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Ewing Sarcoma: What’s in a name?
Vol 1 | Issue 1 | May – August 2015 | page:6-7 | Ashok K Shyam[1,2*]
Author: Ashok K Shyam[1,2*].
[1]Department of Orthopaedics, Sancheti Institute for Orthopaedics and Rehabilitation, Pune India.
[2]Indian Orthopaedic Research Group, Thane, India.
Address of Correspondence
Dr. Ashok K Shyam MS Orth.
Department of Orthopaedics, Sancheti Institute for Orthopaedicsand Rehabilitation, Pune India.
Email: drashokshyam@yahoo.co.uk
Abstract
There appears to be some ambiguity surrounding interpretation of collaborating disciplines on how ‘Ewing sarcoma’ is named, written or spoken. And they mostly are pretty sure about their version (or probably unaware of any other version!). The article will focus on the issue of how Ewing sarcoma is quoted in literature and shed some light on origin of the term. This will also serve as an introduction to our symposium on Management of Ewing Sarcoma.
Keywords: Ewing Sarcoma, Name.
History
Ewing sarcoma was first described by Dr James Ewing in 1921 in his paper read at New York Pathological society proceedings [1]. In his paper he described a 14 year old girl with a bone tumor arising from radius shaft which was diagnosed to be osteosarcoma. Although osteosarcomas were known to be radioresistent, this particular patient underwent radiotherapy and to everyone’s surprise had a ‘miraculous’ response both clinically and radiographically. The tumor did recur but biopsy done this time revealed it to be distinct form osteosarcoma. Ewing described the cells as round using the loose term ’round cell sarcoma’. To him the cells appeared similar to cells of endothelium of the blood vessels of the bone and thus he described the tumor as ‘Endothelioma of the bone’. He further described 6 such similar patients. This tumor was named as ‘Ewing sarcoma’ few years later by Ernest Codman [Ewing sarcoma is the most common differential of Codman Triangle] [2]. Although Dr James Ewing has contributed a lot to medicine his contributions in estabilishing oncology as an independent science is noted by naming him as ‘The Cancer Man’ or ‘Mr Cancer’ by his colleagues and media. He is still best known to every student of medicine by the eponym of ‘Ewing Sarcoma’.
What’s in the Name?
Ewing sarcoma has been reported to be written as ‘Ewing sarcoma’, Ewing’s Sarcoma’, ‘Ewings’ Sarcoma’ or simply ‘Ewings sarcoma’. Which is the correct version? I came across this issue rather accidently on preparing and reviewing for this particular symposium. We have three articles in the symposium [3,4,5], one on radiotherapy, one on medical management and one on surgical aspect. There was difference in how these three manuscripts spelled Ewing sarcoma. The non surgical articles insisted the name to be ‘Ewing Sarcoma’ while the surgical article insisted on ‘Ewing’s Sarcoma’. So what is the correct nomenclature? On sarcomahelp.com site I found this description “The tumor which bears his name is generally referred to as Ewing’s sarcoma when spoken and either Ewing’s sarcoma or Ewing sarcoma when written [6].” I reviewed the policies about the eponymus words and found an interesting fact about them. A cold war is been fought between US and Europe with US wishing to phase out use of eponyms and is against creating any new ones [7]. The argument is that the disease is not ‘Owned’ by a person. They called the eponymus use with an apostrophe as a possessive case of the word that indicates that the person either had the disease or owned the disease. By that example Ewing’s sarcoma indicates that Ewing had the sarcoma! They advocated a non possessive use of the eponyms like ‘Ewing sarcoma’. Following the rule the AMA Manual of Style: a guide to authors and editors recommends use of non-possessive case for writing eponyms. Even if we ask word nerds in true grammatical sense an apostrophe does indicate possessive nature of the noun to which it is attached. On the other hand the European literature holds the eponyms in high regards as historical testaments to physicians who first described the diseases and advice to write eponyms with an apostrophe as in Ewing’s sarcoma. To support this there remains arguments regarding using non possessive case in certain diseases like replacing ‘Down’s Syndrome’ with ‘Down syndrome’ which will then imply that there is an ‘Up Syndrome’! The controversy still rages and anyone interested should read these two articles published in British Medical Journal [8,9].
