Soft Tissue Sarcoma Response to Two Cycles of Neoadjuvant Chemotherapy

Rationale and Objectives

When soft tissue sarcomas are treated with neoadjuvant chemotherapy, the number of cycles of chemotherapy is usually dependent on the tumor’s initial response. Popular methods to assess tumor response include Response Evaluation Criteria in Solid Tumors (RECIST) criteria, which rely solely on tumor size, and maximum standardized uptake value (SUVmax) reduction in positron emission tomography (PET), which requires an expensive and high radiation test. We hypothesized that contrast-enhanced magnetic resonance imaging (MRI) may offer a good alternative by providing additional information beyond tumor size.

Materials and Methods

Following IRB approval, a retrospective review identified patients with soft tissue sarcomas who underwent both PET and MRI before and after two cycles of neoadjuvant chemotherapy. Five readers independently examined the MRI exams for: changes in size, T2 or T1 signal, necrosis and degree of enhancement. Readers then made a subjective binary assessment of tumor response to therapy. Each reader repeated the anonymized randomized reading at least 2 weeks apart. 18 F-FDG PET exams were interpreted by a nuclear medicine specialist. The maximum standardized uptake values (SUVmax) for pre and post-chemotherapy exams were compared. Intra- and inter-reader agreement was assessed using Cohen’s kappa and Light’s kappa, respectively. .

Results

Twenty cases were selected for this multireader study, of which 9 (45%) were responders and 11 were nonresponders by SUVmax. Using all MRI criteria, 43% were classified as responders based on MRI and 1.5% were classified as responders by RECIST criteria. Using PET as the reference, the sensitivity and the specificity of the MRI diagnosis for response using all findings were 50% and 63%, respectively. There was fair to moderate intrareader (kappa = 0.37) and inter-reader (kappa = 0.48) agreement for the MRI diagnosis of response. None of the individual MRI signal characteristics were significantly different between the PET responders and nonresponders. Additionally, no MRI findings were significantly different between those with and without good clinical responses.

Conclusion

By our assessment, there is a poor correlation between tumor response by RECIST criteria and PET SUVmax. In addition, varying MR features did not help in diagnosing tumor response. Imaging of tumor response remains a challenging area that requires further research.

Introduction

Soft tissue sarcomas are rare connective tissue tumors with high mortality that are challenging to treat . Surgery and radiation therapy are the hallmarks of local disease control, but neoadjuvant and adjuvant chemotherapies have been shown to improve outcomes in select circumstances, such as large, high-grade, and recurrent tumors . Different chemotherapy regimens are used ; at our institution, the typical protocol is to start with two cycles of AIM (doxorubicin, ifosfamide, and mesna). After the initial two cycles, the decision to use more chemotherapy is made based on the tumor’s initial response, both clinically and on imaging, in addition to the patient’s tolerance of the treatment .

The traditional use of Response Evaluation Criteria in Solid Tumors (RECIST), which uses change in tumor size to assess tumor response, has been shown to be unreliable in soft tissue sarcomas . Studies have shown that a significant reduction in maximum standardized uptake value (SUVmax) on [F-18]Fluorodeoxyglucose/positron emission tomography-computed tomography ( 18 F-FDG/PET-CT) correlates better with histopathologic response and with improved outcomes . However, positron emission tomography-computed tomography (PET-CT) is an expensive, time-consuming, and high-radiation test. PET-CT, in conjunction with contrast-enhanced magnetic resonance imaging (MRI), has been shown to be useful when distinguishing viable tumor from post-treatment changes . Our providers typically obtain contrast-enhanced MRI at various time points during treatment to assess tumor response, but the criteria to assess response based on MRI have not been well established. Currently, patients with sarcoma at our institution undergo a mixture of PET-CT and contrast-enhanced MRIs after chemotherapy to assess for response, sometimes one or the other, and only occasionally both imaging modalities at the same time.

