Abstract
Ewing’s sarcoma family of tumors (EWSFT) is common in the second decade of life. Achieving good outcomes in EWSFT requires a multimodality approach. We report the clinico-pathological features, treatment, and survival outcomes of patients with EWSFT treated at our center. Patients diagnosed and treated for EWSFT at our center from 2009–2017 were included in this study. Data was collected from the patient’s case records. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan–Meier method. The study included 173 patients among whom 44 (25%) patients were metastatic at diagnosis. The median age of patients was 16 years. The most common site of the primary tumor was the pelvis (16.1%), followed by long bones. The median follow-up was 75 months and the 5-year EFS and OS were 43.7% and 45.1% respectively for the overall cohort whereas for the localized disease were 56.6% and 57.2% respectively. Metastatic disease, tumor volume > 200 ml, tumor diameter > 8 cm, pelvic site, hemoglobin < 10 gms%, elevated lactate dehydrogenase, positive margin, and necrosis less than 90% were significantly associated with inferior OS on univariate analysis. On multivariate analysis, metastasis disease, tumor diameter > 8 cm, and necrosis < 90% were significantly associated with inferior OS. Large tumors, advanced disease, and poor response to chemotherapy are associated with poor outcomes in EWSFT. Whether the use of dose-dense chemotherapy and/or autologous stem cell transplant would improve outcomes without increased toxicity in resource-limited settings needs to be explored.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13193-023-01817-6.
Keywords: Ewings sarcoma, Bone tumors, Chemotherapy
Introduction
Bone tumors are rare and account for 0.2–1% of all malignancies [1]. The Ewing sarcoma family of tumors (EWSFT) includes Ewing’s sarcoma of the bone, extraosseous Ewing sarcoma, primitive neuroectodermal tumor (PNET), peripheral neuroepithelioma, Askin’s tumor (Ewing sarcoma of the chest wall), and atypical Ewing sarcoma [1].
Bone tumors are comparatively uncommon, constituting only 0.5% of the total world cancer incidence [2]. Data from hospital-based cancer registries in India suggest that EWSFT is the second most common bone sarcoma after osteosarcoma accounting for 15–40% of all bone tumors [3–5]. The published literature by India's National Cancer Registry Program (NCRP) has shown that EWSFT comprises around 15% of all bone malignancies, with the highest incidence rates in the 10–14 years age group [6].
About 85% of EWSFTs are due to a reciprocal translocation, t(11,22), between the Ewing's Sarcoma Breakpoint Region 1 (EWSR1) gene on chromosome 22 and Friend Leukemia Virus Integration 1 (FLI1) gene on chromosome 11 [1]. With the multimodality treatment approach and the advances in diagnostics, and supportive care, the development of various non-cross resistant poly-chemotherapeutic regimens has led to the improvement of 5-year overall survival in localized EWSFT to 60–70% in developed countries. However, outcomes in patients with metastatic EWSFT remain dismal [7].
Management of EWSFT in low and middle-income countries (LMICs) has been challenging due to the lack of access to molecular testing, limb salvage surgeries, dose-dense chemotherapy, high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT), and radiotherapy. Whether the outcome in the real-world settings in LMICs replicates that from various international collaborative trials is also unknown. There is a paucity of data on clinical profiles and outcomes of EWSFT from LMICS. Therefore, we have analyzed the clinicopathological, treatment, and survival outcomes in EWSFT from our center.
Methods
Clinical details and treatment outcomes of patients with biopsy-proven EWFST were collected retrospectively from the hospital tumor registry. Patients who were diagnosed at our center and underwent treatment (chemotherapy/surgery/radiotherapy/palliative care) at our center from 1st January 2009 to 31 December 2017 were included in the study. The study was conducted according to the guidelines of the Institutional Ethics Committee. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards [8].
