PET imaging of blood flow and glucose metabolism in localized musculoskeletal tumors of the extremities

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Nuclear Medicine and Biology 38 (2011) 295 – 300 www.elsevier.com/locate/nucmedbio

PET imaging of blood flow and glucose metabolism in localized musculoskeletal tumors of the extremities Paula Lindholma,e,⁎, Eija Sutinena,e , Vesa Oikonene , Kimmo Mattilab , Maija Tarkkanenf , Markku Kallajokic , Hannu Arod , Tom Böhlingg , Aarne Kiviojah , Inkeri Elomaaf , Heikki Minna,e a

Department of Oncology and Radiotherapy, Turku University Hospital, Turku FI-20521, Finland b Department of Radiology, Turku University Hospital, Turku FI-20521, Finland c Department of Pathology, Turku University Hospital, Turku FI-20521, Finland d Department of Orthopaedic Surgery, Turku University Hospital, Turku FI-20521, Finland e Turku PET Centre, Turku, Finland f Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland g Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland h Department of Orthopaedic Surgery, Helsinki University Central Hospital, Helsinki, FI-00029, Finland Received 11 June 2010; received in revised form 2 August 2010; accepted 25 August 2010

Abstract Introduction: Little is known about blood flow in sarcomas. Our purpose was to study glucose metabolism and blood flow in untreated localized musculoskeletal tumors of the extremities using [18F]fluorodeoxyglucose (FDG), oxygen-15 labeled water ([15O]H2O) and positron emission tomography (PET). Methods: Six patients with high-grade osteosarcoma (OS), two with soft-tissue sarcoma (STS) and one with aneurysmal bone cyst had PET studies with [15O]H2O and FDG. Arterial blood sampling and autoradiography calculation method were used to define blood flow as milliliters per 100 g times minutes. Tumor FDG uptake was measured as standardized uptake values (SUVs) and regional metabolic rates for FDG (rMRFDG). Two patients also had FDG PET studies during (one patient) and after (two patients) preoperative chemotherapy. All patients underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The PET findings were compared with the clinical follow-up data and results of DCE-MRI. Results: Blood flow in bone tumors was 31.7–75.2 ml/(100 g×min) and in STS 9.0–45.9 ml/(100 g×min). [18F]-Fluorodeoxyglucose uptake and rMRFDG in untreated bone tumors were 5.4–18.4 and 10.9–57.4 μmol/100 g/min, respectively. [18F]-Fluorodeoxyglucose uptake and rMRFDG in STS were 2.6–11.5 and 5.6–32.2 μmol/100 g/min, respectively. Four of five sarcomas with SUVN9.0 have already relapsed. High blood flow in untreated OS was related to long overall survival, while the predictive power of glucose metabolism was less apparent. Good histopathological response to therapy was not associated with long survival. Conclusions: Measurement of blood flow in musculoskeletal tumors appears to be feasible by PET and [15O]H2O. The influence of tumor blood flow and glucose metabolism on the final outcome in sarcoma is variable and needs further research. © 2011 Elsevier Inc. All rights reserved. Keywords: PET; Blood flow; Metabolism; Musculoskeletal tumors

1. Introduction Musculoskeletal sarcomas represent a heterogeneous group of malignant mesenchymal tumors that differ largely ⁎ Corresponding author. Department of Oncology and Radiotherapy Turku University Hospital, P.O. Box 52, Turku FI-20521, Finland. Tel.: +358 2 313 0000; fax: +358 2 313 2809. E-mail address: [email protected] (P. Lindholm). 0969-8051/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.nucmedbio.2010.08.012

in their biological aggressiveness. The most aggressive sarcomas such as Ewing sarcomas are treated with a combination of surgery and chemotherapy with or without radiotherapy, whereas surgery alone may be adequate for low-grade soft-tissue or bone tumors. However, sarcomas with similar histopathological or radiological appearance and response to therapy may have a totally different clinical course.

