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[¹⁸F]Fluorodeoxyglucose Positron Emission Tomography Predicts Outcome for Ewing Sarcoma Family of Tumors

From the Children’s Hospital and Regional Medical Center; and University of Washington Medical Center, Seattle, WA

Address reprint requests to Douglas Hawkins, MD, Children’s Hospital and Regional Medical Center, 4800 Sandpoint Way, Mailstop B-6553, Seattle, WA 98105-0371; e-mail: Doug.Hawkins{at}seattlechildrens.org

	ABSTRACT

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PURPOSE: Response to neoadjuvant chemotherapy is a significant prognostic factor for the Ewing sarcoma family of tumors (ESFTs). [¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is a noninvasive imaging modality that accurately predicts histopathologic response in several malignancies. To determine the prognostic value of FDG PET response for progression-free survival (PFS) in ESFTs, we reviewed the University of Washington Medical Center experience.

PATIENTS AND METHODS: Thirty-six patients with ESFTs were evaluated by FDG PET. All patients received neoadjuvant and adjuvant chemotherapy. FDG PET standard uptake values before (SUV1) and after (SUV2) chemotherapy were analyzed and correlated with chemotherapy response, as assessed by histopathology in surgically excised tumors. Thirty-four patients had both SUV1 and SUV2.

RESULTS: The mean SUV1, SUV2, and ratio of SUV2 to SUV1 (SUV2:1) were 7.9 (range, 2.3 to 32.8), 2.1 (range, 0 to 4.3), and 0.36 (range, 0.00 to 1.00), respectively. Good FDG PET response was defined as SUV2 less than 2.5 or SUV2:1 0.5. FDG PET response by SUV2 or SUV2:1 was concordant with histologic response in 68% and 69% of patients, respectively. SUV2 was associated with outcome (4-year PFS 72% for SUV2 < 2.5 v 27% for SUV2 2.5, P = .01 for all patients; 80% for SUV2 < 2.5 v 33% for SUV2 2.5, P = .036 for localized at diagnosis patients). SUV2:1 0.5 was not predictive of PFS.

CONCLUSION: FDG PET imaging of ESFTs correlates with histologic response to neoadjuvant chemotherapy. SUV2 less than 2.5 is predictive of PFS independent of initial disease stage.

	INTRODUCTION

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The Ewing sarcoma family of tumors (ESFTs) are collectively the second most common malignant bone tumors in children and young adults, with an incidence of 200 occurrences among children and adolescents younger than 20 years each year in the United States.¹ The introduction of multiagent chemotherapy to surgery and/or radiation therapy for ESFTs has improved the prognosis for ESFTs dramatically. Combined-modality therapy results in 65% to 70% progression-free survival (PFS) for children with localized disease.^2-4 Neoadjuvant chemotherapy allows radiographic and histologic assessment of chemotherapy efficacy on the tumor. Histologic response can be measured by either a qualitative assessment of residual tumor⁵ or the percentage of viable tumor cells remaining after neoadjuvant chemotherapy, similar to systems used to assess response in osteosarcoma.^6,7 Histologic response has prognostic value in predicting PFS for ESFTs.^8,9 In addition, surgical oncologists may be more willing to perform limb-sparing surgical resections in the setting of a favorable response to therapy.¹⁰ Alternatively, preoperative radiation therapy could be used, particularly at surgically challenging sites. The selection of resection technique and preoperative radiotherapy is dependent on accurate prediction of histologic response before surgical resection. Because of the therapeutic and prognostic implications of adequate histologic response, a noninvasive surrogate marker of histologic response would be useful to determine the efficacy of neoadjuvant chemotherapy. The osseous component of ESFT usually does not change size in response to chemotherapy, rendering computed tomography (CT) or static magnetic resonance imaging (MRI) unable to identify chemotherapy-responsive tumors.¹¹

