Ewing’s sarcoma is a highly malignant tumor that metastasizes rapidly and is thus associated with a low survival rate. The intensification of chemotherapy has been shown to improve the overall survival of patients with Ewing’s sarcoma. However, intensified chemotherapy can lead to increased toxicity or even the development of secondary malignancies. The stratification of patients with Ewing’s sarcoma into “good” and “poor” responders may help guide the administration of progressively more intensified chemotherapy. Thus, an accurate assessment of the chemotherapeutic response, as well as the extent of chemotherapy-induced tumor necrosis, is critical for avoiding potential treatment-related complications in these patients. This paper reviews the methods currently used to evaluate chemotherapeutic response in Ewing’s sarcoma, focusing specifically on histopathologic and imaging analyses, and discusses novel therapies and imaging methods that may help improve the overall survival of these patients.
The dramatic improvement in the survival of patients with Ewing’s sarcoma during the past 2 decades can be attributed to the use of aggressive chemotherapy. In the absence of chemotherapy, this highly malignant tumor quickly metastasizes, even when adequate local control has been achieved. In patients without evidence of metastatic disease at presentation, treatment protocols for Ewing’s sarcoma incorporating chemotherapy, surgery, and radiotherapy result in 5-year disease-free survival rates of 40%–50% [
Defining prognostic variables may finally permit the stratification of patients into “poor-risk” and “good-risk” subgroups. This would allow the administration of progressively more intensified therapy in the poor-risk subgroup, decreasing the probability of choosing drug-resistant cellular clones, with an increased risk of metastasis [
The ability to predict the survival of patients with Ewing’s sarcoma is limited, both at the time of diagnosis and after initial preoperative chemotherapy. Clinical signs are insufficient for determining the effectiveness of preoperative chemotherapy and are poorly correlated with histologic tumor response [
In this paper, the methods designed to assess chemotherapy-induced tumor necrosis and how this parameter can influence the prognosis and treatment of Ewing’s sarcoma will be reviewed.
Resection of the primary tumor is the best option for reducing the bulk of soft tissue tumors and has the potential to eliminate tumor cells entirely from bone and soft tissue [
Essentially, 2 different methods of histologic assessment have been established. The first, described by Huvos, is based on his method for evaluating osteogenic sarcoma samples [
Fibrotic replacement of the marrow space occurred following chemotherapy. There were small foci of residual disease grossly and histologically. Overall, systematic mapping of the resection specimen is essential to measure the response to preoperative chemotherapy in the primary tumor (a). Anteroposterior view of the specimen mapped into block segments (b). This response was graded as good, with more than 90% necrosis (Grade 3, Huvos system; Grade 2, Picci system).
This method of histologic grading has been shown to be very effective in the management of Ewing’s sarcoma. The extent of necrosis has been directly correlated with improved survival [
Instead of estimating the amount of nonviable tumor, Picci et al. [
Akermån [
Gross specimen and whole-mount sections demonstrating the areas of (a) necrosis and (b) residual disease.
Thus, an acceptable histologic response grading system depends on a meticulous and precise macroscopic and microscopic examination of the surgical specimen. To accomplish this aim, it is very important to observe the following steps. First, it is necessary to examine the fresh specimen very soon after surgery. Second, it is crucial to keep multiple sections from the preferential sites. Third, it is imperative to cut various sections from the area where the biopsy was obtained. Fourth, it is useful to saw the specimen into halves, using one half for the multiple sections and the other half as a whole tumor section. Fifth, the places where the cuts were made must be represented in an illustration of the specimen and kept as part of the permanent record.
Precise imaging methods have allowed the noninvasive identification, localization, and quantification of residual viable tumor during and after preoperative chemotherapy in patients with Ewing’s sarcoma. Diagnostic imaging may also influence the adjustment of neoadjuvant chemotherapy schedules or the timing of surgical intervention [
Conventional radiography is still useful for developing differential diagnoses, detecting pathologic fractures, estimating tumor aggressiveness, and during followup [
Semiquantitative analysis of tumor activity can be achieved by means of radionuclides, because uptake of the labeled compound depends on cellular function.
