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Journal of Bone and Soft Tissue Tumors (JBST) is the official Journal of The Indian Musculo Skeletal Oncology Society
From TMH-NICE to ResTOR: An Eventful Journey A Treatise of developing a Tumor Megaprosthesis
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.
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.
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The “ODYSSEY”: “Orthopaedic Oncology” My journey thus far!
Vol 1 | Issue 1 | May – August 2015 | page:3-5 | Dr Ajay Puri.
Author: Dr Ajay Puri.
Chief – Orthopaedic Oncology.
Professor & Head – Surgical Oncology, Tata Memorial Centre.
President – Indian Musculo Skeletal Oncology Society,
Chairman – Indian Orthopaedic Association (Oncology)
President Elect – Asia Pacific Musculo Skeletal Oncology Society.
Address of Correspondence
Dr. Ajay Puri.
Email: docpuri@gmail.com
Guest Editorial:The “ODYSSEY”: “Orthopaedic Oncology” My journey thus far!
“The Odyssey is one of two major ancient Greek epic poems attributed to Homer. It centres on Odysseus and describes his journey home after the fall of Troy. It takes Odysseus ten years and multiple trials and tribulations as he seeks to return after the ten-year Trojan War.”
Circa 1999. Well ensconced as Associate Professor in one of Mumbai’s premier teaching University Hospitals living life in my “comfort zone” I was unaware of the cosmic forces building up that were soon to bring about a major upheaval in my professional career. An advertisement brought to my notice by a colleague for an “orthopaedic oncologist” in India’s premier oncology centre triggered a chain of events that I could have little foreseen. To most of us “routine” orthopaedic surgeons, orthopaedic oncology in the last millennium was a dark and forbidding battleground littered with countless mines all waiting to explode in the faces of those who were foolish enough to walk down that path. Besides the occasional giant cell tumor seen infrequently, the little I knew of this “unexplored specialty” was from the lectures heard at meetings where the wise man from the North propounded the theory of “God’s foresight that gave us two fibulae for reconstruction”, equally forcefully countered by the “mega” surgeon from the South who emphatically put forward the benefits of huge metallic monsters for reconstruction that functioned in lieu of our God given bones. [1, 2] To me as a youngster all this was as fascinating and farfetched as “Star Wars” because I never expected to walk down this road where “few men had gone before”.
Having had this “fateful” advertisement brought to my notice and more for lack of an alternate opportunity at adventure rather than a belief in choosing this as “the” career option I ventured to appear for this interview. Sports psychologists will go blue in the face trying to drill into their wards theories about “just enjoy the game” and “don’t let the pressure get to you and you will perform better”. With no pressure to perform, secure in the knowledge that I had a faculty position already and buoyed by the cockiness that was inherent in most young orthopaedic surgeons of my generation, the “enjoyable” interview went like a breeze. Lo and behold, “unexpectedly” I had an appointment letter in my hand to venture into this minefield.
Then is when the “pressure” set in. Should I leave my “comfort” zone to try and navigate this minefield? “Fools rush in – where angels fear to tread”. Angel I definitely was not, but a fool…….?