But what about our question about Ewing Sarcoma? Searching pubmed, I could find 1021 article with Ewing sarcoma , 2147 articles with Ewing’s Sarcoma , 17 article with Ewings sarcoma and 9 articles with Ewings’ sarcoma respectively in their titles (Fig 1 a-d). Thus most of them were divided into either possessive case or non-possessive case and possibly it depends on journal policy and geographical preference. Search of MESH (Medical Subject Heading) in pubmed identifies Ewing sarcoma as Mesh Major Subject Heading. I too would personally agree with non-possessive case [also as per AMA Style and Pubmed MESH term] in form of ‘Ewing Sarcoma’ although authors may choose other versions too. However when one of the version is used, authors should use the same version consistently throughout the manuscript. In this symposium we have used the non-possessive version in medical management and radiotherapy articles while a possessive version is used by the surgical focussed article. We hope the symposium is informative and any queries that remain in readers mind are welcomed as ‘Letter to Editor’ and will be answered by the respective authors.
References
1. Ewing J: Diffuse endothelioma of bone, Proc NY Pathol Soc 1921;21:17.
2. Timothy P. Cripe, “Ewing Sarcoma: An Eponym Window to History,” Sarcoma, vol. 2011, Article ID 457532
3. Valvi S & Kellie SJ. Ewing Sarcoma: Focus on Medical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015; 1(1):4-6
4. 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):4-6
5. Panchwagh Y. Ewing Sarcoma: Focus on Surgical Management. Journal of Bone and Soft Tissue Tumors May-Aug 2015;1(1):4-6
6. http://sarcomahelp.org/ewings-sarcoma.html#tpm1_1
7. Jana N, Barik S, Arora N. Current use of medical eponyms–a need for global uniformity in scientific publications. BMC Med Res Methodol. 2009 Mar 9;9:18.
8. Woywodt A, Matteson E. Should eponyms be abandoned? Yes. BMJ. 2007;335:424
9. Whitworth JA. Should eponyms be abandoned? No. BMJ. 2007;335:425.
Dr.Ashok Shyam
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Current role of FDG-PET in Bone and Soft tissue tumors
Vol 1 | Issue 1 | May – August 2015 | page:29-36 | Junaid Ansari[1], Reinhold Munker[1], Amol Takalkar[2,3*].
Author: Junaid Ansari[1], Reinhold Munker[1], Amol Takalkar[2,3*].
[1]Feist Weiller Cancer Center, Shreveport, Louisiana.
[2]Center for Molecular Imaging & Therapy, Biomedical Research Foundation of Northwest Louisiana.
[3]Dept. of Radiology, LSU Health, Shreveport, Louisiana.
Address of Correspondence
Dr. Amol Takalkar MD.
Dept. of Radiology, Louisiana State University Health Sciences Center – Shreveport, 1505 Kings Highway, Shreveport, LA 71103
Email: atakalka@biomed.org
Abstract
FDG-PET/CT imaging is an established modality for the workup of several malignancies; it is now considered standard for the initial as well as a subsequent treatment strategy in the management of most malignancies. The focus of this article is to discuss the role of FDG-PET/CT imaging in the workup and management of malignant bone and soft tissue tumors in conjunction with standard imaging techniques like MRI and CT scanning. The article also briefly touches upon the potential role of emerging PET-MRI modality.
Keywords: FDG-PET, Musculoskeletal tumors, Bone tumors, CT, MRI, Ewing Tumors, Osteosarcoma, GIST.
