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

May 10, 2015

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. […]

From TMH-NICE to ResTOR: An Eventful Journey A Treatise of developing a Tumor Megaprosthesis

May 10, 2015

Vol 1 | Issue 1 | May – August 2015 | page:40-44 | Ravi Sarangapani[1*]. Author: Ravi Sarangapani[1*]. [1]Development & Quality Director Adler Mediequip Pvt. Ltd, Pune, India. Address of Correspondence Mr. Ravi Sarangapani Development & Quality Director, Adler Mediequip Pvt. Ltd., Sushrut House, Survey 288, Next to MIDC Hinjewadi Phase II, At. Mann, Tal. Mulshi, […]

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

May 10, 2015

From TMH-NICE to ResTOR: An Eventful Journey A Treatise of developing a Tumor Megaprosthesis

May 10, 2015

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

May 10, 2015

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.
12. Volker T, Denecke T, Steffen I, et al. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007;25:5435-41.
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.
28. Donaldson SS. Ewing sarcoma: radiation dose and target volume. Pediatric blood & cancer 2004;42:471-6.
29. Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. International journal of radiation oncology, biology, physics 2003;55:168-77.
30. Group TEESNW. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2014;25:iii113-iii23.
31. 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. The New England journal of medicine 2003;348:694-701.
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.
36. Stahl M, Ranft A, Paulussen M, et al. Risk of recurrence and survival after relapse in patients with Ewing sarcoma. Pediatric blood & cancer 2011;57:549-53.
37. Saylors RL, 3rd, Stine KC, Sullivan J, et al. Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2001;19:3463-9.
38. Wagner LM, McAllister N, Goldsby RE, et al. Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Pediatric blood & cancer 2007;48:132-9.
39. Mora J, Cruz CO, Parareda A, de Torres C. Treatment of relapsed/refractory pediatric sarcomas with gemcitabine and docetaxel. Journal of pediatric hematology/oncology 2009;31:723-9.
40. Biswas B, Rastogi S, Khan SA, et al. Developing a prognostic model for localized Ewing sarcoma family of tumors: A single institutional experience of 224 cases treated with uniform chemotherapy protocol. Journal of surgical oncology 2015;111:683-9.
41. Qureshi S, Laskar S, Kembhavi S, et al. Extraskeletal Ewing sarcoma in children and adolescents: impact of narrow but negative surgical margin. Pediatr Surg Int 2013;29:1303-9.
42. Tiwari A, Gupta H, Jain S, Kapoor G. Outcome of multimodality treatment of Ewing’s sarcoma of the extremities. Indian journal of orthopaedics 2010;44:378-83.

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. Deepa M Joseph

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

From TMH-NICE to ResTOR: An Eventful Journey A Treatise of developing a Tumor Megaprosthesis

May 10, 2015

Vol 1 | Issue 1 | May – August 2015 | page:40-44 | Ravi Sarangapani[1*].

Author: Ravi Sarangapani[1*].

[1]Development & Quality Director Adler Mediequip Pvt. Ltd, Pune, India.

Address of Correspondence
Mr. Ravi Sarangapani
Development & Quality Director, Adler Mediequip Pvt. Ltd., Sushrut House, Survey 288,
Next to MIDC Hinjewadi Phase II, At. Mann, Tal. Mulshi, Pune 411057, Maharashtra, India.
Email: ravi-sarangapani@adlermediequip.com

Abstract

The primary option for patients with osteosarcoma for many decades was an amputation to save life. A review in 1986 demonstrated that limb salvage surgery was as safe as an amputation and provided the evidence to change the surgical management of these patients to limb salvage surgery and megaprosthetic reconstruction. International developments since the 1990s formed the backdrop for the evolution of limb salvage surgery in India. Initial obstacles faced in India were that of patient affordability. In the late nineties, Dr. Ajay Puri and Dr. Manish Agarwal from the orthopaedic oncology department of Tata Memorial Hospital (Mumbai) in association with Sushrut-Adler initiated development of an indigenous limb salvage megaprosthesis (the TMH-NICE). This had to be a low-cost prosthesis by all means. This surgeon industry partnership over time led to overcoming many challenges and failures and continuous learning both on the clinical and engineering fronts resulting in the evolution of the ResTOR modular resection prosthesis system. This journey continues with improvements and modernization of the system contributing to cost-effective limb salvage surgery to patients in India and a number of other countries.
Keywords: Bone Tumor, Osteosarcoma, Limb Salvage, TMH-NICE, ResTOR.