…………And I became the first orthopaedic oncologist to be appointed as full time faculty by Tata Memorial Hospital. I was joined a few months later by a colleague, a lecturer from the adjoining KEM hospital – Dr. MG Agarwal and together we set about navigating these stormy seas. Apart from the complexity of these “first time” surgeries one of the main obstacles that we encountered was the lack of a credible prosthesis for reconstructing large defects after resection. Though individual surgeons earlier had their prosthesis manufactured by local fabricators no national implant company had envisaged interest in these previously, either because of lack of numbers or the absence of an opportunity to develop a prosthesis with surgeon inputs. Armed with little more than the enthusiasm of the “new convert” we set up a collaboration with Sushrut, an implant manufacturer with whom I had the opportunity earlier to help develop their spine and trauma implants while working at “Sion” hospital. The absence of stringent regulatory requirements facilitated rapid development which would otherwise have been a lot slower in today’s era. The TMH –NICE (Tata Memorial Hospital – New Indigenous Customised Endoprosthesis) a custom prosthesis, individually manufactured for each patient was the result of this collaboration.[3] Over a decade, based on our clinical experience and increasing understanding of biomechanics the TMH –NICE metamorphosed into the “ResTOR”. This “off the shelf” modular prosthesis can now reconstruct whole bones and offers a cost effective alternative in many Asian and African countries.[4, 5] Along the way we also practised and refined numerous biological reconstructions.[6, 7] These offered alternative options that were more durable, universally applicable and easier to implement in financially constrained situations. The adrenaline pumping pelvis surgeries; fearful bloodbaths initially, gradually transformed into more controlled battles. We learned to reconstruct these large pelvic resections with options more suited for squatting and sitting cross legged, “activities of daily living” inherent to our patients.[8] Yes, there were complications and disasters. While we hopefully learned from these we did not allow them to overshadow our enthusiasm and possibly were the first believers of the “acche din aayenge” philosophy which encouraged us to keep moving ahead. While benefiting from the published experience of “western” literature we learned to innovate and develop methods and techniques more suited to our own our local socio-economic milieu.
We were fortunate that the environment of the institution we worked in was steeped in the culture of “multi-disciplinary” management, the essence of successful treatment of any cancer. We were easily able to implement “joint clinics” where patients benefited from a “one stop window” where all specialties pooled in their expertise to decide the optimum treatment of a particular case. The concept of our weekly ORP “ortho – radio – path” diagnostic meeting to discuss difficult diagnostic lesions has been the genesis of the hugely popular musculo skeletal oncology ORP gatherings that have been organised all across the country over the last decade or so.
Besides service, “education” has been a core component of the philosophy of the institute that gave me this opportunity to practise the art and science of musculoskeletal oncology. We began by training post M.S. “fellows”. As there was no formal program or rigid curriculum they spent varying amounts of time with us based on their endurance and ability to last the course and tolerate my idiosyncrasies. It is a matter of great pride now to see most of them as well established proponents of “orthopaedic oncology” in various parts of the country. Publishing our results in international peer reviewed journals and presentations at various international meetings helped establish the unit as a credible centre for bone and soft tissue tumors. This drew various international visitors all keen to experience the “large volumes” unlikely to be seen in most other global centres, further enhancing the exposure of the Indian musculoskeletal oncology fraternity on a global platform.[9] The earlier informal training has now formalised into a 2 year recognised “orthopaedic oncology fellowship” program, the only one of its kind in the country.
In ancient Roman religion and myth, Janus is the god of beginnings and transitions. He is usually depicted as having two faces, since he looks to the past and to the future. While certainly no Janus I think this is an appropriate moment to dwell on the future challenges we as a specialty must now try and overcome?[10] We must embrace the responsibility of increasing awareness about these uncommon lesions both in the public and professional domain. We must enhance our ability to disseminate and propagate current information and techniques, continue to train surgeons in larger numbers and help set up collaborative networks to gain further insight into these rare lesions. There is increasing pressure for medical technology assessment to include cost-effectiveness analyses to help determine difficult resource allocation decisions.[11] While the importance of clinical expertise and experience is unquestionable we do need to combine this with the judicious integration of best available scientific evidence to facilitate rational “informed” clinical decision making and help develop evidence based protocols that would be both effective and applicable in our settings.
The Indian Musculo Skeletal Oncology Society (IMSOS) is a step in this direction.[12] It aims to “promote scientific, evidence based, comprehensive multidisciplinary management of bone and soft tissue sarcomas and encourage basic and clinical research.” IMSOS seeks to provide a common forum for interaction and mutual collaboration between different specialists and institutes involved in the treatment of sarcomas. It will help foster training and education opportunities, promote dissemination of knowledge and aid in the development of treatment guidelines suitable for our socio cultural environment. Together we must strive to develop this society to ultimately provide the best possible care to the maximum number of patients. The launch of the “Journal of Bone and Soft Tissue Tumors” cannot have come at a more opportune time. It will provide a fillip to surgeons seeking to share their experience who may have otherwise been intimidated by the “established” journals which currently look askance at individual case reports and series with relatively small numbers.