FDG PET and PET/CT
Positron emission tomography (PET) is a non-invasive nuclear imaging technique which relies on the detection of positrons emitted during the decay of a radionuclide and maps the biodistribution of the administered radiopharmaceutical. Compounds of interest are labelled with a positron-emitting radiotracer and infused and distributed according to the in vivo biologic behavior of the tagged compound. 18F-fluorodeoxyglucose (FDG) is the most commonly used PET radiopharmaceutical for oncology. FDG is a glucose analog in which the hydroxyl group is replaced by positron-emitting fluorine isotope (18F) and FDG-PET or FDG-PET/CT (when PET is combined with computed tomography) provides a map of glucose metabolism in the body. In contrast to anatomical and morphological approaches, FDG-PET provides more metabolic and functional information about the disease and can be an important imaging tool to non-invasively understand cancer biology [1]. FDG is actively taken up by cancer cells and remains metabolically trapped intracellularly. Otto Warburg, a German physiologist in the 1920’s, had shown that most tumor cells generate energy by non-oxidative breakdown of glucose and are hypermetabolic compared to the normal cells (The Warburg Effect). FDG-PET exploits this effect as cancer cells take up more FDG than normal cells and are hence detected on imaging as regions of increased FDG uptake. The concept of FDG-PET was developed in the 1970’s when it was used for functional brain imaging and then in the 1980’s to assess the cardiac metabolism. However, over the past 15 to 20 years, oncologic indications have become the predominant use for FDG-PET imaging and along with technological advances, it has now evolved to integrated PET/CT systems that provide highly sophisticated information with implementation of further hybrid imaging technologies, like combined PET/MRI, on the horizon [2].
With notable exceptions (such as prostate cancer), FDG PET/CT is routinely used for the initial treatment strategy (formerly encompassing diagnosis and staging) as well as a subsequent treatment strategy (formerly encompassing restaging and assessing treatment response as well as disease status) for most cancers, such as: lymphomas, lung cancer, colorectal cancer, melanomas, head and neck cancer, breast cancer, and musculoskeletal tumors and other malignancies. PET has largely been replaced by PET/CT scanners (at least in the Western nations) and this article will largely focus on PET/CT imaging instead of stand-alone PET imaging. Since MRI plays an important role in the evaluation of bone lesions, this article will briefly discuss the potential for combined PET/MRI hybrid imaging in the setting of bone and musculoskeletal tumors.
Musculoskeletal tumors
Malignant musculoskeletal tumors, also known as sarcomas, are rare and account for about 1% of cancer deaths in the United States [3]. They are a heterogeneous group of mesenchymal malignancies arising from bone and soft tissues. Primary bone tumors are seen more commonly in adolescents and younger adults, while primary soft tissue sarcomas are seen more commonly in adolescents with a second peak in the fifth decade. However, these sarcomas can affect all age groups. The World Health Organization’s classification of soft tissue sarcomas is based on the tissue of origin which continues to evolve with the discovery of new molecular genetic abnormalities [4]. The majority of soft tissue sarcomas are sporadic and only a few are linked to environmental factors like exposure to radiation, burns, toxins, viruses like HHV-8 causing Kaposi sarcoma in HIV patients, immunodeficiency syndromes, and germline mutations in Li-Fraumeni syndrome, neurofibromatosis 1, and Gardner syndrome. The common examples of soft tissue sarcomas include liposarcoma, synovial sarcoma, leiomyosarcoma (LMS), rhabdomyosarcoma (RMS), fibrosarcoma, and angiosarcoma. The patients usually present with an asymptomatic mass. The primary diagnosis is made by a tissue biopsy and imaging studies like plain radiograph, CT and MRI. Lungs are the most common site of metastases, and hence a plain radiograph and CT scan of the chest is also advisable. Treatment is based on AJCC staging. Stage IA (T1a-1b,N0,M0,G1,GX) and Stage IB (T2a-2b,N0,M0,G1,GX), low grade patients are usually managed by surgery by obtaining adequate oncologic margins. Stage IIA (T1a-b,N0,M0,G2,G3) can be managed with surgery alone, or surgery followed by radiotherapy or preoperative radiotherapy followed by surgery. Stage IIB (T2a-b,N0,M0,G2,G3) and Stage III (T2a,T2b,N0.M0,G3 and any T,N1,M0, Any G) if resectable with acceptable functional outcomes are managed with surgery followed by radiotherapy and adjuvant chemotherapy, or preoperative chemo-radiotherapy followed by surgery followed by adjuvant chemo-radiotherapy. Unresectable and resectable with adverse functional outcomes Stage II and III are managed with radiotherapy, chemotherapy, chemo-radiotherapy, or palliative surgery, alone or in combination. Synchronous Stage IV with single organ involvement or limited tumor bulk that are amenable to local therapy are managed primarily like Stage II and III tumors. Disseminated metastases are managed with palliative options. Accurate staging is critical for determining the appropriate treatment.
