Developing a Prognostic Model for Localized Ewing Sarcoma Family of Tumors: A Single Institutional Experience of 224 Cases Treated With Uniform Chemotherapy Protocol BIVAS BISWAS, MD, 1 S. RASTOGI, MD, 2 S.A. KHAN, MD, 2 N.K. SHUKLA, MD, 3 S.V.S. DEO, MD, 3 S. AGARWALA, MD, 4 B.K. MOHANTI, MD, 5 M.C. SHARMA, MD, 6 SREENIVAS VISHNUBHATLA, PhD, 7 AND S. BAKHSHI, MD 1 * 1 Department of Medical Oncology, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India 2 Departments of Orthopedics, All India Institute of Medical Sciences, New Delhi, India 3 Departments of Surgical Oncology, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India 4 Departments of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India 5 Departments of Radiotherapy, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India 6 Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India 7 Departments of Biostatistics, All India Institute of Medical Sciences, New Delhi, India Background: Data on patients with localized Ewing sarcoma family of tumors (ESFT) who have received a uniform chemotherapy protocol are minimal. Methods: This is a single institutional review of patients with ESFT treated between June 2003 and November 2011. Results: 224/374 (60%) patients with ESFT presented with localized disease; median age was 15 years (range: 0.1–55). Ninety-nine patients underwent surgery of which 50 received adjuvant radiotherapy; 80 patients received radical radiotherapy following neoadjuvant chemotherapy. At median follow-up of 40.2 months (range: 1.3–129), 5-year EFS, OS, and local-control-rate, were 36.8 3.6%, 52.4 4.3%, and 63 4.3%, respectively. In multivariate analysis, tumor diameter >8cm (P ¼ 0.03), symptom duration >4 months (P ¼ 0.04), and WBC >11 10 9 /L (P ¼ 0.003) predicted inferior EFS; spine/abdomino-pelvic primary (P ¼ 0.009) and WBC >11 10 9 /L (P ¼ 0.003) predicted inferior OS. Tumor size >8 cm (P ¼ 0.03) and radical radiotherapy as local treatment (P ¼ 0.01) predicted inferior local-control-rate. Conclusion: Prognostic hazard models for EFS and OS based on significant prognostic factors suggested that patients with combination of ESFT of spine/abdomino-pelvic region and baseline WBC >11 10 9 /L had inferior OS (hazard ratio 4.44, P < 0.001) while patients with combination of ESFT with symptom duration >4 months, tumor diameter >8 m and baseline WBC >11 10 9 /L had inferior EFS (hazard ratio 3.89, P ¼ 0.002). J. Surg. Oncol. 2015;111:683–689. ß 2014 Wiley Periodicals, Inc. KEY WORDS: chemotherapy; localized; primitive neuroectodermal tumor; outcome; prognostic factors INTRODUCTION The prognosis of Ewing sarcoma family of tumors (ESFT) has improved over last few decades with the introduction of systemic chemotherapy and multimodality approach. Data on prognostic factors in localized ESFT are available from different randomized studies [1–9] with well-defined inclusion and exclusion criteria. Institute-based evaluation of all consecutive patients with intent-to-treat analysis gives a realistic view of outcome. Majority of publications from institutional experience are biased by the fact that they are retrospective in nature with limited number of patients and additionally treated with heterogeneous chemotherapy protocols over a long period of time [10–17]. Here, we have analyzed clinicopathological characteristics, treatment outcome, and prognostic factors of 224 patients with non- metastatic ESFT who were treated with a uniform chemotherapy protocol over an 8 year period and evaluated on intent-to-treat analysis. Our aim was to analyze treatment outcome so as to prognosticate patients on the basis of clinicopathological parameters. MATERIALS AND METHODS Patients This study involves data review of all patients with proven diagnosis of classical ESFT that were treated in our department from June 2003- November 2011. Patients with localized ESFT of all sites other than brain were selected for this analysis. Patients with metastatic disease (after metastatic work-up) were excluded. Patient’s baseline clinic- pathological features, treatment modality, and outcome data were collected. Ethical clearance was taken from institutional ethical review committee. Diagnostic Work Up All patients underwent biopsy (trucut/incisional) of primary lesion with immunohistochemistry. Diagnosis of ESFT required presence of small blue round cell tumor and positivity for CD99 (MIC-2) in the Funding: This research did not receive any specific grant from any funding agencies in the public, commercial, or not-for-profit sectors. Potential conflicts of interest and financial disclosure: The authors declare that there is no conflict of interest for this study. Correspondence to: Prof. Sameer Bakhshi, MD, Department of Medical Oncology, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India. Fax: þ91–11-26588663. E-mail: [email protected]Received 14 November 2014; Accepted 14 November 2014 DOI 10.1002/jso.23861 Published online 29 December 2014 in Wiley Online Library (wileyonlinelibrary.com). Journal of Surgical Oncology 2015;111:683–689 ß 2014 Wiley Periodicals, Inc.