Static studies with methylene diphosphonate (MDP) labeled with technetium-99m (99mTc) are not useful for evaluating primary tumors because they often exaggerate the extent of the tumor. However, serial scintigrams have been used to measure activity in the tumor, which is compared with activity in normal contralateral bone. These dynamic studies of 99mTc-MDP have been utilized to distinguish between good responses and poor responses to chemotherapy [
Uptake of gallium-67 (67Ga)-citrate more closely defines the actual tumor than that of 99mTc-MDP because 67Ga-citrate is taken up quickly by Ewing’s sarcoma cells [
Because of the rapid clearance from the blood and the lack of accumulation in nonneoplastic bone of thallium-201 (201Tl), 201Tl scans appear to be more accurate than 67Ga-citrate scans or bone scans with 99mTc-MDP in indicating the course of disease. However, 201Tl scintigraphy has not been widely used for this purpose [
Computerized tomography (CT) provides a cross-sectional view of sarcoma of long bones. Its contrast resolution permits visualization of the extraosseous soft tissue mass and involved bone marrow [
Efforts to correlate modifications in static magnetic resonance (MR) signal intensity with therapeutic response have yielded conflicting results. Discrimination of good and poor responders by means of conventional static MR imaging (MRI) is mainly based on subjectively interpreted qualitative parameters [
Some limitations in the use of conventional static MRI have been observed. Holscher et al. [
The interpretation of signal intensity on T2-weighted MR images remains a problem. In general, low signal intensities are related to acellular tissues, whereas high signal intensities represent the more cellular parts of the tumor [
Dynamic MR studies with injection of gadopentetate dimeglumine have been used to improve MR images for assessing response to chemotherapy [
In this technique, tumor signal intensity is drawn from serial images obtained at 15- to 20-s intervals, and the inclination of the resultant time–intensity curve is calculated. Different patterns have been described.
Brisk slopes (>30%) represent higher perfusion or faster uptake of the contrast agent, perhaps due to tumor neovascularization. These profiles suggest the presence of viable tumor [
Late and gradually enhancing or nonenhancing areas correspond histopathologically to regions of chemotherapy-induced necrosis, mucomyxoid degeneration, or fibrosis. Alternatively, this response is associated with reactive alterations such as edema, hemorrhage, or osteomyelitis, or with tumor-related extracellular matrices such as abundant osteoid or chondroid.
Early and continuously amplified structures seen on MRI correspond to tumor-feeding arteries, growth plate vessels, or remnant viable tumor at specific sites.
In general, responsive tumors show more gradual increases of gadopentetate dimeglumine after preoperative chemotherapy than do nonresponsive tumors. But retarded uptake has been observed in necrotic areas, in cystic regions, and in cartilaginous or myxomatous tissue [
Comparing the accuracy of different imaging techniques in evaluating the response to preoperative chemotherapy in Ewing’s sarcoma, Erlemann et al. [
Dynamic MRI does have some limitations, as it has been observed to yield some false-positive results. The large pathologic vessels in a zone of active subperiosteal new bone formation, and the physeal vessels in young patients, occasionally lead to overestimation of tumor extent, especially towards the growth plate [
Because Ewing’s sarcoma commonly is an extremely vascular tumor and because tumor neovascularization is associated with prognosis and response to therapy in different human neoplasms [
Magnetic resonance angiography (MRA) permits the study of tumor neovascularity in vivo [
Color Doppler flow imaging (CDFI) has also been used to estimate the response to preoperative chemotherapy in patients with Ewing’s sarcoma. Parameters used in this technique are related to the modification of blood flow resistance. The disordered structure of the vascularity of viable tumor reduces the resistance of the peripheral vascular bed. This is the main reason that the peripheral resistance of tumor-feeding arteries is decreased or unaltered. Additionally, a persistent intratumoral flow is found. These 2 parameters suggest a poor histologic response to chemotherapy in Ewing’s sarcoma [
With CDFI it is possible to obtain qualitative as well as quantitative parameters with spectral analysis. In this way, estimation of qualitative anomalous flow patterns within tumors, and quantitative evaluation of tumor blood flow supply and intratumoral blood flow have been performed [