[¹⁸F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is an alternative modality to assess response to therapy. FDG is a labeled glucose analog that is taken up and retained avidly by malignant cells. We have reported previously the correlation between FDG PET changes and histologic response in pediatric osteosarcoma and ESFTs,¹² similar to correlations seen after neoadjuvant chemotherapy in breast cancer,^13,14 head and neck cancer,¹⁵ and lymphoma.¹⁶ We have reported an association between sarcoma patient outcome for both the initial tumor standard uptake value (SUV)¹⁷ and the reduction in SUV after neoadjuvant chemotherapy.¹⁸ Associations between FDG PET response and outcome have also been observed in GI stromal tumor,¹⁹ adenocarcinoma of the esophagus,²⁰ and gastric carcinoma.²¹ To determine the value of FDG PET response for predicting outcome in ESFTs, we extended our prior analysis correlating FDG PET and histologic response to include a larger cohort with both pediatric and adult patients, and report for the first time an association between FDG PET and PFS.

	PATIENTS AND METHODS

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Patient Population
We evaluated patients presenting to the Children’s Hospital and Regional Medical Center (CHRMC; Seattle, WA) or University of Washington Medical Center (UWMC; Seattle, WA) with ESFTs who were enrolled prospectively onto a study of FDG PET in sarcomas. All patients (or parents for minors) provided written informed consent for participation in the PET study and medical record review as approved by the UWMC Institutional Review Boards of Human Subjects and Radiation Safety in accordance with institutional and federal guidelines. All eligible patients with ESFTs who received treatment at CHRMC or UWMC between July 1, 1996, and May 1, 2004, underwent evaluation by FDG PET imaging. This series included 33 patients who received both chemotherapy and surgery at CHRMC or UWMC, and three patients referred to CHRMC or UWMC for surgical resection after neoadjuvant chemotherapy at other institutions. Patients who received chemotherapy at CHRMC or UWMC underwent PET imaging no more than 1 week before the initiation of chemotherapy.

Initial staging evaluation included primary site MRI or CT, thoracic CT, and total body bone scan. All patients received neoadjuvant chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide according to previously reported regimens,^22-24 or chemotherapy with the addition of cisplatin. PET imaging was repeated after the induction course of chemotherapy before surgical resection or radiation therapy for local control. Histologic response to neoadjuvant chemotherapy was evaluated based on the grading system by Salzer-Kuntschik et al⁷ for osteosarcoma and later applied to ESFTs.⁸ For each patient, the percentage of viable tumor (calculated from multiple samples from the resected bone and surrounding soft tissue specimen) was used to determine the percent viable tumor cells using standard histopathologic analysis. Favorable response to chemotherapy was defined as 10% viable tumor cells, and unfavorable response to chemotherapy was defined as more than 10% viable tumor cells.

PET Imaging
Detailed methods for PET imaging of sarcoma patients have been published previously.^25,26 Briefly, patients fasted for at least 2 hours before imaging. Patients received 7 to 10 mCi of FDG intravenously during 2 minutes. Blood glucose level was recorded in 35 of 36 patients before administration of FDG and was less than 120 mg/dL in all patients. Intrapatient blood glucose levels before injection of FDG varied by less than 20% in 26 of 33 patients. After a 45-minute equilibration period during which the patient rested, both emission and transmission scans were obtained to generate attenuation-corrected images over the known tumor site using a GE Advance Positron Tomograph (General Electric, Waukesha, WI). Typically, the tumor extent was captured in two adjacent 15-cm fields of view. Reconstructed data were rendered into three-dimensional images using a Hanning filter at a resolution of 4.2 mm. The three-dimensional image sets were available for review in slice thicknesses of 4.2 to 12.0 mm. Regions of interest for determination of tumor SUV were then hand drawn around the area of tumor uptake, using plain film, MRI, and CT scan for reference. The FDG PET image was inspected visually for heterogeneity in tumor uptake. The tumor SUV was automatically calculated by the tomograph software, and after careful assessment of the SUV values throughout the tumor, the maximum tumor SUV, rather than the average SUV, was recorded for analysis. SUV1 was defined as the maximal SUV obtained before neoadjuvant chemotherapy, SUV2 was defined as the maximal SUV obtained after neoadjuvant chemotherapy, and SUV2:1 was defined as the ratio of SUV2 to SUV1.