Introduction

Although bone tumours form less than 1% of cancers in adults, they account for 3-5% of cancers in children with osteosarcoma being the most commonly diagnosed form of primary malignant bone tumours, followed by Ewing’s sarcoma [1]. These tumours represent the fourth most common type of cancer in patients under the age of 25.
The primary recourse for these patients for many decades was an amputation with an emphasis on sacrifice of the limb to save life. It was a landmark retrospective review by Simon et al in 1986 that demonstrated that limb salvage surgery was as safe as an amputation and provided the evidence that enabled surgeons to change the surgical management of these patients to limb salvage surgery and megaprosthetic reconstruction [2]. Enneking’s work related to staging of the disease [3] and the importance of surgical margins [4] significantly contributed to the development of limb-salvage surgery.
Not unlike most modern developments in the medical field, the clinical research and evolution of this treatment modality originated in the western world and resulted in limb salvage surgery with a megaprosthetic reconstruction slowly acquiring the status of “standard of care” for the majority of bone tumour patients through the 1990s. These International developments form the backdrop for what can aptly be termed the evolution of limb salvage surgery in India.

Indian Perspective
In late 1999, the Tata Memorial Hospital which is a pioneering initiative in the field of cancer care and research, originally commissioned in 1941, decided to augment their orthopaedic oncology service by bringing in a specialist orthopaedic surgeon to work with Dr. Badhwar, the then surgical oncologist who was also handling bone tumours. This resulted in Dr. Ajay Puri joining the oncology service of Tata Memorial in November 1999. Fate perhaps conspired in creating what would turn out to be a great team as Dr. Badhwar unfortunately took ill and the Tata Memorial management decided to recruit a second orthopaedic surgeon in the form of Dr. Manish Agarwal who came on board in January 2000. (read all about these happenings in the guest editorial by Dr A. Puri in this very issue [5]). Thus, two young and enthusiastic orthopaedic surgeons, well recognized in Mumbai for the contribution to the trauma service at major public hospitals, came on board to develop the orthopaedic oncology service at the Tata Memorial Hospital.
What Dr. Puri and Dr. Agarwal lacked in formal oncology training, they more than made up with their eagerness to learn, their obvious intelligence and most of all their dedication and commitment to make a difference to the lives of patients’ afflicted with this dreaded disease. The challenges they faced were numerous and perhaps too many to enlist; a gigantic workload of patients, a general lack of awareness of bone tumours and their management in the community, patient expectations, sometimes unrealistic to save limbs considering the social stigma attached to amputation considering the general difficulties faced by amputees in a developing country like India [6] and above all fast-advancing international developments in the management of bone tumours and perhaps frustration at not being able to offer the best standard of care to their patients. What they had in their favour was the backing and belief of the Institution, excellent infrastructure and the potential to form a world-class multi-disciplinary team.
As the development of the orthopaedic oncology service in Tata Memorial Hospital in the last fifteen years amply demonstrates, the selection panel which included Prof. Laud and Prof. Bawdekar and Dr. Dinshaw, the then Director of the Institution who also created these positions, did well. The young team, not fazed by the enormity of the challenges confronting them, set about tackling the problems they saw in a methodical and systematic manner.
One of their first priorities was to bring themselves up to date with the current international standard of care which involved offering their patients the option of limb salvage surgery with megaprosthetic reconstruction. As they started efforts to implement this initiative, they were faced with an obstacle not uncommon to the developing world, that of patient affordability. As so eloquently described by Dr. Agarwal and Dr. Puri, “Though all these exciting developments occurred in the West, in our own country limb salvage was still a difficult proposition. Chemotherapeutic drugs were very expensive, endoprosthesis unaffordable, ignorance widespread and the patients poor” [7]. This situation resulted in the team not being able to effectively offer the option of a good quality mega-prosthetic replacement to even ten patients of the approximately 200 new cases [7] or primary malignant bone tumours presenting to the hospital at that time.
It is said that experience can sometimes be a hindrance and the enthusiasm of youth goes a long way in surmounting seemingly impossible hurdles. The young team refused to be dismayed with these setbacks and set about convincing the management of the Sushrut-Adler Group (currently Adler Mediequip Pvt. Ltd., a Smith & Nephew subsidiary) of their mission to save limbs and improve the quality of life of these patients. It is testimony to their eloquence and persuasive skills that the Sushrut-Adler management adopted the surgeons’ goals as their own and agreed to invest the time and resources needed in the service of these patients, in a situation where a financially viable business was nowhere in sight. Thus began the evolutionary journey which took this Indian designed, Made-in-India implant from the early hesitant efforts of the TMH-NICE to the modular resection system, the ResTOR.
The Sushrut-Adler team commenced work, fabricating implants to patient dimensions in a surgeon-led design effort that was blessed by the Institutional Review Board of the Tata Memorial Hospital. In keeping with the objectives defined by Dr. Puri and Dr. Agarwal, the primary consideration was their estimate of what patient’s would be able to afford based on their understanding of the financial situation of these patients. This resulted in certain choices of material and fabrication methods which in hindsight were incorrect choices driven by the early “cost” objectives.
The early period between the years 2000 to 2002 featured implants that were almost entirely fabricated in a custom-basis to patient specific dimensions specified by the surgeon team. The rather crude initial design without femoral condyles (Fig.1a) quickly evolved into a more refined femoral shape (Fig. 1b) under the guidance of the surgeons. These implants were manufactured from 316L stainless steel, the material choice dictated by easy availability, ease of fabrication and cost considerations. The condylar region with the patient specific resection length was welded to the straight intramedullary stem which featured a male thread screwed into the resection shaft. Longitudinal grooves were machined into the stem to inter-digitate with bone cement and a valgus angle of 7 degrees was incorporated. The hinge pin was locked into place using a simple slotted screw.
In a first hint of problems to be faced in the future near the level of the resection or the intramedullary stem junction, a case of failure was encountered in the implant at the location close to the resection level which was fabricated as a threaded junction (Fig.2). This failure was similar to the failure of a humeral implant reported by Bos et al with a fracture at the base of a threaded stem [8] due to stress concentration and a structural weakness.
As the number of operated patients increased, the surgeons began to note certain repetitive dimensions that could be standardized. These were the Antero-posterior and Medio-lateral dimensions of the femoral and tibial condyles. Later on as the project progressed, other dimensions including stem diameters, lengths and types, lengths of resection segments and spacers would get standardized to enable modularity. The standardized condylar dimensions in 2002 enabled the femoral condylar section of the implant to be “cast” in 316L stainless steel, a development that featured in the implants manufactured in the period 2002-2004. The adoption of casting enabled some reduction in lead time by reducing the rather extensive condylar machining that was required earlier. As anatomical understanding grew, intramedullary stems evolved from a straight design to including an option with an anatomical curvature (Fig. 3).

