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The primary objective of this study was to develop and validate simultaneous PET/MRI-MRS as a novel biological image-guided approach to neoadjuvant radiotherapy (RT) and/or chemoradiation (chemoRT) in soft tissue sarcomas (STS). A patient with sarcoma of the right thigh underwent PET/MRI scan before and after neoadjuvant (preoperative) radiotherapy. The Magnetic Resonance Imaging (MRI) and 2-deoxy-2-[fluorine-18]-fluoro-D-glucose-Positron Emission Tomography (18F-FDG-PET) scans were performed simultaneously. In the post-radiation scan, Magnetic Resonance Spectroscopy (MRS) was subsequently acquired with volume of interest positioned in a residual hyper-metabolic region detected by PET. Post-radiation PET/MRI showed a residual T2-hyperintense mass with significantly reduced 18F-FDG-uptake, compatible with near complete response to radiotherapy. However, a small region of residual high 18F-FDG uptake was detected at the tumor margin. MRS of this region had similar metabolite profile as normal tissue, and was thus considered false positive on PET scan. Pathology results were obtained after surgery for confirmation of imaging findings.
STS are malignant tumors that arise in any of the mesodermal tissues of the extremities (50%), trunk and retroperitoneum (40%), or head and neck (10%). (1) The American Cancer Society estimates that in 2015 there will be 11,930 new cases and 4,870 deaths; (2) approximately 40% of patients treated with curative intent will not survive. Preoperative radiation therapy (RT) followed by limb conserving surgery has become the standard of care for truncal and extremity soft tissue sarcomas. (3, 4) This standard technique for preoperative RT in the United States is established by Radiation Therapy Oncology Group (RTOG)-0630, a recently reported multi-institutional prospective phase II trial to assess late effects using preoperative image-guided radiation therapy (IGRT). (5) In RTOG-0630, gadolinium-enhanced T1 and T2 MRI are typically used for evaluating and confirming the diagnosis. However, MRI images exhibit a variable degree of signal changes. (6, 7) Changes seen by T1/T2 images are an indirect reflection of physiological but anatomic changes and thus may be nonspecific. (8) In order to evaluate tumor response, especially in STS with increased metabolic rate, metabolic imaging methods have higher sensitivity for large primary tumors and high-grade sarcoma cases. (9) Both PET and MRS have been used clinically for evaluating tumor metabolism. Although MRS is capable of detecting metabolic dysfunction in tissue that otherwise appears normal on structural imaging, most clinical applications are limited to a small region with single-voxel or multi-voxel acquisitions due to long acquisition time or SNR limitations. (10) In contrast, 18F-FDG-PET can quickly outline potential metabolic abnormalities throughout the body, but may yield false positive results associated with inflammation, etc. With simultaneous MRI, 18F-FDG uptake can be better localized anatomically to the tumor compared to conventional 18F-FDG PET or PET-CT. With the guidance of PET, MRS can be focused on areas of most concern highlighted by the PET and provide further metabolites information on specific areas in addition to 18F-FDG-PET glucose uptake. The combination of 18F-FDG-PET/MRI-MRS can offer a potentially better tool to evaluate response to neoadjuvant therapy than either volumetrics or pathological percent necrosis rate. We assessed the utility of combined 18F-FDG-PET/MRI-MRS in a patient who underwent neoadjuvant chemoradiation for a lower extremity soft tissue sarcoma.
A 60-year-old female patient with soft tissue sarcoma of the right leg underwent simultaneous 18F-FDG-PET/MR on a commercially available whole-body simultaneous PET–MR scanner (Siemens Biograph mMR, Siemens Healthcare, Erlangen, Germany) before and after preoperative radiation treatment. This scanner consists of an MR-compatible lutetium oxyorthosilicate (LSO) crystal based PET camera inside a 3 Tesla MR scanner, which provides 258 mm axial field of view and 4.4 mm full width at half maximum (FWHM) transverse spatial resolution at 1 cm off the center. The patient fasted for at least 12 hours before the 18F-FDG injection for each scan and no premedication was performed. T1- and T2-weighted MRI with fat saturation and 18F-FDG-PET acquisitions were performed simultaneously. In the post-radiation scan, Proton MRS was performed on tumor and normal tissue, as well as on a small region of abnormally high 18F-FDG uptake at the tumor margin. Prior to the MRS acquisition, 3D shimming followed by manual shimming was performed to ensure homogeneity of the magnetic field in MRS voxels. Proton MRS was performed on three volumes of interest (VOI) using the STimulated Echo Acquisition Mode (STEAM) sequence with a repetition time of 1,500 ms, an echo time of 135 ms with 64 acquisitions and water suppression. The first two VOI (4×4×4 cm3) were carefully positioned respectively within the tumor and normal tissue at the same location on the contralateral leg. A third VOI (1.1×1.1×2.5 cm3) was then placed on a region with abnormal 18F-FDG uptake at the tumor margin guided by fused PET/MRI images. The total acquisition time of MRS was approximately 9 min for all three VOIs.