Diagnosis of EWFST was confirmed on histopathology examination and immunohistochemistry, this included patients who were operated at other centres. After 2014 EWS-FLI polymerase chain reaction (PCR) was performed in patients who agreed to undergo the test. PCR to detect translocations associated with EWSFT like EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-ETV4, and EWS-FEV were not performed. Molecular testing to diagnose undifferentiated round cell variants like BCOR and CIC-DUX4-positive sarcomas was not performed. Patients underwent a plain roentgenogram, magnetic resonance imaging (MRI), or computed tomography scans (CT scans) of the primary site. Metastatic disease was diagnosed using bone marrow aspiration and biopsy and bone scan with a CT scan of the chest or whole-body Positron Emission Tomography (PET) scan with a CT scan. All patients also underwent routine baseline laboratory and biochemical tests required for organ fitness for treatment.
Treatment decisions for individual patients were made in the multidisciplinary musculoskeletal tumor board. Patients with curative intent were treated with neoadjuvant chemotherapy (NACT) followed by local therapy and adjuvant chemotherapy as per National Cancer Institute protocol INT-0091 (CCG-7881 and POG -8850) (Supplemental Table 1 and Supplemental Fig. 1) [9]. Curative intent treatment was given to patients with localized disease and those with oligometastatic disease with good performance status. Patients with disseminated disease not for curative intent were planned for palliative chemotherapy, either intravenous chemotherapy for 6 cycles or oral metronomic therapy according to the patient's performance status and physician choice. Palliative radiotherapy was delivered as per standard indications and requirements.
After 9–12 weeks of NACT, local therapy (surgery or definitive radiotherapy where R0 resection was not possible) was planned. Oligometastatic sites were addressed with radiotherapy or surgery on a case-to-case basis as per tumor board discussion. Postoperative radiotherapy (PORT) to the primary site was guided by various factors like positive or close margins and poor histological response to NACT (< 90% necrosis), large tumor volume, or a primary site in the chest wall, head, neck, and pelvis [10]. Definitive radiotherapy was given at a dose of 55.8–60 Gy and PORT was given at a dose of 55.8 Gy for gross disease and 45 Gy for microscopic disease [11]. Radiotherapy was given at a standard fraction (1.8–2 Gy) [11]. PORT was given 4 weeks after surgery [11].
The study's objectives were to identify demographic and prognostic factors, assess event-free survival (EFS) and overall survival (OS), and delineate late toxicities. OS was calculated from the time of diagnosis to the date of death or the date of the last follow-up. EFS was calculated from the date of diagnosis to the first event (progression, recurrence, secondary malignancy, and death due to any cause). Baseline characteristics and outcomes were reported as descriptive statistics. OS and EFS were estimated according to the Kaplan–Meier method and reported with a 95% confidence interval (CI). Median follow-up was calculated using a reverse Kaplan–Meier estimate. Univariate (Log-rank test) and multivariate (Cox proportional hazards regression model) analyses were used to examine the predictive value of significant factors for EFS and OS. Prognostic factors considered in the study were metastatic disease, tumor volume > 200 ml, tumor diameter > 8 cm, pelvic site, hemoglobin < 10 gms%, elevated lactate dehydrogenase, positive margin, and necrosis less than 90% [12]. A p-value less than 0.05 was taken as significant. All statistical analyses were performed using SPSS version 20 (IBM, Armonk, NY).
Results
The study included 173 patients (Fig. 1), among whom 129 (74.5%) had localized disease at presentation, and 44 (25.5%) had metastatic disease. Demographic details of the patients are provided in Table 1. The median age at diagnosis for the cohort was 16 years (range: 6 months to 68 years), with a male-to-female ratio of 1.15:1. Forty percent (n = 68) had a delayed presentation more than four months from the start of symptoms to diagnosis. Swelling (n = 57, 33%) and pain (n = 40, 23%) were the most common presenting symptom, and systemic symptoms (fever, chills, rigors, weight loss, and, generalized myalgia) were seen in ten percent (n = 18) of patients. Forty-four percent (n = 76) of patients were anemic, and thirty-nine percent (n = 69) had hypoalbuminemia at diagnosis.
Fig. 1.
Flowchart of patients included in the study
Table 1.
