Tag Archive for: management

Adamantinoma; An update

Vol 3 | Issue 2 | Sep-Dec 2017 | Page 16-19 | Ashish Gulia, Pankaj Kumar Panda.


Authors: Ashish Gulia [1], Pankaj Kumar Panda [1].

[1] Surgical Oncology (Orthopedic Oncology), 93, Ground Floor, Main Building, Bone & Soft tissue Services (Disease Management Group), Tata Memorial Hospital, Mumbai – 400012, India.

Address of Correspondence
Dr. Ashish Gulia,
Surgical Oncology (Orthopedic Oncology), 93, Ground Floor, Main Building, Bone & Soft tissue Services (Disease Management Group), Tata Memorial Hospital, Mumbai – 400012, India.
Email: aashishgulia@gmail.com


Abstract

Adamantinoma is a rare, malignant biphasic tumor with varied morphological patterns.Adamantinoma mostly occurs in the second to fifth decade and is slightly more common in men than women.The onset is insidious, and its course shows a slow, progressive character.Radiography is the initial and most reliable imaging modality for adamantinoma of bones because of the tumor’s classic location and appearance on a plain radiograph.Present management modalitieswhich includeen blocresection (mostly intercalary resection) with limb salvage and limb reconstruction. Chemotherapy and radiotherapy have no established role. Amputation does not improve survival but may be advisable in cases with local recurrence and in cases with few large, recurrent lesions where en bloc resection is not possible.
Keywords: Adamantinoma, malignant biphasic tumor, management.


References

1. Dahlin DC. Bone Tumors: General Aspects and Data on 6221 Cases. 3rded. Springfield, IL: Charles C Thomas; 1978. p. 296.
2. Kahn LB. Adamantinoma, osteofibrous dysplasia and differentiated adamantinoma. Skeletal Radiol 2003;32(5):245-258.
3. Fisher B. Primary adamantinoma of the tibia. Z Pathol 1913;12:422-441.
4. Van Rijn R, Bras J, Schaap G, van den Berg H, Maas M. Adamantinoma in childhood: Report of six cases and review of the literature. PediatrRadiol 2006;36(10):1068-1074.
5. Czerniak B, Rojas-Corona RR, Dorfman HD. Morphologic diversity of long bone adamantinoma. The concept of differentiated (regressing) adamantinoma and its relationship to osteofibrous dysplasia. Cancer 1989;64(11):2319-2334.
6. Mirra JM. Adamantinoma and fibrous dysplasia. InBone tumors 1sted. Mirra JM, editor. Philadelphia,PA: Lea &Febiger; 1989. p. 1203-1231.
7. Springfield DS, Rosenberg AE, Mankin HJ, Mindell ER. Relationship between osteofibrous dysplasia and adamantinoma. ClinOrthopRelat Res 1994;309:234-244.
8. Moon NF, Mori H. Adamantinoma of the appendicular skeleton-updated. ClinOrthopRelat Res 1986;204:215-237.
9. Lederer H, Sinclair AJ. Malignant synovioma simulating “adamantinoma of the tibia”. J PatholBacteriol 1954;67(1):163-168.
10. Van der Woude HJ, Hazelbag HM, Bloem JL, Taminiau AH, Hogendoorn PC. MRI of adamantinoma of long bones in correlation with histopathology. AJR Am J Roentgenol 2004;183(6):1737-1744.
11. Unni KK. Dahlin’s Bone Tumors: General Aspects and Data on 11,087 Cases. 5thed. Philadelphia, Pa: Lippincott-Raven; 1996. p. 333-342.
12. Hazelbag HM, Taminiau AHM, Fleuren GJ, Hogendoorn PC. Adamantinoma of the long bones. A clinicopathological study of thirty-two patients with emphasis on histologic subtype, precursor lesion, and biological behavior. J Bone Joint Surg Am 1994;76:1482-1499.
13. Weiss SW, Dorfman HD. Adamantinoma of long bone. An analysis of nine new cases with emphasis on metastasizing lesions and fibrous dysplasia-like changes. Hum Pathol 1977;8(2):141-153.
14. Bridge JA, Dembinski A, DeBoer J, Travis J, Neff JR. Clonal chromosomal abnormalities in osteofibrous dysplasia. Implications for histopathogenesis and its relationship with adamantinoma. Cancer 1994;73(6):1746-1752.
15. Ueda Y, Blasius S, Edel G, Wuisman P, Böcker W, Roessner A. Osteofibrous dysplasia of long bones-A reactive process to adamantinomatous tissue. J Cancer Res ClinOncol 1992;118(2):152-156.
16. Hazelbag HM, Fleuren GJ, vdBroek LJ, Taminiau AH, Hogendoorn PC. Adamantinoma of the long bones: Keratin subclass immunoreactivity pattern with reference to its histogenesis. Am J SurgPathol 1993;17(12):1225-1233.
17. Kanamori M, Antonescu CR, Scott M, Bridge RS Jr, Neff JR, Spanier SS, et al. Extra copies of chromosomes 7, 8, 12, 19, and 21 are recurrent in adamantinoma. J MolDiagn 2001;3(1):16-21.
18. Keeney GL, Unni KK, Beabout JW, Pritchard DJ. Adamantinoma of long bones. A clinicopathologic study of 85 cases. Cancer 1989;64(3):730-7.
19. Qureshi AA, Shott S, Mallin BA, Gitelis S. Current trends in the management of adamantinoma of long bones. An international study. J Bone Joint Surg Am 2000;82-A(8):1122-1131.
20. Bovée JV, van den Broek LJ, de Boer WI, Hogendoorn PC. Expression of growth factors and their receptors in adamantinoma of long bones and the implication for its histogenesis. J Pathol 1998;184(1):24-30.


How to Cite this article: Gulia A, Panda P. Adamantinoma – an update. Journal of Bone and Soft Tissue Tumors Sep-Dec 2017;3(2): 16-19.



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The Current Role of Radiation Therapy for Osteogenic Sarcoma

Volume 2 | Issue 1 | Jan-Apr 2016 | Page 33-35  Sangeeta Kakoti, Nehal Khanna, Siddhartha Laskar.


Authers: Sangeeta Kakoti[1] Nehal Khanna[1], Siddhartha Laskar[1]

[1]Department of Radiation Oncology, Tata Memorial Hospital, Mumbai. India

Address of Correspondence
Dr.Siddhartha Laskar
Professor, Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges Marg, Parel, Mumbai – 400012, India.
Email: laskars2000@yahoo.com


Abstract

Osteosarcomas are known to be relatively radio-resistant, definitive radiotherapy has a role in cases that are unresectable or have poor prognostic factors. Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. New technologies like particle beam therapy using proton and carbon ions and use of high precision radiation therapy techniques have further improved the results of definitive radiation therapy. Current review traces the advent of radiotherapy, its current role in management of osteosarcoma and future trends in the field.
Keywords: Osteogenic Sarcoma, Radiotherapy, Management.