Gastrointestinal stromal tumors (GISTs) are discrete forms of sarcomas and are the most common abdominal mesenchymal tumors. They can arise anywhere in the gastrointestinal tract with the stomach being the most common site. Due to identification of driver mutations in the c-KIT and platelet-derived growth factor alpha genes encoding tyrosine kinase receptors, the treatment of GIST has been a role model of targeted therapy with Imatinib mesilate, a tyrosine kinase inhibitor [5, 6]. Surgery is still the main stay of management in resectable non-metastatic lesions with Imatinib playing an adjuvant role [7]. GISTs have variable clinical behavior with some presenting with nonspecific symptoms and some detected incidentally.
Bone sarcomas occur less commonly than soft tissue sarcomas and will account for 0.18% of all new malignancies, with 2970 estimated new cases and 1490 estimated deaths in the US in 2015 [3]. They are classified by Musculoskeletal Tumor Society Staging System based on grade and compartment localization. Osteosarcoma accounts for almost half of the bone sarcomas and is seen mainly in children and adolescent males in the metaphysis of long bones, especially the femur, the proximal tibia and the proximal humerus. Most of the cases are sporadic in nature with few cases arising from inherited genetic diseases like hereditary retinoblastoma and Li-Fraumeni syndrome. The patients usually present with pain and swelling of the affected area. Osteosarcomas are usually detected on imaging studies. The diagnosis is made by tissue sampling and pathology and can be suggested by imaging studies. These are usually high grade tumors with aggressive biological features and are found in or adjacent to areas with high bone growth, with subdetectable tumor spread elsewhere in majority of the cases [8, 9]. They are managed by neoadjuvant chemotherapy, which shrinks the tumor and targets micrometastatic tumor cells, followed by limb sparing surgery and adjuvant chemotherapy [9]. The prognosis is based on the response to chemotherapy. Radiation therapy generally has a limited role in the management of these tumors and is used mainly for unresectable and relapsed lesions [10]. Chondrosarcomas account for almost 25% of all bone sarcomas and are seen mainly in adult and old patients with predilection for flat bones. They have variable clinical behavior with an indolent nature and low metastatic potential [11]. Surgical resection is the standard of treatment. Radiation therapy is given in unresectable lesions. Chemotherapy is the primary therapy for systemic recurrence[10]. Ewing sarcoma constitutes approximately 10-15% of all bone sarcomas and is mainly seen in the second decade of life involving the diaphyseal region of the long bones, mostly in the lower extremity. These sarcomas present with localized pain or swelling of short duration. Constitutional symptoms are seen in small percentage of patients on presentation. They belong to a family of tumors known as PNETs (Primitive neuroectodermal tumors) and are associated with t(11;22) translocation[12]. The disease is aggressive and the presence of widespread metastasis is a sign of poor prognosis. It is primarily treated by multiagent chemotherapy and based on the response, is subsequently managed with radiotherapy, surgery or chemotherapy [10].
Improved diagnostic imaging has changed the primary management of musculoskeletal tumors. MRI is still the primary imaging technique used in detecting lesions and local staging due to its pluridirectional capabilities and superior contrast resolution. MRI thus plays an essential role in surgical planning by providing detailed information about the local extent of the disease and involvement of locoregional structures. MRIs are not, however, able to determine the subtypes of soft tissue sarcomas or differentiate between benign and malignant lesions. The regional nature of MRI also precludes identification of lymph nodes outside of the imaginary plane. Imaging distant metastatic disease is also not practical with routine MRI imaging studies. CT scans are not very sensitive for osseous pathology. Although CT has excellent spatial resolution, it is suboptimal to MRI when it comes to contrast resolution and soft tissue differentiation. CT scans are mainly used to assess pulmonary metastases and for staging of disease in the lungs in such patients [13]. Although used for assessing response to treatment based on shrinkage of the primary lesion, this approach may not be the best in the era of molecular imaging. Both CT and MRI have limitations in assessing local recurrence with altered anatomy and presence of post-therapy changes.