It was also in this period that the first instrument set (Fig. 4) was created. Notably, nearly all surgeries performed by the surgeon team till that time had been carried out by using general orthopaedic instrumentation. With increasing experience came the realization that specifically designed instrumentation would be needed. Also contributing to this development was the fledgling thought in the minds of the surgeons that this system might go out of Tata Memorial Hospital some day in the future and it was important to create instrumentation that would enable easier use of this system by average surgeons. In late 2004, a circumferential groove oriented transversely (Fig. 5a) was added to the stem with the thought of improving cement fixation. This change resulted in early failure at the location of the groove (Fig.5b) and was quickly abandoned.

It was in early 2004 that the project began to face what would turn out to be its most major challenge, the incidence of mechanical failure predominantly located at the intramedullary stem-bone junction (Fig. 6). As subsequently reported in 2010 by Dr. Agarwal and Dr. Puri, there were 22 mechanical failures in 183 patients (12.02%) predominantly at the stem-collar junction with an average time to failure of 38 months [9]. While these failures initially unnerved the team working on the project, reviews of literature reveal that such failures were by no means uncommon and had been faced and continue to be faced by each such group of surgeons and engineers working in the field of limb salvage. Biau et al reported mechanical failures including stem fractures and hinge pin failures in 7 out of 91 patients (7.7%) operated between 1972 and 1994 [10]. More recently in 2013, Nakamura et al [11] reporting on the Japanese early experience with the Kyocera limb salvage system revealed mechanical failures in 7 out of 82 distal femur resections (8.53%) including predominantly stem failures and one tibial tray breakage.
While the stem failures were beginning to present themselves and were being investigated, a number of refinements continued to be made in the period since 2004. The tibial baseplate acquired its rounded geometry (Fig. 7a) conforming to the tibial plateau. The important alignment mark on the stem was added (Fig. 7b) to enable correct rotational alignment of the implant. In mid-2005, bushes and a bumper manufactured from UHMWPE were introduced into the design (Fig. 7c) to minimize metal on metal articulation.
In early 2006, based on initial investigations into the failure location which was centered near the stem-bone junction, a decision was made to introduce a gradual change of diameter in the region and reduce stress concentration by introducing a fillet (Fig. 7d) with a liberal radius of curvature. This change was done based on standard good design principles and was perhaps the first engineering input to what had essentially been a surgeon-led project from inception.