Introduction

Osteosarcoma (OGS), an osteoid-producing malignant mesenchymal tumour, accounts for 20-45% of all skeletal malignancies. It has a bimodal age distribution with peak incidence at 10-19 years and over 60 years (secondary to prior radiotherapy exposure, Paget’s disease etc). Male to female ratio is approximately 1.6:1. The most common sites of involvement are femur (50%), followed by tibia, humerus, pelvis, jaw, fibula and ribs. The major histological variants are conventional osteosarcoma (osteoblastic, fibroblastic or chondroblastic, according to the predominant type of matrix produced), teleangiectatic and small cell osteosarcoma. Patients commonly present with bony pain and local swelling. Patients may also present with symptoms of metastatic disease like dyspnoea, hemoptysis, or bone pain. Diagnostic investigations include Plain radiograph (characteristic ‘Sun burst’ appearance and ‘Çodman’s triangle’), MRI of local part, CT scan of chest, Bone scan (to look for skip lesions) and a histopathological examination. Tumors are staged according to either the AJCC or Enneking (MSTS) systems. Prognostic factors impacting survival [1] include presence of metastasis, response to Neoadjuvant chemotherapy (NACT), histologic type, age (each decade increases mortality rate by 7 fold), tumour location (tumours of tibia fare better than those of femur) and choice of therapy (post operative radiotherapy and amputation was associated with 92% and 76% increased relative risk of death respectively, may be confounded by advanced disease status). Prior to the extensive use of chemotherapy for treating patients with osteosarcoma, aggressive surgery was considered the treatment of choice, resulting in five year overall survival rate of 10-20% [2]. A meta-analysis by Kassir et al [3] on head and neck Osteosarcoma showed that surgical cut margin status was the sole prognostic factor and there was no survival benefit by adding radiation therapy and/or chemotherapy. But subsequently there have been great leaps in the success of osteosarcoma management. Incorporation of highly active chemotherapeutic agents resulted in significant improvement in outcomes to the tune of 60-75% [4]. The MIOS trial [5] reporting 5% versus 65% overall survival rates in patients randomised to surgery versus surgery and chemotherapy respectively, formed the basis for multimodality therapy in these tumours.

Role of Radiotherapy in management of Osteosarcoma
Osteosarcoma was always thought to be a radio-resistant tumour and hence radiotherapy was initially not included in the standard management regimens. Sir Stanford Cade a British surgeon radiotherapist in 1931 treated 133 patients with radiation therapy with an intention to avoid futile amputation in patients developing lung metastases in subsequent 6-9 months [6]. Following completion of therapy (60 Gy over six weeks) the resected specimen revealed 100% tumour necrosis in all patients.

1) Radiotherapy in definitive setting
There are no randomized trials comparing surgery versus radiotherapy (RT) as primary local therapy for osteosarcoma and is unlikely to be one in future due to ethical issues. However there are a few single arm series showing encouraging results. Machak et al [7] treated 31 patients with extremity osteosarcomas with definitive radiotherapy to a median dose of 60 Gy (range, 40–68 Gy). The 5-year local control (LC), metastasis-free and overall survival (OS) rates were 56%, 62%, and 61%, respectively. Similarly, Caceres et al [8] also noted a complete pathological response in 80% patients with limb OGS treated by chemotherapy and 60 Gy of RT. Excellent functional outcomes was noted in 86% of the patients. In 13 patients treated with definitive RT to median dose of 60 Gy, at a median follow up of 161 months, 3 year LC and OS was 70% and 75% respectively [9]. Subsequently, in the COSS registry of 175 patients [10] treated from 1980 to 2007, at a median follow up of 1.5 years (0.2-23 years), the overall survival rates after RT for treatment of primary tumors, local recurrence, and metastases were 55%, 15%, and 0% respectively. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%). Feasibility of Stereotactic body radiotherapy (SBRT) for recurrent OGS lesions was evaluated by Brown et al [11]. Median dose delivered was 40 Gy in 5 fractions (range, 30-60 Gy in 3-10 fractions; total of 14 patients). Two grade 2 and 1 grade 3 late toxicities occurred (in the setting of concurrent chemotherapy and reirradiation); consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy [11]. Efficacy and long term toxicity are yet to be determined. Gaitan-Yanguas showed a dose-response relationship with no lesion controlled at doses of 30 Gy, and all lesions controlled with doses of >90 Gy [12].
Approximately 25% of pelvic and 10% of head and neck osteosarcomas are not resectable and hence are candidates for definitive radiotherapy. In our institute, we prescribe 70.2 Gy in 39 fractions over 8 weeks.

2) Radiotherapy in preoperative setting
Preoperative radiotherapy is gradually evolving to facilitate function preserving less mutilating surgeries. Dincsbas et al [13] treated 44 patients with preoperative RT to a dose of 35 Gy in 10 fractions followed by limb sparing surgery. The tumor necrosis rate was 90% in 87% of the patients. At a median follow-up of 44 months, the 5-year LC and OS were 97.5% and 48.4% respectively. They documented subcutaneous fibrosis in 16%, joint movement restriction in 20%, and osteo-radionecrosis and pathologic fracture in 4% patients. Chambers et al [14] reported an OS of 73% at 5 years of 33 patients treated with preoperative RT and resection for craniofacial OGS.

3) Radiotherapy in adjuvant setting
Delaney et al [15] reported 41 patients with osteosarcoma involving various sites (primary, recurrent as well as metastatic) in different settings to a dose of 10 to 80 Gy (median 66 Gy) preceded by gross total tumor resection in 65.8%, subtotal resection in 21.9% and biopsy only in 12.2%. The local control rates according to the extent of resection were 78.4%, 77.8% and 40% respectively. The overall survival rates in corresponding groups were 74.45%, 74.1% and 25% respectively. The authors concluded that adjuvant RT can help provide local control of osteosarcoma for patients in whom surgical resection with widely negative margins is not possible. Dose response relationship was not found to be significant. Caveat of the study was that the patient population as well as the treatment parameters including dose and timing of radiation (some received preoperative followed by postoperative RT) was very heterogeneous.
Guadagnolo et al [16] reported that the addition of adjuvant RT in head and neck osteosarcoma definitely improves local control for those with positive or uncertain margins. Laskar et al reported the outcomes of patients with head and neck osteosarcomas treated at the Tata Memorial Hospital, Mumbai [17]. The authors highlighted the impact of post-operative adjuvant radiotherapy, even after R0 resection or in patients with adverse prognostic factors (large tumour size, lymphovascular invasion, soft tissue infiltration etc). The patients receiving adjuvant RT at TMH were prescribed a dose of 64.8 Gy in 36 fractions over 7 weeks. The authors reported local control rate of 36%. High dose intra-operative EBRT with kV X rays or electrons is emerging as yet another experimental option. Hong et al reported outcome of extracorporeal irradiation (ECI) in the management of 16 pts with a variety of tumours (OGS being in 4 of them) to a dose of 50 Gy in single fraction. At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis [18]. Puri et al reported the outcomes of patients treated at the Tata Memorial Hospital, Mumbai, using extracorporeal irradiation [19]. Thirty-two patients (16 Ewing’s sarcoma and 16 OGS) with a mean age of 15 years (2 to 35 years) underwent this procedure. There were three local recurrences. All were associated with disseminated disease and the recurrences were in soft- tissue remote from the irradiated graft. There were no local recurrences involving the irradiated bone. The OS for patients with osteosarcoma was 65% with excellent functional outcome.

4) Radiotherapy in palliative setting

There is little data regarding dose fractionation and efficacy of radiotherapy for palliation of advanced osteosarcoma. Considering the similar mechanisms of pain and inflammation like bony metastases, data from the later are often extrapolated [20] and single fraction or protracted fractionation have both been equally used. Oligo-metastatic OGS is treated with curative intent. Metastatectomy is the gold standard as a component of the curative regimen with a documented 5 year OS of approx 22%. Stereotactic body radiotherapy (SBRT) to limited lung metastases is an equally efficacious emerging non invasive option. In a series of 46 patients with oligometastatic disease to lungs from sarcomas, at a median follow up of 22 months after median dose of 10-48 Gy in 1-5 fractions, 31% of patients survived for more than 3 years [21]. In a multicentric phase I/II trial treating 38 patients with oligometastases to a median dose of 38-60 Gy in 3 fractions, LC at two years was 96% and median survival was 19 months. Incidence of grade III-IV toxicity was 8% [22].

5) Particle therapy for osteosarcoma
Ciernik et al, treated 55 patients (42% received definitive RT) with osteosarcoma of all sites [23] using combination of photons and protons to a mean dose of 68.4 Gy. With a median follow-up of 27 months, LC at 3 and 5 years were 82% and 72% respectively. The 5-year DFS and OS was 65% and 67% respectively. Prognostic factors found to have a significant impact on disease control were grade and bulk of the tumour. The extent of surgical resection did not correlate with outcome. Grade 3 to 4 late toxicity was seen in 30.1 % of patients. In another series of 30 patients with unresectable OGS of the trunk treated with definitive Carbon ion therapy to a dose of 52.8–73.6 Gy, the 3 and 5 year LC at a median follow up of 33 months was 62% and 49% respectively. The corresponding OS was 53% and 29%. Severe skin/soft tissue reaction was reported in 5 patients [24]. With neutrons, local control rates of 55% were documented in patients with unresectable OGS of different sites [25]. A median prescribed dose of 66 Gy has been tried in a series to patients with paraspinal osteosarcomas with a resultant LC of 74%. There were no reported late toxicities [26].