The “Odyssey” continues…….. , Indian orthopaedic oncology while having successfully navigated its nascent and adolescent period is successfully maturing into a vibrant specialty seeking to stamp its own unique impression globally. It is heartening to see an ever increasing number of practitioners venturing into these seas, now armed with navigational aids and charts that could help make the journey less turbulent, yet as exciting and exhilarating as it has always been.
Ajay Puri.
References
1. Natarajan MV, Sivaseelam A, Ayyappan S, Bose JC, Sampath Kumar M. Distal femoral tumours treated by resection and custom mega-prosthetic replacement. Int Orthop 2005;29: 309-13.
2. Yadav SS. Dual-fibular grafting for massive bone gaps in the lower extremity. J Bone Joint Surg Am 1990;72: 486-94.
3. 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.
4. Puri A, Gulia A. The results of total humeral replacement following excision for primary bone tumour. J Bone Joint Surg Br 2012;94: 1277-81.
5. 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;46: 470-4.
6. Puri A, Subin BS, Agarwal MG. Fibular centralisation for the reconstruction of defects of the tibial diaphysis and distal metaphysis after excision of bone tumours. J Bone Joint Surg Br 2009;91: 234-9.
7. Puri A, Gulia A, Jambhekar N, Laskar S. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradiation and re-implantation of the host bone: extracorporeal irradiation as an option for reconstruction in diaphyseal bone sarcomas. J Bone Joint Surg Br 2012;94: 982-8.
8. Puri A, Pruthi M, Gulia A. Outcomes after limb sparing resection in primary malignant pelvic tumors. Eur J Surg Oncol 2014;40: 27-33.
9.http://www.indianorthopaedicsociety.org.uk/wp-content/uploads/2012/11/Report-3-Rej-bhumbra.pdf.
10. Puri A. Orthopedic oncology – “the challenges ahead”. Front Surg 2014;1: 27.
11. Brauer CA, Neumann PJ, Rosen AB. Trends in cost effectiveness analyses in orthopaedic surgery. Clin Orthop Relat Res 2007;457: 42-8.
12. http://www.imsos.org.
Dr Ajay Puri
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Intractable Knee pain….it could be Glomus!
Vol 1 | Issue 1 | May – August 2015 | page:48-50 | Umesh M Kulkarni[1], Vijay Zavar[2], Sudhir Sankalecha[3], Ameya Kulkarni[1].
Author: Umesh M Kulkarni[1], Vijay Zavar[2], Sudhir Sankalecha[3], Ameya Kulkarni[1].
[1]Sanjivan Hospital, India Security Press Hospital, Nashik, Maharashtra, India.
[2]Skin Diseases Center, Nashik, Maharashtra, India.
[3]Sankalecha Labs, Nashik, Maharashtra, India.
Address of Correspondence
Dr. Umesh M Kulkarni
Sanjivan Hospital, India Security Press Hospital, Nashik, Maharashtra, India.
Email : umesh_kulkarni76@yahoo.com
Abstract
Introduction: Glomus tumors are areteriovenous anastomoses mostly found on flexor surfaces of fingers and nail beds. Occurrences in lower extremity is rarity and requires high index of suspicion.
Case Report: Thirty eight year old housewife presented with severe knee pain and swelling on the medial side of the knee since last two years. She had taken multiple opinions and was on analgesics and anti inflammatory medications for an extended duration. On examination an ill defined tender nodule was palpable on superolateral aspect of patella. MRI showed hypointense nodule with uniform contrast uptake. Excision biopsy was done to remove the lesion in total. Patient has complete relief of symptoms. Histopathology confirmed the diagnosis of glomus tumor
Conclusion: Glomus tumors can rarely occur in unusual locations. Clinical presentation and MRI help to narrow down the diagnosis. Excision leads to complete relief of symptoms.
Keywords: Glomus tumor, Knee, excision biopsy.
Introduction
The glomus body is a specialised form of arteriovenous anastomosis localised in the dermal soft tissue and acts as a thermoregulator. A glomus tumour (glomangioma, tumors of Popoff, or Barré-Masson syndrome) is a benign mesenchymal neoplasm composed of cells which resemble the modified smooth muscle cells of the normal glomus body (glomocytes) [1]. Extra-digital location of glomus tumour is uncommon [2]. Considering the rarity of this site, we present this case of Glomus tumour (GT) of the knee.