Statistical Analysis
Statistical analysis of PFS was performed using the Kaplan-Meier method for calculating survival curves and 95% CIs.²⁷ PFS was defined as the time from initial diagnosis to either disease progression or death as a result of any cause. Patients who had not developed progression or died were censored at the date of last contact. Differences in PFS among groups defined by patient or treatment characteristics were analyzed using the log-rank test²⁸ with Bonferroni correction for multiple comparisons. PFS data were analyzed as of May 1, 2005, using SPSS for Windows, version 13.0 (SPSS Inc, Chicago, IL).

	RESULTS

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The clinical characteristics of 36 ESFT patients are listed in Table 1. Included in this series are clinical and histologic response data from 14 patients reported previously.¹² Thirty-two patients had FDG PET imaging before (SUV1) and after (SUV2) chemotherapy, followed by surgical resection of the primary tumor. Two patients received only radiotherapy without surgical resection after neoadjuvant chemotherapy. Two patients had FDG PET imaging only after chemotherapy followed by surgical resection. Most patients had SUV2 obtained less than 3 weeks before surgery. Fifteen patients received additional chemotherapy after SUV2 before surgical resection: 11 patients received one course, two patients received two courses, and two patients received five courses (both while receiving preoperative radiotherapy).

Fifteen of the 36 patients have experienced disease recurrence, including 12 at metastatic sites only. No patient died before disease recurrence. The median follow-up for patients who survived without progression was 52 months (range, 10.8 to 86 months). The 4-year PFS for all patients was estimated to be 57% (95% CI, 39% to 75%; Table 4). Univariate analysis of potential prognostic factors (Table 4) demonstrated that improved PFS was associated with nonmetastatic disease at initial diagnosis, favorable histologic response to neoadjuvant chemotherapy, and SUV2 less than 2.5 (Fig 1). When patients with metastases at diagnosis were excluded, SUV2 less than 2.5 remained associated with improved PFS (4-year PFS, 80% v 33%; P = .036; Fig 2). Neither SUV1 less than 6 nor SUV2:1 0.5 were associated with PFS among all patients (Table 4) or among patients with only localized disease (data not shown). Favorable histologic response ( 10% viable tumor) was also associated with improved PFS (4-year PFS, 67% v 25%; P = .005). When patients with metastases at diagnosis were excluded, favorable histologic response remained associated with improved PFS (4-year PFS, 71% v 38%; P = .044).

View larger version (15K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimated progression-free survival by maximum standard uptake value after chemotherapy (SUV2), for all patients.

View larger version (13K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimated progression-free survival by maximum standard uptake value after chemotherapy (SUV2), excluding patients with metastases at diagnosis.

	DISCUSSION

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To our knowledge, this report is the first to describe the prognostic significance of FDG PET imaging in ESFTs. Our analysis has several important limitations, most obviously its relatively small sample size. The association between SUV2 and PFS will need confirmation in a larger, prospective study. The small study population also precludes the use of a multivariate analysis to determine whether FDG PET is an independent prognostic factor for ESFTs. Several other adverse prognostic factors have been identified, including axial primary sites,^3,4 extrapulmonary metastases,^4,29 increased tumor size,^3,4,30 tumor chromosomal translocation type,^31,32 and older age.^3,4,33 A much larger, prospective study is necessary to control for each of these potential prognostic factors. In addition, our observations should be confirmed in the context of uniform therapy. The treatment characteristics of the study population were similar but not uniform. It is possible that minor differences in chemotherapy regimens, surgery, or radiotherapy may have influenced patient outcome. Finally, we demonstrated the prognostic utility of FDG PET with a carefully defined and uniformly followed protocol including preimaging fasting, time course for imaging, and quantification of maximum tumor SUV. Less stringent or nonquantitative FDG PET techniques may be less discriminative in identifying responding patients.

Previous studies, including our own report,¹² used an SUV cutoff point of 2.0 to discriminate between benign and malignant intraosseous lesions³⁴ or responding and nonresponding lesions.¹² For this analysis, we selected an SUV2 cutoff point of less than 2.5 to optimize the discriminatory distinction between favorable and unfavorable FDG PET response and PFS. The same SUV2 cutoff point (< 2.5) predicts PFS in GI stromal tumors treated with imatinib mesylate.³⁵ However, the optimal SUV2 cutoff point for ESFTs after treatment is unclear and will likely be defined in a larger, prospective study.