In monitoring the effect of chemotherapy in Ewing’s sarcoma, CDFI with spectral analysis has some advantages over dynamic gadolinium-enhanced MRI and 3-phase bone scintigraphy because of its claimed superior accuracy, noninvasive nature, accessibility, short duration examination, and low cost [
However, CDFI also has some disadvantages. It is technically difficult to perform; its reproducibility needs to be proven; it has poor spatial resolution; and it is not useful for determining chemotherapeutic response in purely intraosseous tumors [
Preliminary results using MR spectroscopy have demonstrated its ability to show some metabolic modifications in chemoresponsive tumors. However, these results have not been proven in the clinical setting. Positron emission tomography (PET) is another imaging technique under consideration for assessing the effectiveness of neoadjuvant chemotherapy in Ewing’s sarcoma [
Imaging techniques such as CT or MRI cannot distinguish accurately between active and necrotic tumor cells. Furthermore, these techniques are limited in their ability to discriminate viable tumor cells from posttherapeutic changes or to exclude minimal residual disease [
PET is increasingly being used as a diagnostic technique. Because of the similarity between 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) and glucose, PET can be used to detect malignancies with glucose hypermetabolism [
While conventional imaging modalities use morphologic criteria to differentiate between benign and malignant tumors, FDG PET utilizes an increased demand for glucose, which is proportional to FDG uptake [
In several malignancies, PET can accurately predict pathologic changes, differentiate between local and disseminated disease, evaluate the response to therapy, and detect relapsed tumors [
In patients with Ewing’s sarcoma, FDG PET correlates with histologic response to neoadjuvant chemotherapy [
However, PET cannot identify the precise anatomic localization of lesions because of its limited spatial resolution. But the combination of PET with CT mitigates this limitation [
In addition, PET/CT is more accurate than PET alone for patients with Ewing’s tumors [
The parameters obtained from the different methods of assessment described above have important implications for prognosis. A strong correlation between prognosis and tumor volume and necrosis has been observed in patients treated with preoperative chemotherapy and surgery [
The risk of local recurrence and metastatic disease are most strongly associated with the status of operative margins [
The classification of patients into good responders and poor responders through the careful assessment of necrosis may encourage the development of new treatment strategies. In particular, poor responders would be treated with more aggressive therapy.
Preoperative chemotherapy has become one of the cornerstones in the treatment of patients with Ewing’s sarcoma [
Different treatment protocols have been used in Ewing’s sarcoma. In those patients without evidence of metastatic disease at presentation, the combined treatment with chemotherapy, surgery, and radiotherapy produces a 5-year disease-free survival rate of 40%–50% [
The addition of ifosfamide and etoposide to the standard chemotherapy regimen of vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA + IE) has been shown to improve survival. Since the incorporation of these 2 drugs, the disease-free survival rates have increased to between 62% and 78% [
New treatments using alkylating agents, at an even higher dose intensity, have produced a 2-year event-free survival rate of 77% [
In terms of surgical technique, more precise histologic and radiologic techniques have allowed better demarcation of the operative margins and have helped in the evaluation of residual viable tumor at specific preferential sites. In patients with a poor response to chemotherapy (Grade 1 or 2), there is a greater probability of local recurrence than in those with a good response to chemotherapy (Grade 3 or 4) (12.5% versus 4.5%) [
Traditionally, the primary tumor has been treated with definitive local therapy using radiotherapy [
Currently, most cases of Ewing’s sarcoma are treated by limb salvage surgery combined with neoadjuvant chemotherapy, which achieve patient survival and preserve function [
New therapies have been developed for those patients in the high-risk subgroup. These new treatment protocols use conventional chemotherapy and consolidation with very-high-dose short-term chemotherapy containing busulfan and melphalan, followed by autologous blood stem cells [
Finally, other treatments like immunotherapy [