Demographic, pathology, and clinical features
| Clinical Profile (Demographics) | Overall Cohort (n = 173) (%) | Localized (n = 129) (%) |
Metastatic at Presentation (n = 44) (%) |
|---|---|---|---|
| Age at diagnosis, Median (range) | 16 | 15 | 18 |
| (6 mo– 68 y) | (6 mo – 68 y) | (1–55 y) | |
| < 18 | 102 (58.9) | 79 (61.2) | 23 (52.7) |
| ≥ 18 | 71 (41.1) | 50 (38.8) | 21 (47.7) |
| Sex | |||
| Male | 93 (53.7) | 62 (48.1) | 26 (59) |
| Female | 80 (46.3) | 67 (51.9) | 18 (41) |
| Symptoms at Presentation | |||
| Swelling only | 57 (32.9) | 48 (37.2) | 9 (20.4) |
| Pain only | 40 (23.1) | 24 (18.6) | 16 (36.3) |
| Both | 67 (38.7) | 50 (38.7) | 17 (38.6) |
| Others | 9 (5.2) | 7 (5.4) | 2 (04.5) |
| Systemic symptoms | |||
| Yes | 18 (10.40) | 12 (09.30) | 6 (13.63) |
| No | 155 (89.59) | 117 (90.69) | 38 (86.36) |
| Duration of symptoms | |||
| < 4 months | 105 (60.69) | 81 (62.79) | 24 (54.54) |
| ≥ 4 months | 68 (39.30) | 48 (37.20) | 20 (45.45) |
| Diagnosis | |||
| Ewing’s sarcoma - | 116 (67) | 86 (66.6) | 30 (68.1) |
| PNET - | 56 (28.9) | 42 (32.5) | 14 (31.8) |
| Atypical/Undifferentiated | 1 (0.5) | 1 (0.7) | 0 |
| Primary site | |||
| Skeletal - | 127 (72.1) | 99 (76.7) | 28 (63.6) |
| Axial - | 56 | 41 | 15 |
| Appendicular - | 71 | 58 | 13 |
| Extraosseous - | 46 (26.5) | 30 (23.2) | 16 (36.3) |
| Tumour Site (Primary) | |||
| Pelvis | 28 (16.1) | 18 (13.9) | 10 (22.7) |
| Femur | 26 (15) | 21 (16.2) | 5 (11.3) |
| Chest wall | 20 (11.5) | 12 (9.3) | 8 (18.1) |
| Tibia/Fibula | 19 (11) | 13 (10) | 6 (13.6) |
| Head and Neck | 19 (11) | 18 (13.9) | 1 (2.2) |
| Humerus | 13 (7.5) | 12 (9.3) | 1 (2.2) |
| Vertebral/Para-vertebral | 11 (6.3) | 9 (6.9) | 2 (4.5) |
| Scapula | 10 (5.7) | 8 (6.2) | 2 (4.5) |
| Retroperitoneum | 9 (5.2) | 6 (4.6) | 3 (6.8) |
| Forearm | 6 (3.4) | 4 (3.1) | 2 (2.2) |
| Clavicle | 3 (1.7) | 3 (2.3) | 0 |
| Mediastinum | 3 (1.7) | 0 | 3 (6.8) |
| Urinary bladder | 2 (1.1) | 1 (0.7) | 1 (2.2) |
| Kidney | 1 (0.6) | 1 (0.7) | 0 |
| Breast | 1 (0.6) | 1 (0.7) | 0 |
| Testes | 1 (0.6) | 1 (0.7) | 0 |
| Toe | 1 (0.6) | 1 (0.7) | 0 |
| Tumour Diameter (centimeter) | |||
| ≥ 8 | 48 (27.7) | 44 (34.1) | 4 (9.1) |
| < 8 | 91 (52.6) | 58 (44.9) | 33 (75) |