There are at least two potential explanations for the discordance between SUV2 and histologic assessments of response. First, SUV2 may remain elevated due to inflammatory infiltrates or reactive fibrosis without viable tumor remaining. Second, the histologic evaluation of response averages the remaining viable tumor cells across a cross-section of the resected tumor. An extensively necrotic or fibrotic tumor might contain a small, isolated focus of residual viable tumor cells, yet would be categorized as having favorable histologic response. However, the residual focus of viable and metabolically active tumor could result in an elevated SUV2 (given that we analyzed maximum not average SUV with each evaluation). These competing limitations to FDG PET and histologic assessment of response could explain why different assays for the same biologic process (in vivo sensitivity to chemotherapy) can have discordant results. Whether FDG PET or histologic response is more predictive of PFS is unknown and will require investigation within a much larger clinical trial to compare the two modalities.

The optimal timing of FDG PET to determine response is also unknown. One possibility for future investigation would be to characterize the rapidity of response to chemotherapy by SUV.^36,37 Changes in FDG metabolism can occur as rapidly as 24 hours after administration of imatinib in a GI stromal tumor.³⁸ Significant changes of SUV can be seen after 42 days of therapy in patients with lymphoma¹⁶ and after one course of therapy in patients with breast cancer.¹⁴ We currently are exploring this hypothesis with a prospective study of high-grade soft tissue sarcoma patients by obtaining FDG PET imaging after 6 weeks (two courses) of therapy and correlating the results with those obtained immediately before surgery (after four courses). Our preliminary analysis suggests that FDG PET imaging changes are apparent after only two courses, and FDG PET imaging results after two and four courses of therapy are almost always concordant.³⁹ Whether changes in FDG metabolism will be observed in ESFTs after only two courses of therapy is unknown. We plan a future prospective FDG PET imaging study in ESFTs to determine whether early FDG metabolic changes are predictive of histologic response and outcome.

The use of FDG PET as a noninvasive surrogate marker of chemotherapy sensitivity has several potential clinical uses. An unfavorable FDG PET response could identify candidates for preoperative radiation therapy, which may improve the local control rate.⁴⁰ Alternatively, unfavorable FDG PET response could guide a change in systemic chemotherapy. Modification of postoperative chemotherapy based on histologic response has not been evaluated prospectively in ESFTs. The current Euro-EWING 99 study stratifies consolidation therapy partially by response to induction therapy. Instead of using histologic response after 18 weeks of induction chemotherapy to guide consolidation therapy, FDG PET might be able to identify poorly responding patients earlier in therapy. Patients who respond poorly to FDG PET could then receive alternative treatment, if promising novel therapies can be identified. Early modification of chemotherapy guided by FDG PET to improve the outcome of patients with ESFTs will require a prospective study.

In summary, SUV2 less than 2.5 after neoadjuvant chemotherapy for ESFTs is associated with an improved PFS. Although SUV2 and histologic response to treatment are likely measuring the same biologic process (in vivo chemotherapy sensitivity), the two are not always concordant, and neither is completely predictive of PFS. Future prospective studies should determine whether FDG PET imaging is an independent prognostic factor, define the optimal FDG PET imaging characteristics and timing of FDG PET to predict outcome, compare FDG PET to histologic response, and investigate the use of FDG PET early in therapy to modify treatment for patients at higher risk for disease recurrence.

	Authors’ Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Scott M. Schuetze Novartis (A) Ernest U. Conrad III Zimmer Corporation (B); Osteonics (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C) $100,000 (N/R) Not Required

	NOTES

 
Supported by National Institutes of Health and National Cancer Institute Grants No. CA87721 and CA65537.

Presented in abstract form at the Connective Tissue Oncology Society Meeting, November 6-8, 2003, Barcelona, Spain.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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Submitted February 21, 2005; accepted July 22, 2005.

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