FDG PET/CT is not the optimal modality to assess the T-stage of these lesions. Although it can provide metabolic and functional information related to tumor biology, it has lower spatial resolution compared to morphologic imaging modalities and does not provide the intimate details about the local extent and invasiveness of the tumor. However, the intensity of FDG uptake can aid diagnosis by providing better targets for biopsy and increase the yield from biopsies. FDG PET imaging can also overcome some of the limitations of MRI, by separating high- from low-grade tumors, in determining the biological activity of a tumor, and by allowing the detection of abnormal lymph nodes and occult distant metastases, including pulmonary metastases, especially by virtue of almost whole body imaging [13]. However few studies have demonstrated that PET is less sensitive than CT scanning in the detection of pulmonary metastases and a significant number of known pulmonary metastases greater than 1.0 cm on CT, are PET negative (micro-metastases) [14]. Evolution of hybrid PET/MR may be a more efficient diagnostic modality in the future. It can provide additional information regarding soft-tissue analysis, tumor detection, tissue characterization, functional imaging and biological landscape at the same time.
Specific role of PET in musculoskeletal tumors
MRI and CT scanning are still the most commonly used imaging techniques to evaluate bone and soft tissue tumors with known limitations as discussed above. FDG-PET/CT imaging is now routine for cancer workup and the addition of a CT component in integrated PET/CT scanners have made this quite a reliable tool that can provide additional information about the biological behavior of the tumor and can aid in the management of these tumors.
Most soft and bone tumors are FDG-avid and the degree of avidity is usually associated with their clinical outcomes. In soft tissue sarcomas, FDG-PET is able to detect intermediate and high-grade lesions due to their high FDG uptake, but is not able to differentiate between benign and low-grade sarcomas since both of them tend to show low FDG uptake. Dual phase/delayed PET imaging can help in differentiating benign from malignant lesions in some cases as malignant lesions show increasing uptake on delayed images [15]. In bone tumors, low FDG uptake is usually seen in a benign lesion, with high FDG uptake in a malignant lesion. However, the highest FDG uptake is seen in metastases [16]. There are few exceptions to this rule; malignant tumors like plasmacytoma and low-grade chondrosarcoma can have low uptake, and benign tumors with either involvement of giant cells (giant cell tumor of bone) or histiocytic cells (Langerhans cells histiocytosis) can have high uptake. Using a TBR (tumor-to-background ratio) of 3.0 as a positive for malignant bone lesions, FDG PET has a specificity of 67% and a sensitivity of 93% in bone tumors [17]. The latest imaging guidelines set by Children’s Oncology Group Bone Tumor Committee highly recommend FDG-PET as a part of functional imaging in osteosarcoma and Ewing sarcomas at presentation and prior to surgery/local control. It also maintains use of FDG-PET for surveillance during and post chemotherapy [18].
Initial Treatment Strategy
Diagnosis of musculoskeletal tumors is usually established on the basis of directed biopsies after the detection of a mass on clinical exam and/or imaging. As discussed above, they are staged per the AJCC system using the TNM staging criteria. Along with clinical evaluation, contrast enhanced CT and MRI are extremely useful for optimal assessment of the “T” stage as they provide further structural information regarding tumor extension and involvement of adjacent structures. FDG-PET imaging lacks the spatial resolution to provide such exquisite structural details necessary for adequate “T” staging. However, FDG-PET can still play a role in the diagnosis of these tumors. Many of these lesions can be heterogenous and initial biopsy can be “non-diagnostic”. (Figure 1 demonstrates the value of FDG-PET in a patient with a negative/non-contributory biopsy). Since FDG PET relies on the biologic characteristics of the tumor and provides metabolic and functional information, it can be suited in such difficult cases to direct biopsies to the appropriate target site and improve the yield from biopsies. In addition, it can play an important role in the detection of locoregional metastatic lymphadenopathy and distant metastatic disease. Traditional anatomical evaluation of nodal involvement in the malignancies is sub-optimal since nodes may be enlarged as a result of infection/inflammation (that is not uncommon in the groin region), and normal sized nodes can frequently be involved with metastatic disease leading to inaccurate upstaging or downstaging of the disease with conventional imaging methods. FDG-PET (and especially