| Not available | 34 (19.6) | 27 (20.9) | 7 (15.9) |
| Tumour Volume (cucm) | |||
| ≥ 200 | 70 (40.4) | 42 (32.5) | 28 (63.6) |
| < 200 | 69 (39.8) | 58 (44.9) | 11 (25) |
| Not available | 34 (19.6) | 29 (22.4) | 5 (11.3) |
| EWS FLI1 translocation | |||
| Done | 44 (25.4) | 27 (20.1) | 17 (38.6) |
| Positive | 17 (9.8) | 14 (10.8) | 3 (6.8) |
| Negative | 9 (5.2) | 7 (5.4) | 2 (05.5) |
| Inadequate Tissue/Failed/Not done | 103 (59.5) | 81 (62.7) | 22 (50) |
| Haemoglobin (gms%) | |||
| ≥ 10 | 97 (56.1) | 81 (62.7) | 16 (36.3) |
| < 10 | 76 (43.9) | 48 (37.2) | 28 (63.6) |
| White blood cells (mm3) | |||
| ≥ 11,000 | 78 (45.1) | 55 (42.6) | 23 (52.2) |
| < 11,000 | 93 (53.7) | 73 (56.5) | 20 (45.4) |
| Not available | 2 (1.1) | 1 (0.7) | 1 (2.2) |
| Lactate dehydrogenase (U/L) | |||
| ≥ 400 | 106 (61.2) | 70 (54.2) | 36 (81.8) |
| < 400 | 40 (23.1) | 36 (27.9) | 4 (9) |
| Not available | 27 (15.6) | 23 (17.8) | 4 (9) |
| Serum Albumin (g/dL) | |||
| ≥ 3.5 | 78 (45.1) | 59 (45.7) | 19 (43.1) |
| < 3.5 | 69 (39.8) | 46 (35.6) | 23 (52.2) |
| Not available | 26 (15) | 24 (18.6) | 2 (4.5) |
| Serum alkaline phosphatase (U/L) | |||
| ≥ 148 | 53 (30.6) | 40 (31) | 13 (29.5) |
| < 148 | 98 (56.6) | 73 (56.5) | 25 (56.8) |
| Not available | 22 (12.7) | 16 (12.4) | 6 (13.6) |
| Bone marrow biopsy | |||
| Done | 156 (90.1) | 118 (91.4) | 38 (86.3) |
| Positive | 8 (04.6) | 0 | 8 (18.1) |
| No opinion/Not Done/Not available | 17 (09.8) | 11 (08.5) | 6 (13.6) |
Abbreviations. NA: Not Available. PNET: Primitive Neuroectodermal Tumor
Around two-thirds of patients were Ewing’s sarcoma (n = 116, 67%), whereas one-third were PNET (n = 56, 28.9%). Seventy-two percent (n = 127) of patients had skeletal origin tumors, and 27% (n = 46) had an extra-skeletal origin. The pelvis (n = 28, 16.1%) was the most common site, followed by long bones and the chest wall. Tumor diameter of more than eight cm was seen in 28% (n = 48) of patients, and tumor volume of more than 200 ml was observed in around 40% (n = 70) of the patients. Molecular studies (EWS-FLI1 translocations) were done in 40% (n = 44) of the cohort and were seen to be positive in 25% (n = 17) of the patients. Tumor characteristics and baseline lab parameters are available in Table 2.
Table 2.