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Materials and Methods

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Results

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Table 1

Patient, Tumor, and Treatment Characteristics \*

Variable All

( N = 20) Responder by 18 F-FDG PET Yes

( n = 9) No

( n = 11) Female sex 5 (25.0) 2 (22.2) 3 (27.3) Age at diagnosis (y) 50.5 ± 14.6 48.2 ± 17.1 52.3 ± 12.9 Tumor pathology Spindle cell sarcoma † 16 (80.0) 8 (88.9) 8 (72.7) Synovial sarcoma 2 (10.0) 1 (11.1) 1 (9.1) Liposarcoma 2 (10.0) 0 (0.0) 2 (18.2) Tumor grade Low 1 (5.0) 0 (0.0) 1 (9.1) Intermediate 4 (20.0) 2 (22.2) 2 (18.2) Intermediate to High 2 (10.0) 1 (11.1) 1 (9.1) High 13 (65.0) 6 (66.7) 7 (63.6) Location Upper extremity 1 (5.0) 0 (0.0) 1 (45.5) Chest wall 1 (5.0) 1 (11.1) 0 (0.0) Lower extremity 17 (85.0) 8 (88.9) 10 (90.9) Chemotherapy Doxorubicin + ifosfamide 10 (50.0) 5 (55.6) 5 (45.5) Doxorubicin + ifosfamide + pazopanib 8 (40.0) 4 (44.4) 4 (36.4) Epirubicin + ifosfamide 1 (5.0) 0 (0.0) 1 (9.1) Doxorubicin only 1 (5.0) 0 (0.0) 1 (9.1)

18 F-FDG PET, [F-18]fluorodeoxyglucose positron emission tomography.

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Table 2

Intra- and Inter-reader Agreement of MRI Measurements

Variable Intrareader Agreement Inter-reader Agreement ICC or Kappa \* (95% CI) ICC or Kappa \* (95% CI) Longest tumor dimension pretreatment (mm) 0.96 (0.93–0.98) 0.93 (0.83–0.96) Longest tumor dimension post treatment (mm) 0.96 (0.92–0.99) 0.93 (0.84–0.98) Percent change in longest dimension (%) 0.85 (0.75–0.90) 0.73 (0.51–0.85) Change in tumor size † 0.73 (0.60–0.82) 0.61 (0.47–0.71) Change in T2 signal † 0.52 (0.34–0.65) 0.24 (0.13–0.36) Change in T1 signal † 0.45 (0.24–0.62) 0.15 (0.08–0.22) Change in overall tumor enhancement †,‡ 0.44 (0.22–0.59) 0.27 (0.13–0.39) Change in central necrosis †,‡ 0.39 (0.20–0.57) 0.27 (0.12–0.42) Overall tumor response 0.37 (0.12–0.60) 0.35 (0.15–0.54)

CI, confidence interval; ICC, intraclass correlation coefficient.

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Table 3

Comparison of Magnetic Resonance Imaging Measurements with Positron Emission Tomography-defined Response Based on the Maximum Standardized Uptake Value

Variable Responder by 18 F-FDG PET \* p Value † AUC ‡ (95% CI) Yes

( n = 9) No

( n = 11) Percent change in longest dimension (%) 1.2 ± 14.1 10.7 ± 18.9 0.26 0.62 (0.51–0.84) Change in tumor size § −0.0 ± 1.5 0.7 ± 1.1 0.21 0.58 (0.47–0.83) Change in T2 signal § −0.1 ± 0.6 0.2 ± 0.4 0.44 0.44 (0.38–0.61) Change in T1 signal § 0.2 ± 0.6 0.0 ± 0.6 0.85 0.52 (0.43–0.65) Change in overall tumor enhancement §,‖ −0.9 ± 0.9 −0.6 ± 0.8 0.27 0.58 (0.53–0.75) Change in central §,‖ 1.0 ± 0.8 0.9 ± 0.5 0.20 0.60 (0.52–0.73) Response by RECIST criteria 1.1% 1.8% >0.99 — — Overall tumor response 50.0% 37.3% 0.52 — —

AUC, area under the receiver operating characteristic curve; CI, confidence interval; 18 F-FDG PET, [F-18]fluorodeoxyglucose positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors.