PET/CT) imaging can have a tremendous impact in improving the nodal staging of sarcomas cancers compared to CT/MR (sensitivity: 87-90% versus 61-90% and specificity: 80-93% versus 21-100%) [19]. FDG-PET imaging frequently detects metastatic disease in normal-sized lymph nodes. However, caution is recommended in N0 disease per PET as micrometastases cannot be detected by FDG-PET imaging and hence the management of such patients should not solely be determined by FDG-PET findings; other techniques like surgical lymph node dissection should be employed for optimal “N” staging in such patients. Also, sometimes malignant lymph nodes with large extensive central necrosis can be falsely negative on FDG-PET with only mild FDG uptake at the periphery or no uptake at all. However, the most important added value of FDG-PET imaging is the detection of unsuspected distant metastases that can lead to dramatic changes in patient management. By virtue of its near whole body imaging and reliance on metabolic information, it has the potential to detect unsuspected occult metastases and change the management significantly. Moreover, FDG PET imaging is useful in therapy planning for patients undergoing radiation therapy with a curative or palliative intent or as neoadjuvant therapy. The increasing implementation of intensity modulated radiation therapy (IMRT) is well complemented by the additional functional/metabolic information provided by the FDG imaging, as it allows delivery of maximal radiation dose to the most metabolically active areas of the tumor and more complete inclusion of loco-regional disease with sparing of the uninvolved areas.
Subsequent Treatment Strategy
In addition to the above, FDG-PET imaging probably has an important benefit in assessing response to therapy and restaging of musculoskeletal tumors [20-23]. Following surgery or radiation therapy, it is extremely difficult to assess the treated area with conventional imaging modalities like CT/MRI due to inflammatory changes with fibrosis, edema and alteration of normal structures. Determining whether residual neoplasm is present in the postsurgical/postradiated tumor bed is one of the most daunting tasks facing radiologists. When compared to conventional radiological examination, FDG-PET has a better diagnostic accuracy in the assessment of residual or recurrent malignant disease in the post-therapeutic region, including avoidance of unnecessary planned surgery in patients with negative PET. Lack of any significant FDG uptake in the treated area generally indicates no active residual/recurrent disease. There may be some mild to modest irregular FDG uptake related to post-therapy changes, but generally there should be no gross intense focal abnormalities. Dual-phase PET imaging/delayed PET imaging may help in distinguishing post-therapeutic inflammatory changes from cancerous tissue. It may also help in the prediction of PFS (Progression free survival) and OS (overall survival). Focal intense FDG uptake within the area of post-surgical change is worrisome and needs further workup. A negative tissue biopsy after a strongly positive post-treatment PET scan can be caused by sampling error and warrants a closer follow-up rather than routine surveillance. Decrease in the intensity of uptake on the follow-up scan confirms a false positive post-treatment PET scan, usually due to inflammatory changes. However, persistence of a focally intense lesion or increase in the intensity of uptake warrants invasive evaluation. The timing of the post-treatment PET scan is very crucial, especially after radiation therapy. Although there are no specific recommendations in this regards, generally a 3-month interval after completing radiation therapy is felt to be adequate to assess response to therapy. The superior assessment of response to therapy with FDG-PET imaging may facilitate a more conservative approach in management, as patients undergoing combined chemo-radiation therapy with a complete response on the post-treatment FDG-PET scan can be followed with a more watchful approach.
There are several limitations of FDG-PET imaging in the evaluation of musculoskeletal tumors. Although it may detect tumors that may be missed by anatomic imaging (especially in-transit metastases as in Figure 2), the sub-optimal spatial resolution of PET imaging (compared to CT/MRI) limits the evaluation of local extent and invasiveness of the tumor. Also, low-grade tumors may be missed on PET if there is significant intense physiologic FDG uptake in an adjacent structure (like muscle). Conditions like joint inflammation, muscle contraction, radiation induced inflammation and osteoradionecrosis need to be kept in mind when interpreting FDG-PET studies in musculoskeletal pathology. The added information from CT images in a dedicated PET/CT scan can further help to discern this uptake as benign/physiologic.