Case Report
A 38-yr-old housewife presented with severe right knee pains, supero-laterally to the patella, progressive since 2 years. Even the gentle touch would result in disproportionate shooting or stabbing type of pains, sometimes associated with paraesthesia. At times, the touch of clothing was unbearable. There was no seasonal exacerbation of the pains, which increased on extreme flexion of the knee or sitting cross-legged, compromising her daily work. She had abnormal apprehensive behaviour towards any person or object near her knee. There was no history of trauma or any inflammatory episode of the knee. She had received a number of analgesics, anti-inflammatory and anti-psychotic agents without much relief. She was even advised a psychiatric consultation prior to coming to us. On examination, an ill-defined soft nodule was palpable at the point of maximum tenderness only on extreme flexion of the knee (Fig.1). It was exquisitely tender on deep palpation. Movements of knee were painful in terminal flexion. There was no increase in local temperature. Swelling was mobile in the transverse direction, indicating adherence to deeper fibrous layers.
MRI revealed a hypointense nodule with in supero-lateral area of right knee on T1(Fig 2a). Gadolinium contrast showing enhanced and uniform uptake of the contrast (Fig. 2b). This confirmed the vascular nature of the lesion. The authors had earlier treated a similar case of GT of the knee joint and thus a high index of suspicion was present for GT. Excision biopsy was planned for the lesion. Open mini- excision biopsy of the lesion was preferred over arthroscopic shaving so that the lesion could be obtained in toto. The discrete lesion was found to be arising from the capsule of the suprapatellar region of the right knee and was fully excised. The patient had a miraculous recovery from the pain and unusual behaviour pattern. Histological examination revealed a well-circumscribed benign lesion with several vascular spaces (Fig. 3a) and solid aggregates of regular round glomus cells with darkly staining basophilic nucleus in a hyaline stroma.(Fig. 3b). On follow up the patient was completely relieved of all her symptoms. A consent for publication was taken before submitting the case report
Discussion
Histologically GT arises from glomus bodies that are specialised form of arteriovenous anastomosis involved in temperature regulation. Structurally plump endothelial cells line a centrally coiled canal which is surrounded by longitudinal and circular muscle fibres containing rounded epithelial appearing glomus cells (glomocytes) [1,2]. Histologically, GT are divided into 3 subtypes: The classical glomus tumour, glomangiomas and glomangiomyomas, the last being least common. Rarely, glomus tumours may have a malignant potential [3].
Though GT occur more commonly on digits below the nails, they may appear in other anatomical areas. Cutaneous lesions appear as small bluish-red tender nodules in the dermis or sub dermal skin. Pinpoint exquisite tenderness is characteristic. Pain from GT is so severe that at times a patient may even demand an amputation of the limb. The symptoms are generally worse in winter. Extra-digital GT commonly get misdiagnosed for a significant time period before the final diagnosis.4,5,6 In our case too there was a delay of more than a year in diagnosis. GT around the knee are reported infrequently [2,4-22]. In a review of cases GT of mayo clinic, tumors around the knee were 17.8% of all the cases of extradigital GT [2]. The structures around the knee that may be involved can be varied and GT is reported to arise from patellar ligament [9,22], quadriceps muscle [10], vastus lateralis [11], hoffa’s fat pad [13-18], plica synovialis [17]. In our case the lesion was arising from the joint capsule and did not involve muscles or tendons.
We had a very high index of suspicion of GT because of our earlier experience in treating such patients of GT along the knee joint. Often the tumour may not appear for a long time after the pain has begun [23] or may be neglected by the patient [8] or delayed diagnosed [6]. In our case the patient had taken medications from multiple consultants and presented to us with no specific diagnosis. According to Shugart et al, “almost diagnostic is the fact that the patient is reluctant, and often refuses palpation during examination [24]. In our case there was tenderness on deep palpation on complete flexion. This may be because the lesion was deep seated in the capsule and was covered laterally by vastus musculature. The clinical diagnosis needs to be confirmed with MRI and histopathology of the excised tissue. It is important to diagnose glomus tumour because the condition is potentially curable by surgical excision [2,3,4,5]. It however remains intriguing as to why a glomus appeared at this uncommon location.