With all the changes and refinements that had taken place over the years (Fig. 8a,b), the system in mid-2006 was fairly standardized based on a large patient experience of nearly 260 cases, standard condylar and intra-medullary dimensions, UHMWPE bushes and bumpers and a reliable hinge locking mechanism.
What however concerned the entire team was that the intramedullary stems continued to fail at the stem-bone junction and even the reduced stress concentration with the filleted design did not seem to work (Fig. 8c).
It was at this point that the engineering team at Sushrut-Adler brought in a new level of seriousness and application to understanding this problem better. Literature was extensively reviewed [12,13,14] to develop a better appreciation of the forces the implant was being subjected to. Resultant stresses on the implant cross sections were calculated and analyzed with reference to the materials being used. Based on the analytical work, it was clear that the stainless steel being used for these implants did not have the capability to withstand the continuous stresses being imposed on this implant in normal patient activities in the medium to long term. Better materials were needed.The team opted for titanium alloy as the material of choice for the ramedullary stems as a material with no biocompatibility issues given its long history of successful clinical use, the ability of the material to withstand the imposed stresses in this application with an adequate factor of safety and the lower modulus of elasticity which was perceived as a possible advantage.
Titanium alloy is known to have its own difficulties in processing and is not an easy material from a manufacturing standpoint. Fortunately, the engineering and manufacturing teams at Sushrut-Adler had developed strong experience in working with this alloy due to their previous history with successful development and commercialization of spine implants manufactured from titanium alloy and these challenges were not difficult to overcome.
The change of materials and the expected solution to the difficult stem failure issue thus opened the way for the team of surgeons and the Sushrut-Adler engineers to take the next step of modularizing the system paving the way for more widespread use. The difficulties of custom-manufacturing implants by this time were well understood and the constraint imposed on an operating surgeon working with an implant of fixed size was not desirable. Modularity enabled a surgeon to intra-operatively select the most optimum surgical margin for the excision with no concerns about having an implant size that would adapt to the length of the resection.
The surgeons’ need for modularity resulted in many months of manufacturing trials at Sushrut-Adler as the necessary self-locking tapers for the modular components were designed and proven through the manufacturing process.
The final standardized condylar dimensions enabled the team to opt for superior Cobalt Chrome alloy investment castings for the condylar components thus gaining better articulation properties with the UHMWPE components.
The culmination of all these efforts resulted in the first patient implanted with the ResTOR modular resection prosthesis in a limb salvage procedure in late 2006. The modular system was commercialized in early 2007 for distal femur and proximal tibia resections. The addition of an upper limb system and a proximal femur resection system over the next few years enabled a complete portfolio of solutions.
It may be argued, with hindsight, that the inception of this project in 1999-2000 was with a compromised implant. However, as cogently argued by Dr. Agarwal ten years later [9], many patients benefited even with these compromised implants, the failure rate of around 15% was not viewed as catastrophic and was considered acceptable in a situation where an expensive implant was not an option and where amputation or rotationplasty would have been the only alternatives for the patient. The limb salvage procedure allowed many children to continue with education and adults to remain employed. Icing on the cake came in the form of the prestigious Golden Peacock Innovation Award in 2010 which recognized this as a major health-care initiative.
The ResTOR modular resection prosthesis system since 2007 has contributed to cost-effective limb salvage surgery of more than 2000 patients in India and a number of other countries [17] with prosthesis survivorship rates comparable to those reported in literature [15,16]. As a case in point, the Tata Memorial experience of 88% implant survivorship at five years with total femoral replacement [16], a specially challenging procedure with extensive resection does great credit to the team of surgeons and engineers who worked on this project. As implant survivorship improves and a greater number of patients experience disease-free survivorship with continuously improving surgeon experience, the ResTOR team continues to face newer challenges related to the increased demands on the implant.
While many improvements have been made and will continue to be made, as global experience with limb salvage implants has shown, the demands placed on these implants are immense and the way forward promises an abundance of challenges to be faced and problems to be solved.