Transcript
Developing a Prognostic Model for Localized Ewing Sarcoma Family of Tumors:
A Single Institutional Experience of 224 Cases Treated With
Uniform Chemotherapy Protocol
BIVAS BISWAS, MD,1 S. RASTOGI, MD,2 S.A. KHAN, MD,2 N.K. SHUKLA, MD,3 S.V.S. DEO, MD,3
1Department of Medical Oncology, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India2Departments of Orthopedics, All India Institute of Medical Sciences, New Delhi, India
3Departments of Surgical Oncology, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India4Departments of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
5Departments of Radiotherapy, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India6Departments of Pathology, All India Institute of Medical Sciences, New Delhi, India7Departments of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
Background: Data on patients with localized Ewing sarcoma family of tumors (ESFT) who have received a uniform chemotherapy protocol areminimal.Methods: This is a single institutional review of patients with ESFT treated between June 2003 and November 2011.Results: 224/374 (60%) patients with ESFT presented with localized disease; median age was 15 years (range: 0.1–55). Ninety-nine patientsunderwent surgery of which 50 received adjuvant radiotherapy; 80 patients received radical radiotherapy following neoadjuvant chemotherapy. Atmedian follow-up of 40.2 months (range: 1.3–129), 5-year EFS, OS, and local-control-rate, were 36.8� 3.6%, 52.4� 4.3%, and 63� 4.3%,respectively. In multivariate analysis, tumor diameter >8 cm (P¼ 0.03), symptom duration >4 months (P¼ 0.04), and WBC >11� 109/L(P¼ 0.003) predicted inferior EFS; spine/abdomino-pelvic primary (P¼ 0.009) and WBC>11� 109/L (P¼ 0.003) predicted inferior OS. Tumorsize >8 cm (P¼ 0.03) and radical radiotherapy as local treatment (P¼ 0.01) predicted inferior local-control-rate.Conclusion: Prognostic hazardmodels for EFS andOS based on significant prognostic factors suggested that patients with combination of ESFT ofspine/abdomino-pelvic region and baseline WBC >11� 109/L had inferior OS (hazard ratio 4.44, P< 0.001) while patients with combination ofESFT with symptom duration >4 months, tumor diameter>8m and baseline WBC >11� 109/L had inferior EFS (hazard ratio 3.89, P¼ 0.002).J. Surg. Oncol. 2015;111:683–689. � 2014 Wiley Periodicals, Inc.
The prognosis of Ewing sarcoma family of tumors (ESFT) hasimproved over last few decades with the introduction of systemicchemotherapy and multimodality approach. Data on prognostic factorsin localized ESFT are available from different randomized studies [1–9]with well-defined inclusion and exclusion criteria. Institute-basedevaluation of all consecutive patients with intent-to-treat analysis givesa realistic view of outcome. Majority of publications from institutionalexperience are biased by the fact that they are retrospective innature with limited number of patients and additionally treatedwith heterogeneous chemotherapy protocols over a long period oftime [10–17].
Here, we have analyzed clinicopathological characteristics,treatment outcome, and prognostic factors of 224 patients with non-metastatic ESFT who were treated with a uniform chemotherapyprotocol over an 8 year period and evaluated on intent-to-treat analysis.Our aim was to analyze treatment outcome so as to prognosticatepatients on the basis of clinicopathological parameters.
MATERIALS AND METHODS
Patients
This study involves data review of all patients with proven diagnosisof classical ESFT that were treated in our department from June 2003-
November 2011. Patients with localized ESFT of all sites other thanbrain were selected for this analysis. Patients with metastatic disease(after metastatic work-up) were excluded. Patient’s baseline clinic-pathological features, treatment modality, and outcome data werecollected. Ethical clearance was taken from institutional ethical reviewcommittee.