6) Role of brachytherapy
There is very limited role of brachytherapy in osteosarcomas. A new treatment strategy based on direct injections of 90Y-hydroxide into the tumor bed is under preclinical trial   [27].


 Conclusion

Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. Although osteosarcomas are considered to be relatively radio-resistant, definitive radiation therapy results in significant long term disease control in patients with inoperable disease and postoperatively in patients with poor prognostic factors. The outcomes of definitive treatment using radiation therapy has further been improved by the use of particle beam therapy like protons & carbon ions & escalated doses of photon therapy using modern high precision radiation therapy techniques. Hence, Radiotherapy remains an important option for local treatment of unresectable tumors, following incomplete resection, or as an effective tool for palliation of symptomatic metastases


References

1. Prognostic factors and outcomes for osteosarcoma: An international collaboration. Emil-ios E. Pakos, Andreas D. Nearchou, Robert J. Grimer et al. European Journal of Cancer. 2009; 4 5: 2 3 6 7 –2 3 7 5
2. Osteogenic sarcoma: a study of 600 cases. Dahlin DC, Coventry MBBoneJoint Surg 1967; 49: 101-l 10.
3. Osteosarcoma of the Head and Neck: Meta-analysis of Nonrandomized Studies. Laryn-goscope, 1997; 107: 56-61.
4. Dana-Farber Cancer Institute/The Children’s Hospital adjuvant chemotherapy trials for osteosarcoma: three sequential studies, A. M. Goorin, M. Delorey, and R. D. Gelber, Cancer Treatment Symposia. 1985; 3: 155–159.
5. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosar-coma of the extremity. M. P. Link, A. M. Goorin, and A. W. Miser. The New England Journal of Medicine. 1986; 314: 1513
6. Osteogenic sarcoma. A study based on 133 patients. Cade S. J R Coll Surg Edinb. 1955; 1: 79-111.
7. Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the ex-tremities. Machak GN, Tkachev SI, Solovyev YN et al Mayo Clin Proc. 2003;78:147-155
8. Local control of osteogenic sarcoma by radiation and chemotherapy. Caceres E, Zaharia M, Valdivia S, et al. Int J Radiat Oncol Biol Phys . 1984;10:35-39
9. Patrick Hundsdoerfer et al, European Journal of Cancer 4 5 (2009) 24 47 –2451
10. Craniofacial osteosarcoma Experience of the cooperative German–Austrian– Swiss osteosarcoma study group. Sven Jasnau, Ulrich Meyer, Jenny Potratz et al. Oral Oncology (2008) 44, 286– 294
11. Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosar-coma. Brown LC, Lester RA, Grams MP et al, Sarcoma. 2014:418270
12. A study of the response of osteogenic sarcoma and adjacent normal tissues to radiation. Gaitan-Yanguas M. IJROBP. 1981; 7: 593-595
13. The role of preoperative radiotherapy in non metastatic high-grade osteosarcoma of the extremities for limb-sparing surgery. Dincbas FO, Koca S, Mandel NM et al. Int J Radiat Oncol Biol Phys 2005;62:820-828
14. Osteogenic sarcoma of the mandible, current management. Chambers RG, Mahoney WD. Am Surg . 1970;36:463-471
15. Radiotherapy for local control of osteosarcoma. Thomas F. Delaney, Lily Park, Savelli I Goldberg et al, IJROBP, 2005; 61(2): 492-498.
16. Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Guadagnolo BA, Zagars GK, Raymond AK, et al, Cancer 2009;115: 3262-70.
17. Osteosarcoma of the head and neck region: lessons learnt from a single institutional expe-rience of 50 patients, Siddhartha Laskar, Ayan Basu, Mary Ann Muckaden et al, Head & Neck, 2008: 1020-1026.
18. Extracorporeal irradiation for malignant bone tumors. Hong A, Stevens G, Stalley P, et al. Int J Radiat Oncol Biol Phys . 2001;50:441-447
19. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradia-tion and re-implantation of the host bone. A Puri, A Gulia, N Jambhekar, S Laskar. J Bone Joint Surg Br 2012;94-B:982–8.
20. Randomized trial of short versus long-course radiotherapy for palliation of painful bone metastases. Hartsell WF, Scott CB, Bruner DW, et al. J Natl Cancer Inst 2005;97:798–804
21. A retrospective study of SBRT of metastases in patients with primary sarcoma. Christina Linder Stragliotto, Kristin Karlsson, Ingmar Lax et al. Med Oncol. 2012; 29:3431–3439
22. Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy for Lung Me-tastases, Kyle E. Rusthoven, Brian D. Kavanagh, Stuart H. Burri. J Clin Oncol 2009; 27:1579-1584.
23. Proton-Based Radiotherapy for Unresectable or Incompletely Resected Osteosarcoma: I. Frank Ciernik, MD1,2; Andrzej Niemierko, PhD1,3,4; David C. Harmon et al, cancer 2011; 117: 4522–30.
24. Impact of Carbon Ion Radiotherapy on Outcome in Unresectable High-grade Osteosar-coma of the Trunk, T. Kamada, R. Imai, S. Sugawara et al, I. J. Radiation Oncology d Biology d Physics Volume 75, Number 3, Supplement, 2009
25. Fast neutron radiotherapy for sarcomas of soft tissue, bone, and cartilage: Laramore GE, Griffith JT, Boespflug M et al, Am J Clin Oncol, 1989, vol 12, pp 320-326
26. Image-guided intensity-modulated photon radiotherapy using multifractionated regimen to paraspinalchordomas and rare sarcomas. Terezakis SA, Lovelock DM, Bilsky MH et al. Int J RadiatOncolBiol Phys. 2007;69(5):1502-8
27. Dosimetry of a 90Y-hydroxide liquid brachytherapy treatment approach to ca-nine osteosarcoma using PET/CT. Jien Jie Zhou, Arnulfo Gonzalez, Mark W. Lenox. Ap-plied Radiation and Isotopes. 2015; 95: 193-200.


How to Cite this article:Kakoti S, Khanna N, Laskar S. The Current Role of Radiation Therapy for Osteogenic Sarcoma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 33-35.

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Management of Ewing Sarcoma: Current Management and the Role of Radiation Therapy

Vol 1 | Issue 1 | May – August 2015 | page:18-22 | Monica Malik Irukulla[1,*], Deepa M Joseph[1].


Author: Monica Malik Irukulla[1,*], Deepa M Joseph[1].

[1]Department of Radiation Oncology, Nizam’s Institute of Medical Sciences, Hyderabad. India

Address of Correspondence
Dr. Monica Malik Irukulla, MD.
Department of Radiation Oncology, Nizam’s Institute of Medical Sciences, Hyderabad. India.
Email: dr_monica11@yahoo.com


Abstract

The management of Ewing sarcoma has evolved over the last few decades with successive improvement in survival rates. Multidisciplinary management is the key to successful outcomes. Dose intensity of chemotherapy is of vital importance. Local control can be effectively achieved with surgery, radiation therapy or a combination of the two. The choice of appropriate local therapy should be individualized and depends on various factors such as site, size, resectability, expected morbidity, long term effects etc. Metastatic disease remains a significant challenge and optimal therapeutic strategies still need to be defined. Current management and the role of radiation therapy in Ewing sarcoma are reviewed.
Keywords: Ewing sarcoma, radiation therapy, management.