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Magnetic resonance imaging (MRI) is today an essential part of detection, delineation and staging of musculoskeletal tumors as well as in differential diagnostics, monitoring of response to treatment, and during follow-up. In dynamic contrast-enhanced MRI (DCE-MRI), the early intravascular and interstitial distribution of gadolinium contrast media is followed using ultrafast T1-weighted images. Contrast uptake of tissues can be evaluated image by image and slice level by slice level, and curves can be drawn based on highest enhancement rate using region-of-interest (ROI) method. This method enables selection of viable vascularized sites for histopathological tumor samples, avoiding hemorrhagic or necrotic regions. However, the information obtained by DCE-MRI is extensive and diagnostic timeconsuming and sometimes small nests of viable tumor may be missed [1]. Positron emission tomography (PET) imaging with [18F] fluorodeoxyglucose (FDG) has proved its usefulness in clinical oncology. Although functional FDG-PET imaging is not suitable for grading bone and soft-tissue sarcomas (STSs) [2], PET/CT imaging may be useful in detecting and staging sarcomas [2–4], differentiating malignant from benign musculoskeletal tumors [4] and distinguishing recurrencies from benign therapy-related changes such as fibrotic scar [5]. Promising results have been obtained in the evaluation of response to therapy in pediatric bone sarcomas [6], high-grade STSs [7,8] and gastrointestinal stromal tumors [9]. [18F]-Fluorodeoxyglucose-PET may have prognostic value in STS of extremities [7] and Ewing sarcoma family of tumors [6]. According to the guidelines by the Children's Oncology Group Bone Tumor Committee, whole-body FDG-PET is recommended, but not required, for osteosarcoma (OS) and Ewing sarcoma at presentation, at the end of chemotherapy and in surveillance [10]. Angiogenesis is necessary for growth of solid tumors and their ability to metastasize. Adequate blood flow is needed for the delivery of cytostatic agents into the tumor. However, tumor vasculature is disorganized and dysfunctional, leading into spatially and temporally heterogeneous blood flow and hypoxia. Tumor vessels are irregular in shape and hyperpermeable, and they contain arteriovenous shunts resulting in irregular blood flow and high interstitial fluid pressure, which can decrease the delivery of oxygen and cytostatics and, thus, impair the results of chemotherapy and radiotherapy [11]. As a functional imaging tool, PET offers an interesting method for studying and quantitating regional blood flow in tumors [12]. Most PET studies on tumor perfusion have been performed in gliomas [13,14] and breast cancer [15–18], in which changes in blood flow and glucose metabolism correlated with response to neoadjuvant chemotherapy [19]. Much less is known about blood flow in sarcomas. We have previously shown that imaging of perfusion in head and neck cancer was feasible by PET using [15O]-labeled water ([15O] H2O) and autoradiography [20]. Tumor perfusion was significantly higher than that in skeletal neck muscle, and

high tumor perfusion predicted poor response to radiotherapy [21]. The purpose of the present prospective investigation was to measure blood flow and glucose metabolism in untreated musculoskeletal tumors by [15O]H2O, FDG and PET and to evaluate whether these parameters are related to biological behavior of tumor, therapeutic response and the outcome of the patients. 2. Patients and methods 2.1. Patients Nine patients with primary musculoskeletal tumor of the extremity were admitted to the sarcoma centers of the University Hospital of Turku (n=6) or Helsinki (n=3) because of suspected malignancy. Diagnostics included Xrays and dynamic CT and/or MRI of the tumor and the entire bone involved, bone scintigraphy and CT of the thorax and abdomen especially in highly malignant tumors. Histopathological core samples were taken using CT/MR guidance. Six patients had high-grade OS of the tibia (n=4) or the femur (n=2), two had STS of leg or buttock and one tumor turned out to be an aneurysmal bone cyst. Patient characteristics are described in Table 1. Patients underwent PET studies before treatment. All patients with OS underwent PET studies within 1 week before starting chemotherapy. After PET studies, preoperative chemotherapy was started for patients with OS (n=6) according to the Scandinavian Sarcoma Group Osteosarcoma Study VIII [22] or Italian and Scandinavian Sarcoma Groups I [23] treatment protocols or were operated (n=2). Patient 9 received radiotherapy with a curative intent because the large STS turned out to be unresectable. All other patients had radical surgery. All but one patient were operated with limb-sparing technique including radical resection and reconstruction; one had an amputation. Two patients with OS also underwent FDG-PET studies during (Patient 1) and after (Patients 1 and 3) preoperative chemotherapy. Clinical treatment decisions were not influenced by the PET findings. Histopathological response to preoperative chemotherapy in OS was evaluated in the surgical specimens according to the criteria used in the protocols and was classified as either Table 1 Patient characteristics Patient