Osteosarcoma
After the advent of neo-adjuvant chemotherapy in osteosarcoma, which has dramatically improved the prognosis, there has been a need for better imaging modality for tumor staging and grading, pre- and post-treatment evaluation, and detection of tumor recurrence (Figure 3 demonstrates FDG uptake may be quite heterogeneous and intense in osteosarcoma).
Initial Treatment Strategy
FDG-PET/CT imaging has a limited role in the initial workup of osteosarcoma. It is limited in its ability to diagnose osteosarcoma (which definitely requires tissue sampling) and is suboptimal to CT/MRI in delineating the local extent and invasiveness. The correlation between the histological grading and the FDG avidity has been well documented by several studies [24]. However, FDG-PET/CT imaging cannot obviate the need for the tumor biopsy to differentiate between a benign and a malignant lesion and establish the underlying pathology. The highest SUV values are seen in bone metastases. MRI and plain radiographs are still the first line diagnostic tools in staging the disease. In children, there may be an indication of FDG-PET in cases of unequivocal MRI findings due to physiological red blood marrow distribution to detect interosseous skip metastases. Lymph node metastasis is a rare phenomenon in osteosarcoma and hence the need of PET is limited. About 80% of metastases in osteosarcoma involve the lungs and early detection is important. The method of choice for detecting lung metastases is spiral high-resolution CT as PET can miss smaller lung lesions [25] However, whole body imaging in PET has an advantage of finding other sites of occult metastases, which cannot be seen with CT or MRI due to limited field of scanning and so should be employed in situations where clinical suspicion for metastatic disease is high. Infrequently, it may be used to guide biopsies if clinically necessary.
SUVmax and TLG (Total lesion glycolysis) are both strong prognostic factors that can predict progression-free survival, overall survival, and tumor necrosis in osteosarcoma [26].
Subsequent Treatment Strategy
FDG-PET plays a more established role in assessing therapy response and detecting recurrence. It has also been able to predict the tumor response as it relies on functional and metabolic parameters rather than structural changes. Tumor metabolic changes detected by FDG-PET precede morphological changes on anatomic imaging and early evaluation of tumor response allows treatment to be tailored to the individual. In two different studies, FDG-PET was found to be superior to MRI in the assessment of response [20, 21]. There is a direct correlation between SUV and histological grade. SUVmax reduction after therapy is the biggest indicator of whether the patient is responding to therapy or not, and based on this, the therapy can be modulated accordingly. SUVmax > 5 after neoadjuvant therapy is arbitrarily defined as a histological nonresponder and ≤ 2 as a responder [20-22, 27]. Byun et al suggested that the combination of FDG-PET/CT and MRI may be the best way to determine histological response of osteosarcoma after neoadjuvant chemotherapy [23]. The availability of combined PET/MRI imaging in the future may facilitate this.
FDG-PET has also a significant role in the assessment of tumor recurrence and restaging of high risk osteosarcoma patients. (28) It is also more accurate than other imaging studies in differentiating post-therapeutic fibrosis or inflammatory changes from local recurrence [25].
Chondrosarcomas
These sarcomas have less FDG uptake than other sarcomas owing to their high level of acellular gelatinous matrix and lower mitotic rates. Average FDG uptake of chondrosarcoma is as high as Ewing sarcoma but lower than osteosarcoma [29]. The role of PET in the diagnosis and management of chondrosarcoma is almost the same as with other malignant bone lesions. The biological activity helps to assess the tumor grade and to differentiate between benign and malignant tissue, and the whole body imaging helps to identify any occult metastases. Grade II and III chondrosarcomas have higher glucose metabolism and can be easily distinguished from a benign tumor; Grade I chondrosarcomas/atypical cartilaginous tumors cannot be so easily distinguished because of apparently similar metabolism rates [30]. (Figure 4 demonstrates the heterogeneous nature of FDG uptake in chondrosarcoma; intense FDG uptake site can help in guiding the biopsy in such patients)
Ewing sarcomas
Ewing sarcomas are high-grade malignancies and high SUVs are usually seen. PET is very sensitive in the detection of primary and recurrent lesions. PET is also superior to bone scan in detecting bone metastases and is used as a part of metastatic workup. PET has low sensitivity for smaller lesions, especially in lungs which are a common site of metastases for Ewing sarcomas and a CT scan is a superior imaging modality in such cases. PET can also be used for monitoring the tumor response to chemotherapy and radiotherapy and the possibility of a recurrence post-operatively. PET has a limitation in differentiating malignant from inflammatory lesions and cannot be used as a non-invasive diagnostic tool between Ewing sarcoma and osteomyelitis, which are frequently indistinguishable [31].