Introduction

Ewing sarcoma family of tumors (ESFT) are a group of small round cell tumors showing varying degrees of neuroectodermal differentiation with Ewing sarcoma being the least differentiated. Primitive neuroectodermal tumors (PNET) show neuroectodermal differentiation by light microscopy, immune histochemistry (IHC) or electron microscopy [1]. According to WHO classification of bone and soft tissue tumors, Ewings sarcoma/PNET is synonymous with Ewing tumor, peripheral neuroepithelioma, peripheral neuroblastoma and Askin tumor [1]. In most of the patients, a chromosomal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor which is the major oncogene in this pathology [2].

Epidemiology
Ewing sarcoma is the second most common primary bone tumor of childhood and it most commonly occurs in the second decade of life with a slight male preponderance. The incidence of Ewing sarcoma has been reported to be low in Asian population as compared to Caucasians[3]. Data from Indian population show that it is not so uncommon[4]. The common sites of primary Ewing sarcoma are the long bones of the lower extremities (41%), pelvic bones (26%), and bones of the chest wall (16%)[5]. Extraosseous Ewing sarcoma is more commonly axial in location involving the trunk (32%), extremities (26%), head and neck (18%), the retroperitoneum (16%) etc[6]. Approximately 20-25% of patients present with metastasis at diagnosis. Common sites of metastases include lungs, bones and bone marrow.

Diagnostic Evaluation
Typical presenting symptoms include pain and swelling with occasional constitutional symptoms like fever, fatigue and loss of weight. Patients should be evaluated and managed by a multidisciplinary team of experts including pediatric oncologists, orthopedic surgeons, radiologists, pathologists and rehabilitation specialists. A biopsy should be performed in a way such that the track and scar can be included in the subsequent resection or radiation portal. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture and should be through rather than between muscle compartments avoiding the neurovascular bundles. A skilled pathologist should be available onsite to confirm adequacy of the material and review the frozen sections. A needle biopsy may be adequate if sufficient tissue can be obtained for histological, cytogenetic and molecular studies. The risk of diagnostic errors and complications increases by as much as 12-fold when the biopsy is improperly done [7]. Ewing sarcoma/PNETs usually strongly express the cell surface glycoprotein MIC2 (CD99) and this can be helpful in diagnosis of small blue round cell tumors. CD99 is however not exclusively specific for ES/PNET and is found in other tumors such as synovial sarcoma, NHL, GIST etc [8]. Approximately 85% patients have expression of EWS-FLI1 chimeric transcription factor resulting from translocation between EWS and FLI-1 gene t(11;22)(q24;q12) [9]. In most of the remaining patients, alternative translocations between EWS and another ETS- family member (ERG, FEV, ETV1, E1AF) are detected [2]. Molecular analysis for EWS-FLI 1 should be considered. The prognostic value of the same remains inconclusive until now[10]. This is being evaluated as potential therapeutic target [11]. Local imaging with MRI with or without CT scan is recommended. Conventional staging evaluation includes bilateral bone marrow aspiration and biopsy or MRI of spine and pelvis, bone scan and CT scan of the chest. Serum LDH is an important prognostic marker. Positron emission tomography (PET) combined with conventional imaging is a valuable tool in staging and restaging ESFT with a sensitivity of 96% and specificity of 92% [12]. FDG-PET can also serve as a non-invasive method to predict response to chemotherapy which is a useful prognostic marker.13 Whole-body MRI can be a useful radiation-free modality to detect metastatic lesions with a higher sensitivity than bone scintigraphy [14,15]. Fertility consultation should be done for patients desiring future child bearing before starting therapy.

Prognostic factors
5-year event free survival approaches around 70% with standard multimodality approach in localized disease [16]. Favorable prognostic factors include extremity tumors, tumor volume <100ml, normal LDH and absence of metastases at presentation. Common adverse prognostic factors include metastatic disease at presentation, extra skeletal presentation, pelvis as the primary site and poor response to induction chemotherapy. Metastatic disease is the most significant adverse prognostic factor. Those with isolated pulmonary metastasis have a slightly better outcome than those with bone or bone marrow metastasis [17]. Survival depends on the site and number of metastases and the tumor burden with 5 year survival rates ranging from approximately 30% with isolated lung metastasis to less than 20% with multiple bone metastases. Older patients do worse than patients younger than 15 years.18 Poor histologic response to chemotherapy is associated with worse outcomes in patients with localized disease [19].

Treatment
Treatment of Ewing sarcoma has evolved following evidence from large multinational trials over the past few decades with successive improvement in outcomes. Multimodality approach is the key in the management of nonmetastatic Ewing sarcoma.

Chemotherapy
The prognosis in Ewing sarcoma remained very poor until 1960s in spite of good initial response to local treatment. The introduction of chemotherapy into the treatment regimen dramatically improved the response rates and thus the cure rates. Patients are started on induction chemotherapy for 3-4 cycles followed by local therapy at 12weeks. Restaging should be done with a chest imaging and MRI of the local part before local therapy. Further adjuvant chemotherapy is continued for total treatment duration of about 10-12 months. Chemotherapy with Vincristine, Adriamycin/Actinomycin D, cyclophosphamide, (VAC) alternating with Ifosfamide and Etoposide (IE) administered at a three weekly fashion is the standard regimen. Maintaining adequate dose intensity of chemotherapy is of utmost importance. Interval compressed or dose dense chemotherapy improves DFS and has the potential to improve overall survival [20].

Local therapy
Local therapy is delivered at the completion of 3-4 cycles of chemotherapy at 12 weeks and comprises of surgery or radiotherapy or both. There are no randomized trials comparing the two modalities. The choice of local therapy depends on the site of the disease, age of the patient, expected functional outcomes and concern over the late morbidities. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias. A North American intergroup trial showed no difference in local control or survival based on local treatment modality – surgery, radiation therapy, or both [21]. In patients with localized Ewing sarcoma treated in cooperative intergroup studies there was no significant effect of local control modality (surgery, RT, or surgery plus RT) on OS or EFS rates. In the CESS 86 trial, although radical surgery and resection plus RT resulted in better local control rates (100% and 95%, respectively) than definitive RT (86%), there was no improvement in relapse free survival and overall survival [22]. Preoperative radiation therapy can achieve tumor shrinkage and surgical resection with negative margins in cases with borderline resectability and can potentially allow smaller fields and lower radiation doses [23].

Definitive Radiotherapy
Ewing sarcoma was described by James Ewing in 1921 as “diffuse endothelioma of bone”, a distinct entity from osteosarcoma due to its high response to radiation therapy. In the current scenario, definitive radiotherapy remains an effective local therapy strategy for patients with tumors in sites not amenable for surgical resection and in cases where resection is likely to result in unacceptable morbidity. Advances in imaging, tumor delineation, treatment planning and delivery is now allowing greater precision and sparing of normal tissues. Historically, patients were treated with whole bone irradiation. With the POG 8346 trial, adequate involved field RT with MRI based planning became the standard. Current guidelines recommend 1.5 to 2 cm margin from the gross tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2 cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS [24]. Initial treatment volume include the pre-chemotherapy volume with margin up to a dose of 45Gy, further boost is delivered to the post chemotherapy volume upto a total dose of 55.8Gy to 60Gy. Tumor size and RT dose have been shown to be predictive of local control rates in patients with non-metastatic Ewing sarcoma treated with chemotherapy and definitive RT [25]. Role of hyperfractionated radiotherapy in management of Ewing sarcoma has been evaluated in the CESS 86 trial [22]. No significant advantage has been demonstrated over the standard fractionation and dose. Recent reports suggest that Proton beam therapy can potentially spare more amount of normal tissue but longer follow up is needed to determine its impact on morbidity and cure rates [26]. Radiation therapy is associated with the development of second malignant neoplasms. In a retrospective analysis, the incidence of second malignancy was 20% in patients who received doses of 60 Gy or more and 5% in those who received 48 Gy to 60 Gy. Those who received < 48 Gy did not develop a second malignancy [27]