Age/sex

Tumor/grade

Site

Size

1 2 3 4 5 6 7 8 9

16/M 15/M 17/F 16/M 17/M 18/F 28/M 49/M 76/M

OS/high OS/high OS/high OS/high OS/high OS/high ABC/benign LS/low MFS/high

Tibia Femur Tibia Tibia Tibia Femur Femur Leg Buttock

8 15 13 24 12 8 5 10 30

ABC, aneurysmal bone cyst; F, female; LS, well-differentiated liposarcoma; M, male; MFS, myxofibrosarcoma.

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Fig. 1. Tumor blood flow (ml/(100 g×min) and overall survival of five patients with untreated OS. One of the six patients with OS did not undergo a blood flow study for logistic reasons.

good (b10% viable cells) or poor (≥10% viable cells). Chemotherapy was continued postoperatively according to the treatment protocols in OS. Follow-up was measured from the time of diagnostic biopsy, and the median follow-up is 47 months (range 16–141 months). 2.2. Positron emission tomography imaging A GE Advance PET scanner (General Electric Medical Systems, Milwaukee, WI) was used in the studies. The device produces 35 axial planes with a slice thickness of 4.25 mm and a total transaxial field of view of 15.2 cm. The measurements were corrected for scatter, random counts and dead time. Transmission scan for attenuation correction was performed with two rotating rod sources containing 68 Ge/68 Ga. Image reconstruction was performed with filtered back projection. The final in-plane resolution was 6 mm full-width of half-maximum. A low-energy deuteron accelerator, Cyclone 3 (Ion Beam Applications, Louvain-La-Neuve, Belgium) was used for the production of [15O]H2O. [15O]H2O for perfusion imaging was synthesized using a diffusion membrane technique in a constantly working water module. An online radioactivity

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recording was performed with a low-voltage ionization chamber [24]. The patients were advised to fast at least 6 h before the PET studies. Plasma glucose level was measured before, during and at the end of the studies. Eight patients had PET studies with [15O]H2O and FDG on the same day before therapy. After the transmission scan for 10 min, a perfusion study was performed using dynamic acquisition of 7 min (2×10, 10×5, 6×15 and 8×30 s) after an intravenous 20-s bolus injection of 1400 MBq of [15O]H2O. Arterial blood was withdrawn with a pump, and the radioactivity was monitored using an online detector to obtain the input function, as described before [20,21]. After the perfusion study, a dynamic scan for 60 min (5×60, 5×180 and 8×300 s) was performed following an injection of 3700 MBq of FDG. Serial arterial blood sampling was performed to obtain the uptake rate of FDG into the tumor, influx constant Ki. Patient 1 had a static FDG emission scan for 15 min (3×300 s) starting at 45 min postinjection before, during and after preoperative chemotherapy, but for logistic reasons, the patient did not undergo perfusion study. Patient 3 also had a dynamic 60-min FDG scan without blood sampling after preoperative chemotherapy. 2.3. Positron emission tomography data analysis In FDG studies, several ROIs were drawn manually on the hot spots of the tumor representing the highest radioactivity concentration. The ROIs were drawn on the time frame between 55 and 60 min postinjection. In perfusion studies, whole-tumor ROIs with the highest uptake in the FDG studies were carefully matched with the corresponding planes on the flow images. Single tissue compartment model and autoradiography calculation method using a 250-s integration time and arterial input curve were used to measure blood flow in milliliters per 100 g times minutes, as described before [20,21,25]. Tumor FDG uptake was measured as standardized uptake values (SUVs) and regional metabolic rates for FDG