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Table 4

Comparison of Magnetic Resonance Imaging Measurements with Clinical Evaluation of Response

Variable Good Clinical Response \* P Value † AUC ‡ (95% CI) Yes

( n = 11) No

( n = 9) Percent change in longest dimension (%) 3.3 ± 15.5 10.2 ± 19.4 0.29 0.63 (0.50–0.83) Change in tumor size § 0.1 ± 1.4 0.7 ± 1.2 0.32 0.54 (0.47–0.80) Change in T2 signal § 0.1 ± 0.6 0.1 ± 0.4 0.91 0.51 (0.41–0.65) Change in T1 signal § 0.2 ± 0.6 0.0 ± 0.5 0.45 0.53 (0.45–0.67) Change in overall tumor enhancement § , ‖ −0.7 ± 0.7 −0.8 ± 1.1 0.93 0.52 (0.47–0.74) Change in central necrosis § , ‖ 1.0 ± 0.4 0.9 ± 0.9 0.77 0.54 (0.51–0.71) Response by RECIST criteria 1.8% 1.1% >0.99 — — Overall tumor response on MRI 46.4% 38.9% 0.62 — — PET response 54.5% 33.3% 0.41 — —

AUC, area under the receiver operating characteristic curve; CI, confidence interval; PET, positron emission tomography.

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Discussion

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References

1. Eilber F.C., Brennan M.F., Eilber F.R., et. al.: Validation of the postoperative nomogram for 12-year sarcoma-specific mortality. Cancer 2004; 101: pp. 2270-2275.
2. Kattan M.W., Leung D.H., Brennan M.F.: Postoperative nomogram for 12-year sarcoma specific death. J Clin Oncol 2002; 20: pp. 791-796.
3. Eilber F.C., Tap W.D., Nelson S.D., et. al.: Advances in chemotherapy for patients with extremity soft tissue sarcoma. Orthop Clin North Am 2006; 37: pp. 15-22.
4. Eilber F.C., Rosen G., Eckardt J., et. al.: Treatment-induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high-grade extremity soft tissue sarcomas. J Clin Oncol 2001; 19: pp. 3202-3209.
5. Canter R.J.: Chemotherapy: does neoadjuvant or adjuvant therapy improve outcomes?. Surg Oncol Clin N Am 2016; 25: pp. 861-872.
6. DeLaney T.F., Harmon D.C., Gebhardt M.C. Treatment of locally recurrent and unresectable, locally advanced soft tissue sarcoma of the extremities. In: UpToDate, Version 25.0. Waltham, MA: UpToDate. Accessed September 19, 2016.
7. Rosen G., Caparros B., Huvos A.G., et. al.: Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982; 49: pp. 1221-1230.
8. Evilevitch V., Weber W.A., Tap W.D., et. al.: Reduction of glucose metabolic activity is more accurate than change in size at predicting histopathologic response to neoadjuvant therapy in high-grade soft-tissue sarcomas. Clin Cancer Res 2008; 14: pp. 715-720.
9. Eary J.F., Conrad E.U., O’Sullivan J., et. al.: Sarcoma mid-therapy [F-18]fluorodeoxyglucose positron emission tomography (FDG PET) and patient outcome. J Bone Joint Surg Am 2014; 96: pp. 152-158.
10. Benz M.R., Czernin J., Allen-Auerbach M.S., et. al.: FDG-PET/CT imaging predicts histopathologic treatment responses after the initial cycle of neoadjuvant chemotherapy in high-grade soft-tissue sarcomas. Clin Cancer Res 2009; 15: pp. 2856-2863.
11. Bredella M.A., Caputo G.R., Steinbach L.S.: 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: pp. 1145-1150.
12. Landis J.R., Koch G.G.: The measurement of observer agreement for categorical data. Biometrics 1977; 33: pp. 159-174.
13. Bates D., Maechler M., Bolker B., et. al.: lme4: Linear mixed-effects models using Eigen and S4. R package version 1.1–10; Available at http://cran.r-project.org/package=lme4 Accessed October 2, 2016

Soft Tissue Sarcoma Response to Two Cycles of Neoadjuvant Chemotherapy

Rationale and Objectives

Materials and Methods

Results

Conclusion

Introduction

Materials and Methods

Results

Discussion

References

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