Diagnostic Work Up
All patients underwent biopsy (trucut/incisional) of primary lesionwith immunohistochemistry. Diagnosis of ESFT required presence ofsmall blue round cell tumor and positivity for CD99 (MIC-2) in the
Funding: This research did not receive any specific grant from any fundingagencies in the public, commercial, or not-for-profit sectors.
Potential conflicts of interest and financial disclosure: The authors declarethat there is no conflict of interest for this study.�Correspondence to: Prof. Sameer Bakhshi, MD, Department of MedicalOncology, Dr. B. R Ambedkar Institute Rotary Cancer Hospital, AllIndia Institute of Medical Sciences, New Delhi 110029, India. Fax:þ91–11-26588663. E-mail: [email protected]
Received 14 November 2014; Accepted 14 November 2014
DOI 10.1002/jso.23861
Published online 29 December 2014 in Wiley Online Library(wileyonlinelibrary.com).
Journal of Surgical Oncology 2015;111:683–689
� 2014 Wiley Periodicals, Inc.
membrane, and/or synaptophysin or chromogranin. Other round celltumors were ruled out by performing immunohistochemistry withleucocyte common antigen, desmin, and myogenin, and if found to bepositive were not included for this analysis. Terminal deoxynucleotidyltransferase immunohistochemistry was used to differentiate the tumor fromlymphoblastic lymphomas ifmediastinumor nodeswere primarily involved.Evaluation for translocation (t[11;22][q24;q11.2–12]) was not performed inthis cohort as it was not available routinely in our institute. Tumors such asmesenchymal chondrosarcomaandsmall cell osteosarcomawhichmimic theabove mentioned immunohistochemical staining were excluded by theabsence of lobules of cartilaginous differentiation and production of osteoidby tumor cells respectively, along with radiological findings. In the intra-abdominal location, desmoplastic small round cell tumorwas excluded usingtheabovementioned immunohistochemistry for roundcell tumorsalongwiththe addition of immunohistochemistry for cytokeratin and WT1.
For the purpose of this study, diagnosis of ESFT was made onlyafter review of pathology slides with immunohistochemistry paneland correlation with radiological findings of the tumor site. Althoughthere is conflicting data as to whether atypical ESFT behavedifferently from typical ESFT [18,19], a pathological distinctionbetween typical ESFT and atypical ESFT was not done in this study.Extent of lesion was determined by computed tomography (CT) ormagnetic resonance imaging of local site. All patients underwentmetastatic work-up including bone scan, CT scan of the chest and abone marrow biopsy.
Treatment and Response Evaluation
Treatment protocol consisted of three phases: neo-adjuvantchemotherapy for 9–12 weeks, local therapy, followed by adjuvantchemotherapy.Chemotherapywas given3-weekly cycle of [email protected]/m2, max¼ 2mg; doxorubicin @ 75mg/m2 or actinomycin D @1.25mg/m2 and cyclophosphamide@ 1.2 gm/m2withMesna alternatingwith ifosfamide@9gm/m2withMesna and etoposide@500mg/m2 [20]for total 48 weeks. This is the standard treatment protocol used for non-metastatic ESFT in as per guidelines from National Cancer Institute(USA) (www.cancer.gov). Local therapy was radiotherapy or surgerywith or without post-operative radiotherapy. The choice of local therapywasmade on an individual basis depending on the primary tumor site andresectability of tumor after neo-adjuvant chemotherapywith care to avoidlong-term morbidity and disfigurement. Surgery was preferred whereverwide local excision was possible with clear surgical margins and withoutmutilating surgery (decision for surgical resection was taken by treatingsurgeon). In general, patients with pathological complete response werenot subjected to adjuvant radiotherapy, although decisions for adjuvantradiotherapy were taken on an individual case to case basis afterdiscussion in the multidisciplinary clinic. After local therapy, all patientswere subjected to receive adjuvant chemotherapy up to planned total48weeks.Disease responsewas assessed by radiology after neo-adjuvantchemotherapy and after completion of local therapy. Complete remission(CR), partial response (PR), stable disease (SD), and progressive disease(PD) were defined as per response evaluation criteria in solid tumors [21]wherever applicable. All patients underwent local therapy if post neo-adjuvant chemotherapy response was CR/PR/SD.