Table 2 Glucose metabolism and blood flow in nine untreated musculoskeletal tumors measured by PET Tumor

Response

Flow (ml/(100 g×min))

rMRFDG (μmol/100 g/min)

SUV

SUV2

SUV3

Follow-up months

OS OS

Poor Good

– 51.9

– 28.7

12.1 9.9

4.2 –

2.1 –

OS

Good

45.2

57.4

18.4

–

3.0

OS OS OS ABC LS MFS

Poor Poor Poor – – –

31.7 62.2 75.2 49.4 9.0 45.9

32.3 13.9 17.5 10.9 5.6 32.2

11.0 5.4 6.1 5.5 2.6 11.5

– – – – – –

– – – – – –

NED 141+ months LR 15 months, DM 22 months, DOD 38 months DM 12 months, LR 16 months, DOD 20 months DM 12 months, DOD 28 months DM 24 months, DOD 47 months NED 112+ months NED 47+ months NED 99+ months DM 10 months, DOD 30 months

ABC, aneurysmal bone cyst; DM, distant metastases; DOD, dead of disease; LR, local recurrence; LS, well-differentiated liposarcoma; MFS, myxofibrosarcoma; NED, no evidence of disease; Response, histopathological response to preoperative chemotherapy. Good response, b10% viable cells, poor response, ≥10% viable cells.

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(rMRFDG) as micromoles per 100 g per minute, which is the average plasma glucose concentration during the emission scan multiplied by influx constant Ki. The maximum SUV, rMRFDG and blood flow values of the tumors were chosen for the analysis. Positron emission tomography findings were compared with the clinical follow-up data using linear regression, and correlation coefficients were calculated.

3. Results Regional blood flow and glucose utilization varied greatly between different musculoskeletal tumors and also within the same tumor. The highest measured blood flow in OS varied between 31.7 and 75.2 ml/(100 g×min) (n=5) and, in the two STSs, it was 9.0 and 45.9 ml/(100 g×min), respectively. An aneurysmal bone cyst of the femur appeared to have high, but rather homogeneous, blood flow of 49.4 ml/(100 g×min). Osteosarcoma with the lowest blood flow was clinically found to progress during therapy and was operated after only one cycle of chemotherapy. The histological response was poor. High blood flow in untreated OS was related to long overall survival (r=.85, Pb.03; Fig. 1). Glucose metabolism measured as SUVs and rMRFDG in untreated OS were 5.4–18.4 (n=6) and 13.9–57.4 μmol/100 g/min (n=5), respectively (Table 2). Standardized uptake values and rMRFDG in untreated STS was 2.6–11.5 and 5.6– 32.2 μmol/100 g/min (n=2), respectively. An aneurysmal bone cyst had an SUV was 5.5 and rMRFDG 10.9 μmol/100 g/min. Although four of five sarcomas with SUVN9.0 relapsed with distant metastases, tumor SUV in untreated OS did not correlate with overall survival (Fig. 2). Regional metabolic rates for FDG correlated somewhat better with overall survival in OS (r=.63, Pb.04; Fig. 3), but not as well as tumor blood flow. During and after preoperative chemotherapy, Patient 1’s SUV in OS decreased significantly (83%) and also had poor histopathological response to therapy even though conventional MRI suggested progression. In Patient 3 (Fig. 4A,B),

Fig. 2. Tumor SUV and overall survival of all the six patients with untreated OS.