In conclusion, intractable knee pain with focal exquisite tenderness may be due to glomus tumour and should be suspected early to minimize painful endurance by the patient.
References
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2. Schiefer TK, Parker WL, Anakwenze OA, Amadio PC, Inwards CY, Spinner RJ. Extradigital glomus tumors: a 20-year experience. Mayo Clin Proc. 2006 Oct;81(10):1337-44
3. Hiruta N, Kameda N, Tokudome T, Tsuchiya K, Nonaka H, Hatori T, Akima M, Miura M. Malignant glomus tumor: a case report and review of the literature. Am J Surg Pathol. 1997 Sep;21(9):1096-103..
4. Clark ML, O’Hara C, Dobson PJ, Smith AL. Glomus tumour and knee pain: a report of four cases. Knee. 2009; 16: 231-4.
5. Puchala M, Kruczynski J, Szukalski J, Lianeri M. Glomangioma as a rare cause of knee pain. J Bone Joint Surg Am. 2008; 90: 2505-8.
6. Panagiotopoulos E, Maraziotis T, Karageorgos A, Dimopoulos P, Koumoundourou D. A twenty-year delay in diagnosing a glomus knee tumor. Orthopedics. 2006 May;29(5):451-2.
7. Caughey DE, Highton TC. Glomus tumour of the knee. Report of a case. J Bone Joint Surg Br. 1966 Feb;48(1):134-7.
8. Davenport D, Colaco HB, Edwards MR. The 30-year wait for treatment of an acutely painful knee. BMJ Case Rep. 2014 Sep 29;2014.
9.Mabit C, Pecout C, Araud JP. Glomus tumour in the patellar ligament: A case report. J Bone Joint Surg [Am] 1995; 77: 140-141.
10.Negri G, Schulte M, Mohr W. Glomus tumour with diffuse infiltration of the quadriceps muscle: A case report. Hum Path 1997; 28: 750-752.
11.Amillo S, Arriola FJ, Munoz, G. Extradigital glomus tumour causing thigh pain. J Bone Joint Surg [Br] 1997; 79B: 104-106.
12.Oztekin HH. Popliteal glomangioma mimicking baker’s cyst in a 9-year-old child: an unusual location of a glomus tumour. Arthroscopy 2003; 19(7); 1-5.
13.Hardy P, Muller GP, Got C. Glomus tumour of the fat pad. Arthroscopy 1998; 14: 325-328.
14.Waseem S, Jari S, Paton R. Glomus tumour, a rare cause of knee pain: a case report. Knee 2002; 9:161-163.
15. Clark ML, O’Hara C, Dobson PJ, Smith AL. Glomus tumor and knee pain: a report of four cases. Knee. 2009 Jun;16(3):231-4.
16. Gholve PA, Hosalkar HS, Finstein JL, Lackman RD, Fox EJ. Popliteal mass with knee pain in a 57-year-old woman. Clin Orthop Relat Res. 2007 Apr;457:253-9.
17. Kato S, Fujii H, Yoshida A, Hinoki S. Glomus tumor beneath the plica synovialis in the knee: a case report. Knee. 2007 Mar;14(2):164-6.
18. Prabhakar S, Dhillon MS, Vasishtha RK, Bali K. Glomus tumor of Hoffa’s fat pad and its management by arthroscopic excision. Clin Orthop Surg. 2013 Dec;5(4):334-7.
19. Gonçalves R, Lopes A, Júlio C, Durão C, de Mello RA. Knee glomangioma: a rare location for a glomus tumor. Rare Tumors. 2014 Dec 18;6(4):5588.
20. Sraj SA, Khoury NJ, Afeiche NE, Abdelnoor J. Thigh pain of 5 years’ duration in a 48-year-old man. Clin Orthop Relat Res. 2008 Sep;466(9):2291-5.