Statistical Analysis
Descriptive statistics were used for demographics and clinicalcharacteristics. Chi-square test was used to detect association betweencategorical variables. Student’s t-test was applied to compare continuousvariables between groups. Survival was estimated by the Kaplan–Meiermethod and compared using log-rank test. Data were censored on 15thMarch 2014. Univariate Cox proportional hazard model followed bymultivariate Cox regression analysis was done to identify the predictors ofoutcome. Factors with significance (P-value) of up to 0.1 in univariate
analysiswere taken intomultivariateanalysis.Event-free-survival (EFS)withstandard errorwas calculated fromdate of diagnosis to date of disease relapseor progression, death from any cause. Overall survival (OS) with standarderror was calculated from date of diagnosis to date of death from any cause.Local site recurrencewithorwithoutdistant site recurrencewas takenas localfailure for analysis of local control rate. Patientswhowere lost to follow-uporhad treatment abandonment were also included for EFS andOS analysis andoutcome in these patients was confirmed by telephonic contact. Treatmentabandonment was included for survival analysis in the present study as it has
TABLE I. Baseline Clinical and Tumor Characteristics (n¼ 224)
Variables Number Percentage
Age (median) 15 years (0.1–55)�15 years 120 54>15 years 104 46
SexMale 153 68Female 71 32
SymptomsSwelling 182 81Pain 172 77
Systemic symptoms 48 21Fever 46 21Weight loss 10 4
been proposed that non-compliant and treatment abandonment patientsshould be included in survival analysis for studies fromdeveloping nations toprovide a true picture of outcome from these countries [22]. On the basis ofsignificant baseline clinical factors affectingEFSandOS, a prognosticmodelfor individual andcombinedhazards for survivalwasdeveloped.STATA/SE9.0 (StataCorp LP, Texas) was used for statistical analysis.
RESULTS
Clinicopathological Profile
During the study period, of a total 403 patients with ESFT, 374patients were evaluable for survival analysis (29 patients did not taketherapy). Of the 374 patients, 224 (60%) had localized disease. Theclinical findings of the 224 patients with non-metastatic ESFT aresummarized in Table I. Median age was 15 years (range: 0.1–55) withmedian symptom duration of 4 months (range: 0.5–36 months). Mediantumor diameter was 8 cm (range: 1.6–25 cm) and tumor size>8 cmwasobserved in 44% (n¼ 86/194) patients. Most common primary regionsof disease included extremity in 89 (40%), thorax in 57 (25%), head andneck in 32 (14%), and abdomino-pelvic in 31 (13%) patients.
Treatment
All 224 patients were subjected to neo-adjuvant chemotherapy and amedian of 6 cycles (range: 4–7) of neo-adjuvant chemotherapy wasadministered to all patients. Twenty-eight patients discontinued neo-adjuvant chemotherapy (PR-16, SD-5, and Not Evaluated-7); 16
patients had PD and one had toxic death while receiving neo-adjuvantchemotherapy. Thus, 179 patients (80%) received local therapy:surgery was performed in 99 (55%) patients of which 50 receivedadjuvant radiotherapy; definitive (or radical) radiotherapy alone wasadministered in 80 (45%) patients. Of the 99 patients who underwentsurgical resection, R0 resection was achieved in 90 patients. Definitiveradiotherapy was given at a median dose of 50Gy (range: 50–60Gy)administered as 1.8–2Gy/day, 5-days a week over 5–6 weeks. Tenpatients were lost to follow-up (PR-4, CR-2, not evaluable-4), 8 hadPD and 2 patients died of toxicity during or after receiving localtreatment. Thus, remaining 159 patients received adjuvantchemotherapy (Fig. 1).
Response to NACT and Local Therapy
Out of 224 patients, re-evaluation after neo-adjuvant chemotherapywasperformed in 216 patients (not evaluated-7 and toxic death-1) and theresponse was as follows: CR-32, PR-152, SD-16, and PD-16 with overallresponse rate of 85% (n¼ 184/216). Of the 179 patients who underwenteither surgery and/or radiotherapy, post local therapy response were CR-109, PR-51, SD-5, PD–8, toxic death-2, and not evaluated-4.