Postoperative RT
Postoperative radiation (PORT) is recommended in cases of intralesional or marginal resection, intraoperative spill and poor pathological response to chemotherapy and is usually initiated at 6-8 weeks following surgery. Current Children’s Oncology Group (COG) protocols have more specifically defined adequate margin status. Complete resection is defined as a minimum of 1 cm margin and ideally 2–5 cm around the involved bone. The minimum soft tissue margin for fat or muscle planes is at least 5 mm and for fascial planes at least 2 mm. The Intergroup Ewing Sarcoma Study (INT-0091) recommends 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy boost for patients with microscopic residual disease. In the absence of gross residual disease there seems to be no clear benefit to doses over 45 Gy [28]. No radiation therapy is recommended for those who have no evidence of microscopic residual disease following surgical resection. Although not statistically significant, local relapse was least in the combined arm (10.5%) compared with 25% for either surgery or radiotherapy alone [21]. EICESS 92 evaluated the role of postoperative RT in patients with poor pathological response to induction chemotherapy (<90% necrosis). In their analysis there was reduction in local failures (5% vs.12%) in the poor responders if they received PORT [29 In the CESS and EICESS trials, the local failure rate for central primaries was reduced by 50% with PORT. However the role of adjuvant radiotherapy in poor responders and central tumors needs to be clearly defined and the benefits need to be balanced against potential risks of long term effects and second malignancies. For extraskeletal ES, PORT is generally recommended except in good prognosis superficial tumors [30].

Management of metastatic disease
Standard treatment guidelines for metastatic Ewing sarcoma recommend treatment similar to localized disease [30]. Different chemotherapy agents used are Vincristine, Adriamycin, Cyclophosphamide, Ifosphamide and Etoposide. Addition of IE to VAC does not seem to have additional benefit in this subset of patients [31]. Dose-intense treatment approach with high dose chemotherapy and autologous stem cell transplantation (HDT/SCT) was evaluated in the nonrandomized Euro-EWING 99 R3 study [32]. Even though this may have a potential to improve outcome, it has not become the standard of therapy.
Following induction chemotherapy, patients are reassessed with local and chest imaging and previously abnormal investigations are repeated. A progressive disease is treated with palliative intent and the good responders are managed with treatment of primary disease and metastatic sites. Timing of local therapy for both primary site and metastatic sites remain unclear.

Radiotherapy in metastatic disease
Whole lung irradiation (WLI) in patients with lung-only metastases has shown improved disease free and overall survival in various trials. Patients with lung metastasis should be considered for whole lung irradiation even after complete resolution following chemotherapy [33] Doses of 12 to 21 Gy have been used and are usually well tolerated [34]. Hemithoracic irradiation is recommended in patients with chest wall tumor with pleural nodules, pleural effusion or positive pleural cytology.
Bone metastases in Ewing sarcoma should be treated with similar doses as the primary site. They may be treated simultaneously or following completion of chemotherapy depending on the risk of marrow suppression. In the phase II POG/CCG trial which evaluated the role of intensive chemotherapy, local treatment for primary disease was done after completion of 21weeks of chemotherapy and that of metastatic disease was done after week 39 chemotherapy [35]. With the emergence of stereotactic body radiotherapy (SBRT), it is now possible to deliver ablative doses to sites of bone metastases with excellent sparing of normal tissues. SBRT delivered in one to five fractions can also minimize interruptions of systemic therapy.

Treatment of relapse
Outlook of patients who relapse remain unfavorable. Late onset relapse (>2years) and strictly localized disease has a favorable outcome [36]. Chemotherapy regimens in relapse settings are not standard. Two phase II studies have demonstrated upto 33% partial responses in relapsed refractory Ewing’s sarcoma with the combination of Topotecan and Cyclophosphamide [37]. The combination of Irinotecan and Temozolomide has demonstrated clinical responses.38 Gemcitabine in combination with Docetaxel has shown modest activity [39]. Newer drugs and targeted therapies are being evaluated. Radiotherapy and/or surgery may play a role in improving control rates.

Indian Data
There is paucity of data from Indian population. In a retrospective analysis, symptom duration >4 months, tumor diameter >8cm and baseline WBC >11×10(9)/L were predictive of poorer outcomes [40]. Optimal surgical margin in extra skeletal Ewing sarcoma in children was evaluated by Laskar et al who concluded that clear margins of resection correlated with local control irrespective of margin size[41] Survival rates in India remain dismal in spite of the advancement seen in the western world [42]. Patients tend to present with advanced stage disease and often default treatment due to socioeconomic factors.


Conclusion

The management of Ewing sarcoma has significantly evolved over the last few decades with consequent improvements in survival and functional outcomes. Treatment mandates multidisciplinary co-ordination involving Medical, Surgical and Radiation Oncologists, Orthopedic surgeons, Rehabilitation specialists, Pediatricians and others. Dose intensity of chemotherapy and optimal timing and modality of local therapy appear to significantly influence outcomes and survival rates. Metastatic disease represents a major challenge and optimal treatment strategies still need to be defined.


References

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11. Herrero-Martin D, Fourtouna A, Niedan S, Riedmann LT, Schwentner R, Aryee DN. Factors Affecting EWS-FLI1 Activity in Ewing’s Sarcoma. Sarcoma 2011;2011:352580.
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13. Dimitrakopoulou-Strauss A, Strauss LG, Egerer G, et al. Impact of dynamic 18F-FDG PET on the early prediction of therapy outcome in patients with high-risk soft-tissue sarcomas after neoadjuvant chemotherapy: a feasibility study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2010;51:551-8.
14. Mentzel HJ, Kentouche K, Sauner D, et al. Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions. European radiology 2004;14:2297-302.
15. Burdach S, Thiel U, Schoniger M, et al. Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone marrow transplantation 2010;45:483-9.
16. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of Ifosfamide and Etoposide to Standard Chemotherapy for Ewing’s Sarcoma and Primitive Neuroectodermal Tumor of Bone. New England Journal of Medicine 2003;348:694-701.
17. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2000;18:3108-14.
18. Ladenstein R, Potschger U, Le Deley MC, et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:3284-91.
19. Paulussen M, Ahrens S, Dunst J, et al. Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2001;19:1818-29.
20. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012;30:4148-54.
21. Yock TI, Krailo M, Fryer CJ, et al. Local control in pelvic Ewing sarcoma: analysis from INT-0091–a report from the Children’s Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:3838-43.
22. Dunst J, Jurgens H, Sauer R, et al. Radiation therapy in Ewing’s sarcoma: an update of the CESS 86 trial. International journal of radiation oncology, biology, physics 1995;32:919-30.
23. Wagner TD, Kobayashi W, Dean S, et al. Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. International journal of radiation oncology, biology, physics 2009;73:259-66.
24. Craft A, Cotterill S, Malcolm A, et al. Ifosfamide-containing chemotherapy in Ewing’s sarcoma: The Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1998;16:3628-33.
25. Krasin MJ, Rodriguez-Galindo C, Billups CA, et al. Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. International journal of radiation oncology, biology, physics 2004;60:830-8.
26. Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical outcomes. International journal of radiation oncology, biology, physics 2012;82:1142-8.
27. Kuttesch JF, Jr., Wexler LH, Marcus RB, et al. Second malignancies after Ewing’s sarcoma: radiation dose-dependency of secondary sarcomas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1996;14:2818-25.
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30. Group TEESNW. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2014;25:iii113-iii23.
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32. Ladenstein R, Pötschger U, Le Deley MC, et al. Primary Disseminated Multifocal Ewing Sarcoma: Results of the Euro-EWING 99 Trial. Journal of Clinical Oncology 2010;28:3284-91.
33. Paulussen M, Ahrens S, Burdach S, et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 1998;9:275-81.
34. Bolling T, Schuck A, Paulussen M, et al. Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors. Toxicity analysis and treatment results of the EICESS-92 trial. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al] 2008;184:193-7.
35. Bernstein ML, Devidas M, Lafreniere D, et al. Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children’s Cancer Group Phase II Study 9457–a report from the Children’s Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:152-9.
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How to Cite this article: Irukulla MM, Joseph DM. Management of Ewing Sarcoma: Current Management and the Role of Radiation Therapy. Journal of  Bone and Soft Tissue Tumors May-Aug 2015;1(1):18-22.