Note

The author was privileged to be associated with this program right from inception till date and will remain forever grateful for the opportunities this program has provided to learn, develop and evolve. The team of engineers who have contributed at various stages are too numerous to name and their efforts will always be remembered and recognized by the surgeons who care for patients with these difficult conditions..

References

1. Mirabello L, Troisi RJ, Savage SA. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer. 2009 Jul 1;125(1):229-34..
2. Simon MA, Aschliman MA, Thomas N, Mankin HJ. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am. 1986 Dec;68(9):1331-7.
3. Enneking WF, Spanier SS, Goodman MA. A System for the surgical staging of musculo-skeletal sarcoma. Clin. Orthop., 153;106-120, 1980.
4. Springfield DS, Schmidt R, Graham-Pole J, Marcus RB Jr, Spanier SS, Enneking WF. Surgical treatment for osteosarcoma. J Bone Joint Surg Am. 1988 Sep;70(8):1124-30.
5. Puri A. The “ODYSSEY”: “Orthopaedic Oncology” – My journey thus far! Journal of Bone and Soft Tissue Tumors May-Aug 2015; 1(1):3-5
6. Agarwal M, Anchan C, Shah M, Puri A, Pai S. Limb salvage surgery for osteosarcoma: effective low-cost treatment. Clin Orthop Relat Res. 2007 Jun;459:82-91.
7. Agarwal M, Puri A. Limb Salvage for malignant primary bone tumours: current status with a review of literature. Indian J Surg 2003;65:354-60.
8. Bos G, Sim F, Pritchard D, Shives T, Rock M, Askew L, Chao E. Prosthetic replacement of the proximal humerus. Clin Orthop Relat Res. 1987 Nov;(224):178-91.
9. Agarwal M, Gulia A, Ravi B, Ghyar R, Puri A. Revision of broken knee megaprostheses: new solution to old problems. Clin Orthop Relat Res. 2010 Nov;468(11):2904-13..
10. Biau D, Faure F, Katsahian S, Jeanrot C, Tomeno B, Anract P. Survival of total knee replacement with a megaprosthesis after bone tumor resection. J Bone Joint Surg Am. 2006 Jun;88(6):1285-93.
11. Nakamura T, Matsumine A, Uchida A, Kawai A, Nishida Y, Kunisada T, Araki N, Sugiura H, Tomita M, Yokouchi M, Ueda T, Sudo A. Clinical outcomes of Kyocera Modular Limb Salvage system after resection of bone sarcoma of the distal part of the femur: the Japanese Musculoskeletal Oncology Group study. Int Orthop. 2014 Apr;38(4):825-30.
12. Perry J, Antonelli D, Ford W. Analysis of knee-joint forces during flexed-knee stance. J Bone Joint Surg Am. 1975 Oct;57(7):961-7.
13. Paul JP. Approaches to Design – Force actions transmitted by joints in the human body. Proc. R. Soc. Lond. B. 1976; 192: 163-172.
14. Taylor SJ, Walker PS, Perry JS, Cannon SR, Woledge R. The forces in the distal femur and the knee during walking and other activities measured by telemetry. J Arthroplasty. 1998 Jun;13(4):428-37..
15. Puri A, Gulia A. The results of total humeral replacement following excision for primary bone tumour. J Bone Joint Surg Br. 2012 Sep;94(9):1277-81..
16. Puri A, Gulia A, Chan WH. Functional and oncologic outcomes after excision of the total femur in primary bone tumors: Results with a low cost total femur prosthesis. Indian J Orthop. 2012 Jul;46(4):470-4.
17. Data on file at Adler.

How to Cite this article: Sarangapani R. From TMH-NICE to ResTOR: An Eventful Journey. Journal of Bone and Soft Tissue Tumors May-Aug 2015; 1(1):40-44.

: Dr. Ravi Sarangapani

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

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

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