Treatment Failure and Outcome
Treatment failure was observed in 99 (44%) patients: recurrencesafter achieving CR in 42 patients and PD during or post therapy in 57patients (post neo-adjuvant chemotherapy PD-16, post local therapyPD-8, and during/post adjuvant chemotherapy PD-33). Site of failure
Fig. 1. Flow diagram showing treatment and outcome of study patients. ESFT, Ewing’s sarcoma family of tumors; CR, complete response; LFU,lost to follow up; N, number; PD, progressive disease; PR, partial response.
Journal of Surgical Oncology
Localized Ewing’s Sarcoma 685
was local site alone in 44 patients, distant metastasis in 30 patients, andcombined failure in 25 patients.
Total 76 (34%) patients died during or after treatment (PD—52, toxicdeaths—10, and 14 patients died at home cause of which could not beascertained). After a median follow-up of 40.2 months (range: 1.3–129),5-year EFS, OS, and local-control-rate were 36.8� 3.6%, 52.4� 4.3%,and 63� 4.3%, respectively for entire cohort. Five-year local-control-rate in surgery group, surgery plus radiotherapy group, and definitiveradiotherapy group were 69.4%, 78.9%, and 50.1%, respectively.
Prognostic Factors
Univariate analysis. Univariate analysis showed that tumor size>8 cm (P¼ 0.01), skeletal primary (P¼ 0.02), white blood cell (WBC)count >11� 10[9]/L (P¼ 0.003), lactate dehydrogenase >2�N U/L(P¼ 0.003), and radical radiotherapy as local treatment (P¼ 0.02)adversely predicted EFS. Patients with symptom duration >4 months(P¼ 0.07) and those with spine and abdomino-pelvic primary(P¼ 0.07) had a trend towards inferior EFS (Table II).
Tumor size >8 cm (P¼ 0.006), spine and abdomino-pelvic primary(P¼ 0.002), WBC count >11� 10[9]/L (P¼ 0.009), lactatedehydrogenase >2�N U/L (P¼ 0.05), and radical radiotherapy aslocal treatment (P¼ 0.05) predicted inferior OS (Table II).
Tumor size >8 cm (P¼ 0.007), spine and abdomino-pelvic primary(P¼ 0.03), skeletal primary (P¼ 0.04), WBC count >11� 10[9]/L(P¼ 0.003), and radical radiotherapy as local treatment (P¼ 0.001)predicted inferior local-control-rate, and lactate dehydrogenase>2�NU/L (P¼ 0.07) had a trend toward inferior local-control-rate(Supplemental Table SI).
Multivariate analysis. Multivariate analysis showed that tumordiameter >8 cm (P¼ 0.03), symptom duration >4 months (P¼ 0.04),
and WBC count >11� 10[9]/L (P¼ 0.003) predicted inferior EFS(Table III) (Fig. 2A–C). For OS, spine and abdomino-pelvic primary(P¼ 0.009), and WBC count >11� 10[9]/L (P¼ 0.003),independently predicted inferior outcome (Table III) (Fig. 3A,B).Tumor diameter >8 cm (P¼ 0.03) and radical radiotherapy as localtreatment (P¼ 0.01) adversely predicted local-control-rate (Table III)(Fig. 3C,D).
Analysis after exclusion of patients whose final survival statuscould not be assessed for OS. Although EFS and local-control-ratecould be assessed in all patients, yet some patients did not opt for asalvage therapy after PD and thus the final survival status of 83 (37%)patients could not be assessed for OS (Defaulted during or aftertherapy-41; Defaulted after PD-42). After excluding these patientswhose final survival status for OS could not be assessed, spine andabdomino-pelvic primary (P¼ 0.04), tumor diameter >8 cm(P¼ 0.01), and WBC count >11� 10[9]/L (P¼ 0.001) continued topredict inferior OS on multivariate analysis (Supplemental Table SII).
Prognostic Model Based on Baseline Characteristics
Taking outcome of patients with ESFT of head and neck/chest/limblocation and baselineWBC�11� 10[9]/L as reference, the outcome ofpatients with either ESFT of spine/abdomino-pelvic region or baselineWBC >11� 10[9]/L had significantly inferior OS (Hazard ratio¼ 1.7,P¼ 0.03); however, when the patients had a combination of ESFT ofspine/abdomino-pelvic region and baseline WBC > 11� 10[9]/L, thehazards for poor OS was 4.44 with P< 0.001 (Table IV).