Dr. Monica M. Irukulla
Dr. Monica M. Irukulla
Dr. Deepa M Joseph
Dr. Deepa M Joseph

(Abstract)      (Full Text HTML)      (Download PDF)


 

Ewing Sarcoma: Focus on Medical Management

Vol 1 | Issue 1 | May – August 2015 | page:1-2 | Santosh Valvi, Stewart J Kellie


Author: Santosh Valvi [1,2*], Stewart J Kellie [3,4]

[1]Kids Cancer Centre, Sydney Children’s Hospital, Randwick 2031, New South Wales, Australia
[2] Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick 2031, New South Wales, Australia
[3] Oncology Unit, The Children’s Hospital at Westmead, Westmead 2145, New South Wales, Australia
[4] Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Westmead 2145, New South Wales, Australia

Address of Correspondence
Dr. Santosh Valvi FRACP
Kids Cancer Centre, Sydney Children’s Hospital, Randwick 2031, New South Wales, Australia
Email: santosh.valvi@health.nsw.gov.au


Abstract

The management of Ewing sarcoma has evolved over the last few decades with successive improvement in survival rates. Multidisciplinary management is the key to successful outcomes. Dose intensity of chemotherapy is of vital importance. Local control can be effectively achieved with surgery, radiation therapy or a combination of the two. The choice of appropriate local therapy should be individualized and depends on various factors such as site, size, respectability, expected morbidity, long term effects etc. Metastatic disease remains a significant challenge and optimal therapeutic strategies still need to be defined. Current management and the role of radiation therapy in Ewing sarcoma are reviewed.
Keywords: Ewing sarcoma, radiation therapy, management


Introduction
In 1921, James Ewing reported a group of primary radiosensitive tumors as diffuse endothelioma of bone, believing they arose from the blood vessels of bone tissue [1]. A few years later the noted Boston surgeon, Ernest Codman, referred to this new entity as Ewing sarcoma (EWS) [2]. EWS, a rare malignancy with a strong pediatric predilection, typically presents as a bone tumor [3]. It is the second most common primary malignant bone tumor in children and young adults, following osteosarcoma and accounts for approximately 3% of all childhood malignancies [4].

Epidemiology
Over the last 30 years, the incidence of EWS has remained unchanged at around 3 cases per million per year [5]. With a median age of 15 years, it most commonly occurs in the second decade of life (Fig 1) [6]. There is a slight male predilection (male: female 1.2:1) and Caucasians are much more frequently affected than Asians and Africans [7,8]. Lower extremities are the most common site of bone disease (43%) while extraosseous primary tumors mostly occur in the trunk (32%) (Fig 2). Metastatic disease is present at diagnosis in about 20-25% of patients and affects the lungs, other bones or multiple systems [5,9].

Biology & Pathology
The World Health Organisation (WHO) classification uses EWS/primitive neuroectodermal tumor (PNET) as an inclusive term which encompasses classic EWS, Askin tumor of the thoracic wall, Ewing tumor, peripheral neuroepithelioma, peripheral neuroblastoma, Ewing family of tumors and Ewing sarcoma family of tumors [10]. EWS is derived from a primordial bone marrow-derived mesenchymal stem cell [11,12]. Histologically, EWS is characterised by a monotonous population of small round blue cells with a low mitotic activity of 15-20%. Cytoplasmic glycogen is abundant which gives periodic acid-Schiff (PAS) positivity [13]. The MIC2 gene product, CD99, a surface membrane glycoprotein is overexpressed [14] but it is not specific for EWS. Neural differentiation is evident in the form of positive vimentin in approximately one third of cases.
A reciprocal chromosomal translocation involving the EWSR1 gene on chromosome 22 band q12 combined with any of a number of partner chromosomes is pathognomonic of the diagnosis of EWS. The breakpoint was first cloned in the 1990s [12,15]. Although abnormalities of chromosome 11 are involved in 95% of cases [16], the translocation may involve chromosomes 21, 7 and 17 uncommonly [17,18]. The fusion protein resulting from this chromosomal rearrangement is a potent transcriptional factor which inappropriately activates the target genes, thereby exerting the oncogenic activity.
Other numerical and structural alterations seen in EWS are gains of chromosomes 2, 5, 8, 9, 12, and 15; deletions on the short arm of chromosome 6; the nonreciprocal translocation t(1;16)(q12;q11.2); and trisomy 20 [19,20].

Figure 1: Investigation Workflow for a newly diagnosed Patient with EWS
Figure 1: Investigation Workflow for a newly diagnosed Patient with EWS

Staging
EWS is defined by clinical and imaging techniques as localized when there is no spread beyond the primary site or metastatic when the tumor has disseminated to distant organs. Of all imaging modalities, 18FDG PET-CT has the highest specificity (96%) and sensitivity (92%) [21] and is superior to the traditionally used 99mTc-MDP bone scan for detection of bone metastases except for skull lesions [22]. Current recommendations for staging work-up include CT and/or MRI of the primary tumor, chest CT to detect lung metastases and 18FDG PET-CT for identification of distant metastases [23]. As bone marrow involvement is an independent risk factor [24], marrow biopsy has been an integral part of the initial work-up and is still recommended in ongoing clinical trials [25] (26). But recent studies have questioned the utility of bone marrow biopsy in localized [22,27] and metastatic disease [23].

fig 2

Prognosis
The 5 year survival rate for EWS was less than 10% before the advent of modern chemotherapy [28,29]. Currently, the survival rates are 70% for the patients with localized disease [30] and 30% for the patients with metastatic disease [9]. Among patients with refractory or recurrent disease, fewer than 20% of patients can expect to be long term survivors [31,32].
The presence of metastatic disease at diagnosis remains the most important adverse prognostic factor in EWS [33,34,35,36]. In patients with metastatic disease the site(s) of metastases can have an impact on the outcome. Patients with only lung metastases fare better (event free survival, EFS 29% to 52%) than patients with bone and/or bone marrow involvement (EFS 19%) [37,38] or combined bones and lungs involvement (EFS 8%) (34). Unilateral lung involvement has a better outcome compared with bilateral lung lesions [39].
Younger age (<15 years old) [5,40,41], female gender [42], tumor site (distal extremity better than proximal extremity and pelvis) [9], tumor size (volume less than 200 ml and single dimension less than 8 cm) [43], normal serum lactate dehydrogenase (LDH) levels at diagnosis [44], and decreased metabolic activity on 18FDG PET scan after presurgical chemotherapy [45,46] are associated with a more favourable prognosis.
Complex karyotypic abnormalities or chromosome number less than 50 in tumor cells at diagnosis [19], detection of fusion transcripts by polymerase chain reaction (PCR) in morphologically normal bone marrow [47], p53 protein overexpression, Ki67 expression, loss of 16q [48,49], overexpression of microsomal glutathione S-transferase (associated with doxorubicin resistance [50] may be associated with inferior outcome. Patients with secondary Ewing sarcoma [51] or with a poor response to presurgical chemotherapy [52,53] and patients relapsing less than two years after diagnosis (early) have a poorer prognosis [54].

9

Treatment options
Chemotherapy for a total of 10-12 months before and after local control is common practice [33,55]. Initial chemotherapy aims to shrink the tumor to increase to probability of effective local control. Alkylating agents, mainly ifosfamide and cyclophosphamide and anthracyclines form the chemotherapeutic backbone Etoposide, vincristine and actinomycin-D make up the remainder of the four-to five-drug combination chemotherapy.