Treatment Details
| Characteristic | N = 173 (%) |
|---|---|
| Upfront surgery | 16 (9.2) |
| NACT | 170 |
| Median number of cycles | 5 (01–09) |
| VAC/IE | 146 (82.1) |
| VAC | 20 (11.5) |
| OMC | 4 |
| None (best supportive care) | 3 |
| Adverse events to NACT | |
| Grade 1–2 | 32 (18.8) |
| Grade 3–4 | 26 (15.2) |
| NACT Dose Reductions | |
| Not required | 126 (74.1) |
| 25% reduction | 26 (15.2) |
| 50% reduction | 16 (9.4) |
| TRM | 2 (1.1) |
| Surgery | |
| Type | 103 (59.5) |
| • WLE | 67 |
| • LSS | 30 |
| • Amputation | 06 |
| Margin status | 75 (72.8) |
| • Negative | 16 (15.5) |
| •Positive | [R1: 12 (11.6), R2:4 (3.8)] |
| • Unknown | 12 (11.6) |
| Chemotherapy Response status (Necrosis)* | |
| • > 90 | 27 (26.2) |
| • < 90 | 50 (48.5) |
| • Not known/Not applicable | 26 (25.2) |
| Surgical complications | |
| • Yes | 12 (11.6) |
| • No | 91 (88.3) |
| Radiation Therapy | |
| Definitive | 49 (28.3) |
| PORT | 38 (21.9) |
| Palliative | 14 (08.1) |
| WLI | 4 (02.3) |
| Extracorporeal Irradiation | 1 (0.5) |
| Adjuvant chemotherapy after definitive treatment to primary | 134 |
| Median number of cycles | 10 (1–15) |
| VAC/IE | 115 (66.4) |
| VAC | 3 |
| Others | 16 |
| Nil | 39 |
|
Adjuvant chemotherapy Adverse events |
|
| Grade 1–2 | 32 (23.8) |
| Grade 3–4 | 39 (29.1) |
|
Adjuvant chemotherapy Dose Reductions |
|
| Not required | 79 (58.9) |
| 25% reduction | 45 (33.5) |
| 50% reduction | 9 (6.7) |
| Chemotherapy stopped due to toxicity | 1 (0.5) |
| Total number of chemotherapy cycles | |
| Median | 15 (1–16) |
| 16 | 76 |
| 12–15 | 27 |
| < 12 | 63 |
| Late Toxicities | |
| Cardiomyopathy | 3 |
| Secondary neoplasm | 1 |
| Renal failure | 1 |
| Cirrhosis | 1 |
Abbreviations. NACT: Neoadjuvant Chemotherapy; VAC: Vincristine, Adriamycin, Cyclophosphamide; IE: Ifosfamide and Etoposide; WLE: Wide Local Excision; LSS: Limb Salvage Surgery; TRM: Treatment Related Mortality; PORT: Post-operative Radiotherapy; WLI: Whole Lung Irradiation; OMC: Oral metronomic chemotherapy. R1: microscopic margin positive; R2: macroscopic margin positive
Sixteen (9.2%) patients had undergone upfront surgery/biopsy outside our hospital and presented to us. One hundred seventy-three patients were included in the study among whom 170 received chemotherapy after diagnosis and three patients were not treated and received best supportive care due to advanced disease at presentation. One hundred thirty-four among the 170 patients (79%) who received chemotherapy after diagnosis received adjuvant chemotherapy after definitive treatment to the primary site. Thirty-six patients did not receive adjuvant chemotherapy because of disease progression in 32 patients, mortality due to febrile neutropenia in one patient, and treatment abandonment in 3 patients. The median number of NACT cycles was 05 (range: 1–9 cycles). Twenty-six (15.2%) patients experienced grade 3 or 4 toxicities due to NACT. NACT dose reduction was required in 42 (24.7%) patients who had any grade toxicity. Two patients (1.1%) had treatment-related mortality due to multi-drug-resistant gram-negative bacterial sepsis, one patient had localized disease, and the other had metastatic disease. Surgery and definitive radiotherapy were given to 103 (59.5%) and 49 (28.3%) patients, respectively. Thirty-eight (21.9%) patients had received PORT. Twenty-four out of 44 patients with metastatic disease were treated with curative intent.
Hundred thirty-four (77.4%) patients completed adjuvant chemotherapy. The median number of adjuvant chemotherapy cycles was 10 (range: 1–15 cycles). Thirty-nine (29.1%) patients experienced Grade 3 or 4 toxicities due to adjuvant chemotherapy. Adjuvant chemotherapy dose reduction was required in 55 (41%) patients.