Similarly, a prognostic model was developed for EFS using thebaseline clinical characteristics which showed that the patients of ESFTwith symptom duration>4months, tumor diameter>8 cm and baselineWBC >11� 10[9]/L had a hazards ratio of 3.89 (Table IV).
TABLE II. Univariate Analysis for Event-Free-Survival (EFS) and Overall Survival (OS) (n¼ 224)
EFS OS
Variables Category HR 95% CI 5 year estimate (%) P HR 95% CI 5 year estimate (%) P
CI, confidence interval; HN, head and neck; HR, hazard ratio; LDH, lactate dehydrogenase; N, normal; Sx, surgery; RT, radiotherapy; WBC, white blood cell.
Journal of Surgical Oncology
686 Biswas et al.
DISCUSSION
We have analyzed 224 cases of localized ESFT who were treatedwith a uniform chemotherapy protocol over an 8-year period. This isthe largest data of ESFT from Asia. Most common site of primaryESFT was thorax (25%) followed by head and neck (14%) and femur(14%). In our total cohort of ESFT, 60% of patients had localizeddisease which was lower as compared to the proportion of localizeddisease as observed previously in published literature wherein non-metastatic disease ranged from 71–87% [6,9,23,24]. This differencemay be reflective of referral bias. Survival in our cohort was inferior
as compared to other published reports of localized ESFT[5,6,8,9,24,25] (Supplemental Table SIII). This inferior result maybe due to the fact that our cohort was in a resource-challenged settingwherein patients had delayed presentation (symptom duration of >4months in 48% of patients) and larger tumor burden (>8 cm tumor in44% of patients).
Our data showed that use of radical radiotherapy as the only localcontrol modality without surgery resulted in poor local control rate.Patients who underwent surgery for local control had lower pelvic orspinal primary (15% vs. 28%, P¼ 0.04) and higher number of tumors ofsoft tissue origin (25% vs. 13%, P¼ 0.03) as compared to the patients
TABLE III. Multivariate Analysis for Event-Free Survival (EFS), Overall Survival (OS) and Local-Control-Rate (LCR) (n¼ 224)
EFS OS LCR
Variables Category HR 95% CI P HR 95% CI P HR 95% CI P
Tumor diameter � 8 cm 1 — 1>8 cm 1.8 1.08–3 0.03 2.19 1.09 – 4.4 0.03
CI, confidence interval; HN, head and neck; HR, hazard ratio; LDH, lactate dehydrogenase; N, normal; Sx, surgery; RT, radiotherapy; WBC, white blood cell.
Fig. 2. Five-year EFS of whole group was 43.8� 5.1% for patients with symptom duration�4 months versus 28.8� 5% for those of<4 months(A). Five-year EFS of whole group was 49� 5.2% for patients with tumor diameter �8 cm versus 26.6� 5.8% for those of >8 cm (B). Five-yearEFS of whole group was 46.2� 4.2% for patients with WBC �11� 109/L versus 20� 6.1% for those with WBC>11� 109/L (C).
Journal of Surgical Oncology
Localized Ewing’s Sarcoma 687
who underwent radical radiotherapy for local control. However,amongst patients who received radical radiotherapy (n¼ 80) versusthose who underwent surgery (n¼ 99), there was no difference in theirmean tumor diameters (8.5 cm vs. 8.4 cm, P¼ 0.8), or post neo-adjuvant chemotherapy response (ORR of 91% vs. 96%, P¼ 0.13).Although this is not a randomized study to assess the role of
radiotherapy versus surgery as primary local treatment, the analysissuggests that those receiving radical radiotherapy were not necessarilypoor responders and did not have any adverse baseline tumorcharacteristics other than tumor site, yet the group receiving radicalradiotherapy had worse local-control-rate. Thus, even if there is goodresponse to neo-adjuvant chemotherapy in localized ESFT, an attemptshould be made for a surgical resection.