Chemotherapy for newly diagnosed patients:
Clinical trials in the early years (pre-1990)
Before 1960s, radiation therapy and surgery were used for the treatment of EWS which provided adequate control of the primary disease but patients invariably died of metastatic disease [56]. Chemotherapy was added based on the hypothesis that, in most cases of apparently localized disease, tumor cells were already disseminated without clinical manifestations. Single chemotherapy agents including cyclophosphamide [57,58,59], vincristine [60], daunorubicin [61] and actinomycin-D [62] were trialled in 1960s with promising results.
From two- to as many as six-drug combinations have been used in various randomized and non-randomized trials for the treatment of EWS. Hustu et al [63] used a first ever combination with vincristine and cyclophosphamide with 80% overall survival. In Europe, the French Society of Pediatric Oncology (SFOP) [64,65,66], the United Kingdom Children’s Cancer Study Group (UKCCSG) [35,67], the Scandinavian Study Group (SSG) [68, 69] and the German/Austrian Cooperative Ewing Sarcoma Study Group (CESS) [70,71] performed early clinical trials. Subsequently, the European Intergroup Cooperative Ewing Sarcoma Study group (EICESS) and the European Ewing Tumor Working Initiative of National Groups (EURO-EWING) continued the trials. In the United States, initially the Intergroup Ewing Sarcoma Study (IESS) group [72,73,74], the Children’s Cancer Group (CCG), the Pediatric Oncology Group (POG) and subsequently the Children’s Oncology Group (COG) conducted trials for EWS.
Four-drug combination chemotherapy including vincristine, actinomycin-D, cyclophosphamide and doxorubicin was universally accepted for the treatment by the early 1980s [75] with survival rates between 36-60%. Ifosfamide and etoposide were identified as effective single agents [76,77] and subsequent studies established a survival benefit of their addition to VACD [78]. National Cancer Institute protocol INT0091 was a randomized trial conducted by the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) from 1988 through 1992. Patients were assigned to receive VACD or VACD plus ifosfamide and etoposide (VACD-IE). In patients without metastatic disease, the five-year EFS for the VACD group was 54% while the same for the VACD-IE group was 69%. These results established VACD-IE as the gold standard for the treatment of localised Ewing sarcoma [30].
Clinical trials for standard risk (SR) and high risk (HR) EWS since 1990
The disease risk stratification into SR and HR has varied depending on the trial but in general SR means localized small tumors (<200 mL), or tumors with a good histological response to preoperative chemotherapy (<10% cells). HR tumors include metastatic tumors, or large localized tumors (>200 mL).
The trials for SR EWS have tried to address the important questions like the superiority of one alkylating agent over the other (cyclophosphamide and ifosfamide) and survival advantage by dose intensification or addition newer chemotherapy agents.

t2

Cyclophosphamide vs Ifosfamide
Historically, cyclophosphamide was used for the treatment of EWS. Promising results were seen with ifosfamide in relapsed patients who did not respond to cyclophosphamide [83]. It was postulated that 9 g/m2 of ifosfamide was equimyelotoxic to 2.1 g/m2 of cyclophosphamide [84]. With the potential for less myelotoxicity and high-dose administration, cyclophosphamide was replaced with ifosfamide in the 1980s. But the results of these non-randomized, single-arm studies were mixed, with one study showing no benefit [66] while others proving superiority of ifosfamide over cyclophosphamide [71,67,69]. With this uncertainty of greater efficacy and long-term renal tubular damage with the cumulative dose of ifosfamide [85], its role in the consolidation treatment of EWS was debated. Two large randomized trials, EICESS-92 [79] and its successor Euro-Ewing99-R1 [80] investigated if cyclophosphamide can replace ifosfamide in the consolidation treatment of standard-risk EWS. The results of these studies confirmed that both the drugs had similar efficacy and though cyclophosphamide was associated with more haematological toxicity, the incidence of renal toxicity was much less as compared to ifosfamide. But the question of superiority of one drug over the other is far from resolved and needs further investigation in light of their efficacy to improve the survival [75].

Standard dose vs dose intensification
To improve the outcome, intensification of chemotherapy drug doses was investigated. One way of achieving dose intensification is by escalating the doses of chemotherapy agents while keeping the interval stable. National Cancer Institute protocol INT0154 used VDC+IE chemotherapy and randomized patients to standard (17 cycles over 48 weeks) or intensified (11 cycles over 30 weeks) arms. This study showed no improvement in the outcome of patients with nonmetastatic disease by dose escalation of alkylating agents (81) which was in contrast to an earlier similar study, IESS-II [74].
AEWS0031 trial investigated the feasibility of dose intensification by interval compression (increased dose density) in patients with localized disease [82]. Patients treated every two weeks (intensified arm) had an improved five-year EFS (73%) compared with the standard arm group receiving chemotherapy every 3 weeks (65%) with no increase in toxicity. Due to its superiority, interval compression is used in many ongoing trials.
The Children’s Oncology Group is currently conducting a phase III randomized trial of adding vincristine, topotecan and cyclophosphamide to standard chemotherapy for patients with localized EWS in an attempt to improve the outcome further [25].
The EICESS-92 study recruited 492 high risk patients of which 157 had metastatic disease at diagnosis. These patients were randomized to receive either VAID or etoposide in addition to VAID (EVAID). Although there was evidence that etoposide had a more pronounced effect in localized HR group, there was no benefit for the patients with metastatic disease with a three-year EFS of 30% [79].
The EURO-EWING99-R3 study enrolled 281 patients with primary disseminated multifocal EWS. 169 patients received the high dose therapy (HDT)/stem cell transplant (SCT) post completion of chemotherapy and local therapy. 3-year EFS for whole cohort was 27% and for patients receiving HDT was 37% [24].

Local therapy
The goal of local therapy is to maximize the local control with minimal morbidity. Surgery and radiation therapy are the two local control modalities employed for EWS. No randomized trials have compared these and as such their relative roles remain controversial [13].
Surgical resection provides information about the amount of tumor necrosis and may be less morbid in the younger patients. Radiation therapy is also associated with the development of second malignant neoplasms in a dose and time dependent manner [86]. A retrospective analysis of patients treated on three consecutive clinical trials for localized EWS showed that the risk of local failure was greater for patients receiving definitive radiotherapy but the EFS and OS were comparable for both surgery and radiation as local control modalities [87]. Microscopically complete surgical resection of localised disease remains the goal of neoadjuvant (or upfront) chemotherapy. Large bone defects after the surgery may be reconstructed using autogenous or allogenic bone grafts and endoprosthetic replacements [13]. Radiation therapy may be used as the main modality of primary disease control in patients with axial or unresectable primary disease. Careful consideration about the use of radiation, dose and volume is required, particularly in younger patients.
In patients with lung metastases, upfront whole-lung radiation may be used irrespective of the radiographic response following chemotherapy [88]. The results of the recently concluded Euro-EWING99 R2 pulmonary (AEWS0331) study which compared the HDT and peripheral blood stem cell (PBSC) rescue with the standard chemotherapy and whole lung irradiation are awaited. A multivariate analysis of the R3 arm of this trial including patients with metastatic disease emphasized the importance of aggressive local control of primary and metastatic sites. The EFS was higher with combined surgery and radiation compared to either modality alone or no local control [89].

High-dose therapy (HDT) and stem cell transplantation (SCT)
Despite advances in multimodal therapy of EWS, there remains a group of patients with high risk of treatment failure. These are primarily the patients with metastatic disease or with extensive unresectable localized disease and patients with a poor response to chemotherapy. This group has a poor 20%-30% disease free survival (DFS) [90,91]. Although conventional chemotherapy regimens induce remission, patients with metastatic disease relapse after a median of one to two years after completion of therapy owing to minimal residual or metastatic disease (MRD/MMD). In the 1980s trials investigating the role of SCT to consolidate remission by reduction of MRD/MMD began. The results of the initial National Cancer Institute (NCI) studies investigating total body irradiation (TBI) with autologous bone marrow transplant (ABMT) showed no improvement in survival [92]. Since then multiple reports have been published of consolidation using HDT followed by SCT but its role in the treatment of EWS has yet to be conclusively determined [93].