The median follow-up of surviving patients was 75 months. The 5-year EFS and OS were 43.7% (95% CI: 36.1–51), and 45.1% (95% CI: 37.3–52.6), respectively (Supplemental Fig. 2A-B), for the overall cohort. For patients with localized disease 5-year EFS and OS were 56.6% (95% CI: 47.4–64.7) and 57.2% (95% CI: 47.9–65.5), respectively (Fig. 2A-B). The 5-year EFS and OS for patients with metastatic disease were 0% and 4.1% (95% CI: 0.4–15.7) respectively (Fig. 2A-B). Site-specific analysis showed that the head and neck and long bones had better EFS and OS than the pelvic primary (Fig. 3A-B). The treatment for all the sites was the same as described in the methods section.
Fig. 2.
Kaplan Meier survival curves for A. Event-free survival for metastatic and localized disease; B. Overall survival for metastatic and localized disease
Fig. 3.
Kaplan Meier survival curves for A. Event-free survival for disease primary site; B. Overall survival for disease primary site. “Others” included sites kidney, bladder, breast, retroperitoneum, and other soft tissues
Metastatic disease (p = 0.0001), tumor volume > 200 ml (p = 0.011), tumor diameter > 8 cm (p = 0.01), pelvic site (p = 0.039), hemoglobin < 10 gms% (p = 0.006), elevated lactate dehydrogenase (p = 0.003), positive margin (p = 0.001), and necrosis less than 90% (p = 0.028) were significantly associated with inferior OS on univariate analysis.
On multivariate analysis, metastasis disease [Hazard Ratio (HR) = 3.94 (95% CI: 2.53—6.14)], tumor diameter > 8 cm [HR = 2.24 (95% CI:1.30 -3.87)], and necrosis < 90% [HR = 1.57 (95% CI: 1.29 -1.93)], were significantly associated with inferior OS.
On follow-up, cardiac dysfunction was seen in three patients, all of them were managed conservatively and recovered well whereas end-stage renal and liver disease was seen in one patient each. One patient developed secondary neoplasm (differentiated thyroid cancer with lung metastasis) along with liver cirrhosis.
Discussion
The present study is one of the few that report real-world outcomes of treating ESFT in children and adults in a real-world setting in LMIC. A recently published prognostic model for Ewings sarcoma from a single center reported that 40% of 860 patients had metastatic disease at presentation, similar to our observation of metastatic disease [13]. A tumor diameter > 5 cm, baseline metastases, and total leucocyte count > 11000/mm3 were independent predictors of overall survival and included the prognostic score [13]. In our study, on multivariate analysis, metastatic disease, tumor diameter > 8 cm, and necrosis < 90% were significantly associated with inferior OS.
Dose-dense chemotherapy has shown OS benefits in non-metastatic tumors [14, 15]. We have not used dose-dense chemotherapy in the past due to the apprehension of increased toxicity and cost. However, we have been routinely using dose-dense chemotherapy for two years, and the toxicities have been manageable. This suggests that centers in LMICs should try to move towards dose-dense chemotherapy in the non-metastatic setting. All studies on Ewing sarcoma from India have used non-dose-dense chemotherapy [16–18]. Whether dose-dense chemotherapy improves survival outcomes in the real-world setting must be evaluated.
The Euro-Ewing 2012 trial compared non-dose-dense VIDE (Vincristine, Ifosfamide, Doxorubicin, and Etoposide) chemotherapy with dose-dense VAC/IE in localized Ewing sarcoma [15]. Dose-dense VAC/IE showed superiority over VIDE [15]. The projected 5-year EFS and OS in the VIDE arm were 55% and 64%, respectively, while in the dose-dense VAC/IE arm, they were 61% and 72%. The 5-year EFS of 56.6% in localized Ewing sarcoma, as reported in our study, is comparable to the projected 5-year EFS of 55% in the standard arm (VIDE) of Euro-Ewing 2012 [15]. In the AEWS0031 trial, patients with localized Ewing sarcoma in the dose-dense arm had a 5-year EFS of 73% compared to 65% in the standard arm (P = 0.028) [14]. Biswas et al. reported a 5-year EFS and OS of 36.8% and 52.4% in a cohort of 224 patients aged 0.1–55 years with localized Ewing sarcoma [17]. The 3-year EFS and OS in 159 patients younger than 15 years with localized Ewing sarcoma treated at Tata Memorial Hospital, Mumbai, were reported as 70.9% and 82.8%, respectively [16]. A study from the same institution reported a 3-year EFS and OS of 67.3% and 91.1% in patients above 15 years with localized Ewing sarcoma [18]. The 3-year EFS and OS in localized Ewing sarcoma in our cohort was 60.1 and 64.1 respectively.