Amongst the 99 patients who underwent surgical resection, asignificantly higher 5-year EFS was observed in the group of patientswho received adjuvant radiotherapy (n¼ 50) versus those who did notreceive adjuvant radiotherapy (n¼ 49) (59.6� 7.5% vs. 39.7� 7.5%,P¼ 0.04), although the OS was comparable (5-year OS 70.9� 7.7% vs.65.7� 7.5%, P¼ 0.28). In this group of patients who underwentsurgical resection, 76 tissue blocks were reviewed. It was observed thatthere was no difference in histological response to neo-adjuvantchemotherapy between the group receiving adjuvant radiotherapy incomparison to those who did not receive adjuvant radiotherapy (�90%necrosis in 22/36 vs. 27/40, P¼ 0.32); however, the number of resectedspecimens with presence of tumor in the surgical margins was higher inthe adjuvant radiotherapy group (8/50 vs. 0/49, P¼ 0.04). Thus, itappears that the patients who underwent surgery and thereafter adjuvantradiotherapy had better EFS despite high incidence ofmargin positivity.It is difficult to conclude whether adjuvant radiotherapy is beneficial inlocalized ESFT as it did not emerge as a significant factor for EFS or OSin multivariate analysis, and thus requires further evaluation in aprospective manner.
Fig. 3. Five-year OS of whole group was 60.5� 5% for tumor of Head and neck, chest and limb versus 26.3� 8.3% for tumor of spine andabdomino-pelvic location (A) (HN, Head and neck). Five-year OS of whole group was 58.6� 5.3% for patients with WBC �11� 109/L versus37.1� 8.4% for those with WBC>11� 109/L (B). Five-year local failure rate of whole group was 30.4� 5.1% for patients with tumor diameter�8 cm versus 61.3� 8.2% for those with tumor diameter>8 cm (C). Five-year local failure rate of whole group was 27.1� 5.8% for patients whoreceived surgery� radiotherapy versus 53.1� 6.7% for those who received radical radiotherapy (D).
TABLE IV. Prognostic Model for Overall Survival (OS) and Event-Free-Survival (EFS)
Prognostic factors HR 95% CI P
OSHead and neck/chest/limbprimary or WBC �11,000/ml
1
Either spine/abdomino-pelviclocation or WBC >11,000/ml
1.71 1.05–2.8 0.03
Both spine/abdomino-pelviclocation and WBC >11,000/ml
4.44 2.1–9.4 <0.001
EFSNone of the factors present* 1Any one factor present 2.03 1.22–3.38 0.006Any two factors present 2.42 1.4–4.18 0.002All three factors present 3.89 1.63–9.26 0.002
Baseline high WBC count (>11� 109/L) was an independentpredictor of worse EFS andOS. This suggests that highWBC countmaybe a marker for micro-metastasis in localized ESFT. This observationhas not been observed or analyzed in the previous published literature ofESFT. Notably, the group with high WBC count had higher systemicsymptoms (31% vs. 18%, P¼ 0.04) and larger mean tumor size (9.9 cmvs. 8.3 cm, P¼ 0.04), but no difference in tumor location (P¼ 0.98).
The limitations of our study include the lack of translocation (EWS-FLI) study in our patients at diagnosis even though all patients wereevaluated with extensive IHC panel. In addition, approximately 18%(n¼ 41) of our patients defaulted during therapy. Further, since theabove is not a randomized study, it was not designed to detect thedifference between surgery and radical radiotherapy as local treatmentmodality in ESFT.
The strength of our study is that it is the largest single institutionaldata of localized ESFT from Asia and all patients were treated with auniform chemotherapy protocol with intention-to-treat analysis. Tumorsite andWBC adversely affectedOS in entire cohort and continued to beindependent prognostic factors for OS even after exclusion of patientswhose final survival status for OS could not be ascertained. Weidentified new prognostic factors such as high WBC count to adverselyaffect outcome. At baseline presentation, the presence of two and threeunfavourable prognostic factors had a significant hazard for OS andEFS, respectively. Based on this data, there is a need to evaluatebiological differences in patients who present with ESFT of spine orabdomino-pelvic location with high WBC count; further this subgroupof patients may need different or more aggressive strategy for treatment.In such patients, one possible option may be to consider high dosetherapy with autologous stem cell transplantation once their diseaseachieves control; however, this approach would have to beprospectively evaluated.
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