the feasibility of multiagent PET studies for assessment of the dynamic cancer biologic process is presented. TABLE 1 PET Agents for Risk Stratification in Sarcoma