Tumor necrosis after NACT is an important prognostic factor in localized Ewing sarcoma. Patients with tumor necrosis greater than 90% have better OS compared to those with necrosis less than 90% [19]. This was observed in our study also.
Patients with metastatic disease have dismal outcomes. The 5-year EFS and OS in our cohort were 0% and 4.1% respectively. HDCT and ASCT are no longer recommended for metastatic disease in Ewing sarcoma [20]. It has shown to be beneficial only in patients with high-risk localized disease receiving non-dose-dense chemotherapy [21]. Therefore, it is unlikely that the poor survival in our cohort was because the majority did not undergo HDCT and ASCT. The lack of specific targeted therapy and poor response to immune checkpoint inhibitors are some of the reasons why there has been no improvement in outcomes in this subset of patients [22].
Non-relapse mortality in our study was 1.1% which was due to gram-negative bacterial sepsis secondary to febrile neutropenia. This was lesser than the 6.5% non-relapse mortality reported in another study in India, where bacterial sepsis was the most important cause of death [16].
Bulky disease (Tumor diameter > 8 cm or tumor volume > 200 ml) is a poor prognostic factor in EWSFT [23]. This has been confirmed in our study, studies from India and high-income countries [13, 23]. The proportion of patients presenting with bulky disease is similar in India and high-income countries with about one-third of patients having bulky disease at presentation.
Molecular confirmation for EWSFT includes Fluorescent In-Situ Hybridization (FISH) testing or PCR testing to identify the translocations associated with the EWS gene. The majority of patients in our study could not undergo molecular testing to confirm the diagnosis due to the non-availability of the tests till 2014. The high cost of testing was also a barrier to performing the tests on all patients. Among the 44 patients who underwent PCR tests for EWS-FLI, 26 had a result and the rest 18 could not be reported due to technical issues. Seventeen out of 26 patients (65%) were positive for EWS-FLI translocation. This is less than 80–85% reported in the literature [24]. The reason for lower positivity could be sample heterogeneity, technical limitations, and methodological variability, and also because we did not test for translocations other than EWS-FLI1.
Ewing-like sarcoma/undifferentiated round cell sarcoma (ELS/URCS) denotes a type of sarcoma that resembles Ewing sarcoma in numerous aspects but doesn't exhibit the typical EWSR1 gene rearrangements that are a defining trait of Ewing sarcoma [25]. ELS/URCS tends to occur at younger ages and is more aggressive than Ewing sarcoma and has been linked to two recurring fusion rearrangements known as BCOR-CCNB3 and CIC-DUX4 [25]. They are managed like EWSFT, however, have poor outcomes. Patients who do not have the classical EWSFT translocation should be tested for BCOR-CCNB3 and CIC-DUX4 [25].
The study has its limitations because of its retrospective nature. Accurate data on toxicities and long-term consequences of treatment could not be captured. However, our study reports the longest follow-up on Ewing sarcoma from India and includes both pediatric and adult patients. The study highlights that multidisciplinary management of EWSFT in specialized centers is essential to achieve high cure rates.
Supplementary Information
Below is the link to the electronic supplementary material.
Data Availability
Data for research will be available on request from the principal investigator and approval by the Cancer Institute Institute Ethics Committee.
Declarations
Conflict of Interest
Dr. Anand Raja is a member of the Editorial Board of the Indian Journal of Surgical Oncology.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Supplementary Materials
Data Availability Statement
Data for research will be available on request from the principal investigator and approval by the Cancer Institute Institute Ethics Committee.