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22. Akgün RC, Güler UÖ, Onay U. A glomus tumor anterior to the patellar tendon: a case report. Acta Orthop Traumatol Turc. 2010;44(3):250-3.
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24. Shugart RR, Soule EH, Johnson EW. Glomus tumor. Surgery, Gynecology & Obstetrics. 1963;117:334–340.
Dr.Umesh M Kulkarni
Dr.Vijay Zavar
Dr.Sudhir Sankalecha
Dr.Ameya Kulkarni
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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].
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].
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].
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.
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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145. Results of a Sarcoma Alliance for Research through Collaboration (SARC) phase II trial of dasatinib in previously treated, high-grade, advanced sarcoma. Schuetze, S, et al. 15s, 2010, Journal of Clinical Oncology, Vol. 28, p. abstract 10009.
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147. Suppression of Ewing’s sarcoma tumor growth, tumor vessel formation, and vasculogenesis following anti-vascular endothelial growth factor receptor-2 therapy. Zhou, Z, et al. 2007, Clinical Cancer Research, Vol. 13, pp. 4867-4873.
148. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children’s Oncology Group study. Bender, JLG, et al. 2008, Journal of Clinical Oncology, Vol. 26, pp. 399-405.
149. Feasibility of bevacizumab (NSC 704865, BB-IND# 7921) combined with vincristine, topotecan, and cyclophosphamide in patients with first recurrent Ewing sarcoma (EWS): A Children’s Oncology Group (COG) study. Leavey, P, et al. 15s, 2010, Journal of Clinical Oncology, Vol. 28, p. abstract#9552.
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Journal of Bone and Soft Tissue Tumors: A New Beginning
Vol 1 | Issue 1 | May – August 2015 | page:1-2 | Dr. Yogesh Panchwagh & Dr. Ashok Shyam.
Author: Dr. Yogesh Panchwagh [1], Dr. Ashok Shyam [2,3].
[1]Orthopaedic Oncology Clinic, Pune, India.
[2] Indian Orthopaedic Research Group, Thane, India
[3] Sancheti Institute for Orthopaedics &Rehabilitation, Pune, India
Address of Correspondence
Dr. Yogesh Panchwagh.
Orthopaedic Oncology Clinic, 101, Vasanth plot 29, Bharat Kunj Society -2, Erandwana, Pune – 38, India.
Email: drpanchwagh@gmail.com
Editorial: Journal of Bone and Soft Tissue Tumors: A New Beginning
The faculty of bone and soft tissue tumors has seen tremendous growth in terms of recognition and advancement in recent years. As pointed out by Dr Ajay Puri [1] the field is fairly new in India but has shown great promise both in terms of patient care and education. The aspects of education on which the Journal of Bone and Soft Tissue Tumors (JBST) will focus is on inter disciplinary collaborations and providing platform for publication of relevant research and clinical studies from all over the world and specially from Asia. The journal also aims to provide the most relevant and practice based information to everyone involved in care of bone and soft tissue tumors.
Cancers on a whole and bone tumors specifically require multidisciplinary approach towards managing patients. Orthopaedic Oncology as it is termed is not simply a surgical branch but requires inputs from various different faculties including orthopaedic oncologist, radiologist, pathologist, medical oncologist, radiation oncologist, pediatric medical oncologist, surgical oncologist, plastic surgeons and micro-vascular surgeons. In fact the first symposium published in JBST is written by pediatric oncologists, radiation oncologist and orthopaedic oncologist which say a lot about how important this interdisciplinary collaboration is to JBST[2,3,4]. JBST specifically aims to provide a platform where multiple faculties can come together and interact. We have inter disciplinary members on the editorial board and in coming months we will be expanding this further to include many more faculties like biomechanics, genetics, basic sciences and Prosthetics. This will help us understand the viewpoints of each other and also help us provide better patient care.