Fig. 3. Tumor rMRFDG and overall survival in five patients with untreated OS. One of the six patients with OS did not have serial blood sampling needed for measurement of tumor rMRFDG for logistic reasons.

who was studied twice before surgery, the tumor SUV decreased markedly (84%) after preoperative chemotherapy and the histopathological response was good. However, unfortunately, an early distant relapse was confirmed at 12 months and a local recurrence at 16 months after diagnosis. In this small series of OS patients, good histopathological response was not associated with long overall survival.

4. Discussion The histopathological response to chemotherapy is considered to be the most important prognostic factor in high-grade OS and Ewing sarcoma, and adequate blood flow is needed for optimal cytostatic effect. However, the initial histopathological response to therapy does not always correlate with aggressiveness of OS or better outcome of the patient. New biomarkers are needed for monitoring clinical response and optimization of cancer therapy. These results suggest that determination of blood flow in sarcoma is feasible by PET and [15O]H2O. After injection of radioactive water, a time–concentration curve reflecting radioactive oxygen uptake in the tissue can be measured. In this small series of patients, blood flow in OS correlated better than glucose metabolism with overall survival. This technique may also be useful in studying the effects of antiangiogenic drugs on tumor vasculature. Some STSs such as angiosarcomas possess rich vasculature, and therefore, tyrosine kinase inhibitors with activity against vascular endothelial growth factor receptors such as sunitinib are being studied in the treatment of inoperable or metastatic nongastrointestinal sarcomas [26]. Isolated leg perfusion (ILP) is another method in the treatment of inoperable sarcomas of the extremities, and PET using FDG or 11Ctyrosine has been investigated in evaluating response to treatment [27,28]. Positron emission tomography imaging with [15O]H2O before ILP treatment could give useful information about the perfusion of the tumor. However, this technique is technically demanding. It requires a nearby cyclotron for the production of short-lived [15O]-labeled

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Fig. 4. Example of PET images with (A) [15O]H2O and (B) FDG in untreated OS of the proximal tibia (Patient 3).

tracer and arterial cannulation of the patient for the measurement of input function, and these are the main limitations of the study. Estimates of tumor blood flow can be derived using parametric images in patients with tumors that can be imaged simultaneously with the heart or large vessels such as abdominal aorta by PET. The arterial input function can be determined noninvasively, and the model fitting is performed on a pixel-by-pixel basis [29]. Breast, lung and pancreatic cancers [16,30,31] have been studied using such technique. Combined imaging of blood flow and metabolism has been found to complement conventional clinical evaluation, and prediction of resistance to antivascular therapy with this form of functional imaging has been suggested [16,19]. In line with this, our initial experience in pancreatic cancer shows that the most aggressive tumors had reduced blood flow coupled with high metabolism [31]. In the current study, high blood flow pretreatment is associated with a good response to neoadjuvant chemotherapy, while such a relationship has not been seen in breast cancer [19] or head and neck cancer in patients receiving radiotherapy [21]. These observations underline differences and heterogeneity in vasculature of various disease and histology entities and the impact of treatment modality on effect of the studied biomarker. Other imaging techniques such as dynamic contrastenhanced CT or DCE-MRI or have also been suggested for measurements of tumor vascularity. After the injection of a contrast agent, time–intensity curves of perfusion parameters can be obtained for each ROI. Direct visual interpretation of these images allows detection of highly vascular areas representing highly perfused viable tumor, whereas cell death leads to poor perfusion and slow enhancement. However, the exact extent of cell death may be difficult to estimate based on enhancement [1,32]. In conclusion, measurement of blood flow in sarcoma is feasible by PET and [15O]H2O. In this pilot study, we study high blood flow to be associated with long survival in OS, while the relationship between glucose metabolism and survival time was less apparent. This technique could also be useful in imaging angiogenesis and development of antiangiogenic drugs. The influence of tumor glucose

metabolism and blood flow on the final outcome of the patients with sarcoma needs to be substantiated in a larger study.

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