There is no difference observed in the size or characteristics of the tumor on MRI T2-weighted images before or after radiation treatment. In contrast, pre-radiation PET-MRI showed extensive high 18F-FDG uptake within the tumor, while post-radiation PET-MRI showed significantly reduced extent and intensity of 18F-FDG uptake, compatible with response to radiotherapy. (Figure 1) A small region of high 18F-FDG uptake was detected at the tumor margin. (Figure 2) MRS of this 18F-FDG avid region showed similar metabolite profile to the surrounding normal tissue. Choline-to-creatine ratio (Cho/Cr) within this avid region is 1.13 (Figure 2.F, at Region F, Cho/Cr = 1.13), which is comparable to that of normal tissue in contralateral site (Figure 2.D, at Region D, Cho/Cr =1.30), but much lower than the residual tumor (Figure 2.E, at Region E, Cho/Cr = 2.43). Therefore the small region of high 18F-FDG uptake was considered a false positive on PET scan. This was later confirmed by pathology showing no viable cells in the 18F-FDG avid region. (Figure 3) MRS performed at the tumor core demonstrated increased Choline levels, which is a sign of higher membrane turnover, compared to the spectrum obtained from normal tissue. Radiation-induced cell-death prevents glucose transportation across cell membranes, resulting in no 18F-FDG uptake in treated tumor. However, radiation damage may take weeks to break down cell membranes that are reflected by the high Choline level on MRS. Pathology results were obtained after surgery for confirmation of imaging findings. The gross specimen consisted of a 9.5×8.5×6.2 cm well-circumscribed mass showing areas of necrosis and cystic degeneration, surrounded by skeletal muscle and fibroadipose tissue. Histologically, the tumor showed no specific line of differentiation and was diagnosed as an undifferentiated pleomorphic sarcoma (UPS). The tumor showed scattered single highly pleomorphic cells, with 98% of the tumor replaced by necrosis and fibrosis. The area corresponding to the small region of 18F-FDG uptake but negative on MRS was indeed necrotic. The combined PET and MRI-MRS therefore provided complementary information on the tumor response.
Currently T1 (with and without contrast) and T2 MRI sequences are used routinely to assess soft tissue sarcomas. However, it is difficult to assess treatment response using MRI because most soft tissue sarcomas do not show significant changes in size when comparing pre- to post-radiation imaging. Metabolic imaging with MRS or 18F-FDG-PET has shown higher sensitivity and specificity in a variety of cancers. MRS is capable of simultaneous measurement of multiple metabolites. Therefore, MRS is often used in situations where other medical imaging modalities are inconclusive. Since nearly all metabolites contain protons, in vivo proton MRS is a powerful technique to quantify a large number of biologically important compounds in tissue. A prominent resonance in proton spectra is Choline (Cho) which is involved in pathways of phospholipid synthesis and degradation, thereby reflecting membrane turnover. Increased choline signal has been observed in cancer, Alzheimer’s disease and multiple sclerosis, while increased choline levels are associated with cancer proliferation. Although MRS allows non-invasive measurement of selected metabolites in vivo, recent evidence suggests that metabolic abnormalities in cancerous tumors are characterized by the heterogeneity of the distribution rather than absolute concentrations of one or more metabolites.(11) Most clinical applications of proton MRS are limited to single-voxel spectroscopy or low resolution Chemical Shift Imaging (CSI) because of the long acquisition times required by MRS due to the intrinsic low concentrations of these metabolites compared to protons in water. This limitation can be overcome by using novel integrated PET/MRI systems. With its sensitivity and whole body capability, PET can quickly highlight the location of potential metabolic abnormalities. MRS can then be performed at those regions of interest as in the case presented. Potential applications of simultaneous PET-MRI-MRS can also be expanded to other cancers where assessing treatment response may be difficult using traditional anatomic imaging, including gliomas, bone tumors, gastrointestinal cancer, and others. The MRI obtained simultaneously with 18F-FDG-PET provides superior soft tissue anatomic detail than PET-CT. The 18F-FDG-PET can be used for the detection of enhanced glucose metabolism in these tumors, while MRS provides more specific information about metabolite concentrations at areas where tumor may be difficult to differentiated from inflammation/scar/necrosis. This combination provides potentially more accurate information for assessment of response to therapy. PET/MRI-MRS could potentially also be useful for imaging-guided radiation to escalate treatment dose to residual areas of tumor after initial treatment or for image-guided surgery.
While PET can quickly identify regions with abnormal metabolism, MRS can provide additional specific metabolic information in suspicious regions. Simultaneous PET/MRI-MRS imaging can serve as a gross quantitative, in vivo analog of the postsurgical histological exam, able to classify imaged tissues as either normal, inflamed, tumor, or necrotic. Therefore, it has the potential to provide more accurate treatment response assessment in sarcoma patients with equivocal 18F-FDG-PET findings.
It is becoming increasingly clear that combining PET and MR imaging have tremendous advantages over standalone devices. During the past a few years, simultaneous PET/MR imaging has achieved success in many areas, especially in oncology, cardiac and neurological applications. Combining PET and MR spectroscopy is a natural synergistic combination and a promising new direction for integrated PET/MR systems, which can produce new insights into metabolic processes. This paper proposed the novel simultaneous PET/MRS concept and validates it as an approach for a clinical application of neoadjuvant radiotherapy in soft tissue sarcomas. PET can identify regions with abnormal metabolism prior to treatment and guide MRS post treatment to provide additional specific metabolic information in suspicious regions. Simultaneous PET/MRS imaging can serve as a quantitative, in vivo analog of the postsurgical histological exam, able to classify imaged tissues as either normal, inflamed, tumor, or necrotic. Therefore, it has the potential to provide more accurate treatment response assessment in sarcoma patients with equivocal 18F-FDG-PET findings.
Financial support: NIH R01CA165221; NIH T32 5T32EB013180-04
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