The other aim of the journal is promotion of research activities and publication of clinically relevant articles not only from the western world but also from Africa and Asia. Although research has been increasingly seen as gaining importance in our country but there exists a lot of research apathy and research lethargy. JBST aims to provide a platform for publication and will also provide assistance in manuscript preparation which will be useful for new researchers and writers. This assistance will be provided through the writers club of the orthopaedic research group which is also involved in conception and publication of the Journal. Thus the authors will be supported at every stage of publication and best quality articles will be made available to readers
The main focus of the Journal will be to provide clinically relevant articles that will be directly applicable to treating patients in real world and not only on paper with statistics. We urge our authors to keep statistics to minimal and to use only basic statistics in their articles and focus on bringing out the clinically relevant points in their articles. The reviewers too are advised to focus on the clinical relevance of the article and on the paradigm in which the particular article will be useful in treating patients. The journal will focus both on Evidence based medicine and on Practice based medicine and will try to find a balance between the two. With this in mind features like expert reviews, narrative reviews will be published along with systematic reviews. Technical notes and case reports, case studies will be regular features and will have specific focus on case based approach to particular clinical scenario.
With these aims we have embarked on a journey toward excellence in treatment of bone and soft tissue tumors. We would like to thank all the editorial board members who encouraged us and helped us in every way to start this venture. We thank all our authors who provided us with excellent articles and lastly we thank our reviewers who did rapid reviews and corrections in the articles. We thank the Orthopaedic Research Group for supporting this venture and helping at every step of the publication process. The future of JBST looks very promising specially with the support from the editorial board. We as a team are committed to JBST and aim to make this journal a landmark publication in years to come.
With this we leave you to enjoy the First issue of the Journal of Bone and Soft Tissue Tumors.
Yogesh Panchwagh & Ashok Shyam
References:
1. Puri A. The “ODYSSEY”: “Orthopaedic Oncology” – My journey thus far! Journal of Bone and Soft Tissue Tumors May- Aug 2015;1(1):3-5
2. Valvi S & Kellie SJ. Ewing Sarcoma: Focus on Medical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015;1(1):8-17
3. 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
4. Panchwagh Y. Ewing Sarcoma: Focus on Surgical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015;1(1):23-28
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OncoMedia Journal of Bone and Soft Tissue Tumors (JBST) May-August 2015
Vol 1 | Issue 1 | May – August 2015 | page:51-52 | Dr Ashish Gulia[1], Dr Ashok Shyam[2,3].
Author: Dr Ashish Gulia [1], Dr Ashok Shyam [2,3].
Dr. Ashish Gulia MS (Ortho), Mch – Surgical Oncology
[1]Fellowship – Musculoskeletal Oncology (TMH – HBNI)
Asst. Professor – Orthopaedic Oncology, Tata Memorial Hospital, Mumbai, India.
Dr Ashok Shyam MS (Ortho)
[2]Indian Orthopaedic Research Group, Thane, India.
[3] Sancheti Institute for Orthopaedics &Rehabilitation, Pune, India.
Indian Musculo Skeletal Oncology Society (IMSOS)
Musculoskeletal oncology is a relatively new specialty, both as far as orthopaedics and oncology goes. For sarcoma care to evolve, ideas to surface and multi institute or multi disciplinary collaborations to develop in the fields of basic research, patient care, biomaterials and prosthesis, there is a need for a common platform where all of us involved in the treatment of sarcomas can interact. This would also help foster training and education opportunities, promote dissemination of knowledge and aid in the development of treatment guidelines suitable for our socio cultural environment. As the field of musculoskeletal oncology continues to develop globally and in India, it is time for us to reflect on what is required for it to grow further so that we are able to offer the best care to the maximum number of patients.
The Indian Musculo Skeletal Oncology Society (IMSOS) is a step in this direction. It aims to “promote scientific, evidence based, comprehensive multidisciplinary management of bone and soft tissue sarcomas and encourage basic and clinical research.” In the words of Henry Ford “Coming together is a beginning; keeping together is progress; working together is success”.
The Indian Musculoskeletal Oncology Society 1st Annual Conference was organised on 13th and 14th March, 2015 at the Tata Memorial Hospital, Mumbai.
The theme of the conference was “Cure, control or comfort – In tumors teamwork triumphs!” reflects the ethos of IMSOS of bringing together all specialties interested in sarcoma care to interact on a continuous basis and help further advances in musculoskeletal oncology. The second meeting is planned in Cochin in 2016. Visit www.imsos.org for more information.
Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors
Tissue specificity of tumor cells to metastasize, for example predilection of lung carcinoma to spread to bone, is still poorly understood. It is believe that the tumor cells with seed into tissues that act as good soil form them to grow. In this respect bone marrow is said to be the metastatic niche for seeding and growth of variety of tumors. The tumor cells mimic the homeopoetic stem cells and capture the niche for themselves through series of complex steps involving cytokines, adhesion molecules and physical factors. The detailed mechnism still eludesus but we do grasp the importance of this phenomenon. This colonisation may play important role in cases that relapse after chemotherapy. In these cases the tumor cells may find safe haven in the bone marrow niche and can emerge later to cause further metastasis and disease spread. Understanding of these mechanism will help in developing effective chemotherapeutic solutions and may allow to restrict the disease for spreading too. Recent article published in BoneKey1 elaborates on the function of metastatic niche and provides insight into new developments to tackle this. But we are still far away from any clinical implication of the theory.
1. Shiozawa Y, Eber MR, Berry JE, Taichman RS. Bone marrow as a metastatic niche
For disseminated tumor cells from solid tumors. Bonekey Rep. 2015 May 20;4:689Osteoclasts cause muscle weakness and bone pain in bone tumorsOsteoclasts cause muscle weakness and bone pain in bone tumors.
Osteoclasts cause muscle weakness and bone pain in bone tumors
Understanding the basic mechanisms by which tumors cause certain systemic symptoms will help in understanding and planning therapeutic strategies. Tumor cells stimulate osteoclastic activity which lead to outpour of excess of bone derived growth factor. The bone derived growth factors have direct effect on the muscles and cause muscle weakness as well as muscle wasting. It is believed that in this muscle-bone synergy it’s the muscle that is a more powerful secretary gland and has strong influence on bone homeostasis. However in cases with bone tumor this relationship is reversed and also distorted leading to muscle wasting. Most important factor is TGF-beta family of ‘osteokines’. These may cause reduction is both muscle mass as well as muscle function. The weak bones add to the impaired function. The same hyperactive osteoblasts create an acidic environment in the bone which is directly related to severity of bone pains. Two good article clear a lot of confusion and provide fresh insights into the subject[1,2].
1. Waning DL, Guise TA. Cancer-associated muscle weakness: What’s bone got to do
with it? Bonekey Rep. 2015 May 20;4:691.
2.Nagae M, Hiraga T, Yoneda T. Acidic microenvironment created by osteoclasts
Causes bone pain associated with tumor colonization. J Bone Miner Metab. 2007;25(2):99-104.
Hair Bucket Challenge’ helping Sherwood boy with Ewing’s Sarcoma
Social impact of bone tumors are not unknown but this is unique. We all know about the ice bucket challenge, but an hair bucket challenge is unheard of. This was created for fourth-grader Tony Budesilich, who was recently diagnosed with Ewing sarcoma, a rare bone cancer in his leg (fibula which was surgically excised. The boy underwent seven rounds of chemotherapy and started losing hair. His friends noticed this change specifically Aidan Cook (12 yrs) who shaved his head and thus started a challenge the other boys to shave theirhead. This became an internet sensation and lot of kids [not only friends of Tony] from the locality participated and we could see a lot of shaved head in Sherwoods.
Tony has been given a good prognosis but has to continue the complete course of chemotherapy, but he definitely feels great about how his friends and family have supported him in a very difficult phase of his life
Read more: http://www.kptv.com/story/29109392/hair-bucket-challenge-helping-sherwood-boy-with-rare-bone-cancer#ixzz3d8e4tHuP.
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Join the OncoMedia Team and keep the interesting news coming through. We invite trainees of all faculties involved in the care of bone and soft tissue tumors to become a part of this active and dynamic team. They will be required to search the web and find interesting news and facts (which we will otherwise miss) and send it to the editorial board. A short original write-up will be necessary for the same. If accepted your news article will be published with your photograph and affiliation. To be a part of OncoMedia please write an email to us at editor.jbst@gmail.com
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