Melphalan vs busulfan-based conditioning regimens
Response to melphalan-based HDT has been variable. Some studies showed no additional benefit with poor survival rates between 5%-27% [34,90,94,95] while others [96,97,98] reported improved survival rates of 45%-50%. As use of high-dose busulfan combined with melphalan or other agents has shown promising results with survival rates between 36%-60% [99,100,101,102,103,104], these regimens have been widely used in high-risk patients.

Role of total-body irradiation (TBI)
Use of TBI during the consolidation phase had no survival advantage but increased the incidence of toxicity [92,94]. Two Meta European Intergroup Cooperative Ewing Sarcoma Studies (MetaEICESS) assessed the role of TBI in consolidation treatment. Patients received systemic consolidation in the form of hyperfractionated TBI with melphalan/etoposide in the first HyperME study or two times the melphalan/etoposide in the second TandemME study. EFS were similar in both studies while TBI containing regimen was associated with a higher incidence of toxicity [105]. In conclusion, although EWS is a radiosensitive tumor, there is limited role of TBI in its treatment because of poor efficacy and increased toxicity.

Autologous vs allogenic BMT
Allogeneic transplant may overcome the concerns with tumor cell contamination of stem cell products during autologous transplant [106] and have a potential of graft-versus-tumor (GVT) effect with improved survival. A retrospective analysis of the MetaEICESS study data showed that the EFS was 25% after autologous and 20% after allogeneic transplant [54]. As there was increased incidence of toxicity and no evidence of GVT effect after allogeneic transplant, there seems to be no advantage of allogeneic over autologous transplant.

Chemotherapy for recurrent EWS
Although around 80% of relapses occur within 2 years of initial diagnosis [107], late relapses occurring more than five years from the initial diagnosis are more common in EWS than any other pediatric solid tumors. The Childhood Cancer Survivor Study (108) retrospectively assessed more than 12,700 childhood cancer survivors and concluded that survivors with EWS were at a higher risk of late recurrence, 5-20 years after the diagnosis, than survivors with acute lymphoblastic leukemia. Time to relapse is an important prognostic factor with recurrences occurring within two years of initial diagnosis having worse five-year survival of 7% compared to 30% for patients relapsing after two years [32,107]. Number of recurrences also impacts the outcome with multiple metastatic recurrences having worse prognosis than isolated local or metastatic recurrence [107]. There is no established treatment for these patients and the preferred approach is to combine multi-agent chemotherapy with local modality of surgery and/or radiotherapy [109,110].
High dose Ifosfamide alone [111] or with carboplatin and etoposide (ICE) has been commonly used with survival rates between 29%-33% [112,113]. Cyclophosphamide and topotecan combination achieved response rates of 23%-44% with low toxicity and an added advantage of outpatient administration [114,115] but with a small median duration of response of 8 months [116]. Response rates of 29% to 68% and median time to progression of 3 to 8.5 months were seen with irinotecan and temozolomide [117,118,119,120]. Diarrhea was a troublesome complication which was managed effectively with oral cephalosporins. The combination was otherwise well tolerated. Although gemcitabine and docetaxel showed activity in one study [121], the results were not confirmed by subsequent studies. [122].
In case of recurrent EWS, the addition of HDT to salvage regimens is controversial. Some studies showed a good response in specific groups of patients who responded to relapse therapy and underwent HDT with OS rates of 53 to 66% [123,124], but most of the reports indicate HDT does not improve prognosis [54,125,126].

Targeted therapy for EWS
Tyrosine kinase (TK) inhibitors
TKs are important modulators of growth factor signaling and play a critical role in tumor growth. TK inhibitors are used alone or in combination with conventional chemotherapy agents in treatment of various cancers (127). A number of TK inhibitors have been tried in EWS with variable response.

Insulin-like growth factor 1 receptor (IGF1R) inhibitors
IGF1R is necessary for growth and development of normal as well as cancer cells [128]. With promising pre-clinical results showing IGF1R inhibition in EWS cell lines and xenografts [129], more than 25 agents inhibiting IGF1R are currently under investigation [130].
IGF1R monoclonal antibodies including R1507 (131), figitumumab [132], ganitumab (AMG479) [133], cixutumumab [134,135], and robatumumab (SCH-717454) [136] have shown activity in early phase clinical trials with response rates ranging from 6-14% and a favourable safety profile. But the results of the phase II studies were less impressive compared with the promising preclinical and early clinical data [137]. Small-molecule inhibitors of IGF1R such as GSK1838705A [138], GSK1904529A [139], BMS-754807 [140], and INSM-18 [141] are also in preclinical and clinical development.
Phase II clinical trials of imatinib, a TK inhibitor of the BCR-ABL fusion protein [142,143,144] and dasatinib, a multitargeted TK inhibitor [145] showed no efficacy in EWS.

Biologic agents
Angiogenesis inhibitors
Neovascularization plays a critical role in the pathogenesis of EWS [146] and targeting vascular endothelial growth factor (VEGF) may interfere with vasculogenesis, providing a novel therapeutic approach [147]. A phase I study [148] and a randomized phase II trial [149] conducted by the Children’s Oncology Group have shown the feasibility and tolerability of bevacizumab in EWS patients. Another phase II study investigated the role of vinblastine and celecoxib as angiogenesis inhibitors in combination with the standard chemotherapy (150). Although the feasiblity of this combination was established, there were significant pulmonary and bladder toxicities.

Histone deacetylase (HDAC) inhibitors
HDAC inhibition suppresses EWS-FLI1 expression and may represent a novel therapeutic target for EWS (151).

Mammalian target of rapamycin (mTOR) inhibitors
MTOR is a serine/threonine kinase with critical role in protein synthesis, cell growth and proliferation regulation. mTOR inhibitors have shown activity in preclinical models. A phase I study of temsirolimus, irinotecan and temozolomide demonstrated efficacy and tolerability [152]. But another phase II study of temsirolimus with cixutumumab did not show any objective response despite the encouraging preclinical data [153]. Ridaforolimus was associated with a statistically significant but clinically small benefit on PFS [154].

Aurora A kinase inhibitors
Although alisertib (MLN8237), an Aurora A kinase inhibitor produced promising results in the Pediatric Preclinical Testing Program [155], a recently concluded Children’s Oncology Group phase II trial failed to establish its efficacy in EWS [156].

Hedgehog pathway modulation
Arsenic trioxide was effective in inhibiting EWS growth in preclinical cell culture models by targeting p38(MAPK) and c-Jun N-terminal kinase [157]. These observations warrant further investigation.

Bisphosphonates
Zoledronic acid acts by inducing apoptosis by upregulating osteoprotegerin which was the basis of activity seen in EWS pre-clinical models [158,159]. However, confirmatory clinical trials have not been performed.

Immune therapy
Interleukin-15-activated natural killer (NK) cells combined with HDAC inhibitors improve immune recognition of therapy-sensitive and –resistant EWS and sensitize for NK cell cytotoxicity [160]. Allogenic NK cells have shown activity against EWS cells on their own [161].

EWS-FLI1 targeting
Targeting the EWS-FLI1 fusion protein or its key signalling pathway is another attractive approach [162]. YK-4279, a small molecule inhibitor of EWS-FLI1 protein activity [163,164], mithramycin, a chemotherapy drug [165] and midostaurin (PKC412), a multikinase inhibitor [166] have shown activity in preclinical models.


 Conclusion 

Many advances have been made in the management of EWS since its first description almost 100 years ago. Molecular and imaging techniques are progressing at a rapid pace allowing for newer insights into the biology of this disease. From radiation therapy alone, the treatment has evolved to include multiple modalities. The outcome for localized disease has improved dramatically but more needs to be done for patients with metastatic or recurrent EWS. Targeted therapies may offer some hope for the latter group.


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How to Cite this article: Valvi S & Kellie SJ. Ewing Sarcoma: Focus on Medical Management. Journal of  Bone and Soft Tissue Tumors May-Aug 2015;1(1):8-17.

Dr. Santosh Valvi
Dr. Santosh Valvi
Dr. Stewart J Kellie
Dr. Stewart J Kellie

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