Fibrosarcoma
Fibrosarcomas arising from polyostotic fibrous dysplasia have intense FDG uptake indicating sarcomatous transformation. Fibrous dysplasia sarcomas are well known to have intense FDG uptake despite their benign nature [32]. Fibrous synovial sarcomas originate from the mesenchymal tissue and their histological appearance resembles the synovium. FDG-PET can also be used for the staging of these malignant tumors. (Figure 5 demonstrates intensely FDG avid soft tissue mass)
Gastrointestinal stromal tumors
Metabolic imaging with FDG-PET in GIST has proven to be an effective tool to evaluate the treatment response with tyrosine kinase inhibitors like imatinib. The functional imaging with FDG-PET provides earlier evidence of response in comparison to morphological changes seen with a CT scan. Jager et al observed that changes in tumor metabolism were seen as early as 1 week after the start of the treatment, which helped in delineating responders from non-responders in 14/15 cases [33]. Studies done by Stroobants et al and Goerres et al showed that PET responders had a better progression free survival and better prognosis than PET non-responders with residual FDG activity.(34, 35) However a recent study done by Chacon et al showed the early metabolic response (EMR) does not correlate with the progression-free survival or overall survival in patients with metastatic GIST. (36) GIST-specific molecular tracers are also in the making which can provide more accurate prognosis and development of treatment resistance. (37) FDG negativity however does not preclude the diagnosis of a GIST [38] (Figure 6 demonstrates the value of FDG-PET as a prognostic tool in the management of GIST)
Benign Tumors
FDG-PET has a limited role in the management of benign musculoskeletal tumors. Benign soft tissue lesions usually do not have substantial FDG uptake. Fibrous dysplasia can have variable FDG uptake, and in some cases intense FDG activity. In such situations, it is important to differentiate benign tumors from any possibility of a sarcomatous changes [39]. Hemangiomas can also be a site of intense FDG activity which can sometimes mimic metastasis. Lipomas have the lowest uptake. Careful history, physical examinations and other imaging tests like CT and MRI should help in the accurate diagnosis.
Conclusion
The evolution of PET in the recent years has changed the previous paradigm in the management of malignancies. In general, it is not the primary diagnostic modality for workup of musculoskeletal tumors but can play a role in certain clinical scenarios. Along with other imaging techniques, FDG PET/CT plays an important role in musculoskeletal tumors by guiding biopsies in heterogeneous tumors, predicting tumor response to preoperative neo-adjuvant chemotherapy, detecting skip metastases and reflecting risk of recurrence and prognosis. It also plays a more robust role in subsequent treatment strategy. Overall, it is more useful in evaluating primary soft tissue tumors relative to primary osseous lesions. However, the potential availability of integrated PET/MRI may allow for a more robust role for FDG-PET imaging in the workup of primary osseous tumors as well. FDG-avidity correlates negatively with survival and positively with disease progression. It can be used to tailor treatment, surgical versus chemo-radiotherapy. More prospective trials are needed to develop new tracers that can be more specific and lead to higher signal to noise ratio (SNR), which may help in establishing the response to treatment with newer agents and can set guidelines. Suboptimal T-stage and heterogeneous uptake in some cases, insufficient topography, radiation exposure and higher costs are a few of the limitations of using FDG-PET. In the current times, its role is still considered as an adjunct and has not replaced MRI and CT scanning. The combined PET-MRI multimodality imaging systems can provide adequate information about the morphology as well as the metabolic status of the lesion in a single imaging session and may potentially become the standard of imaging for musculoskeletal tumors in the near future. Precision medicine (prevention and treatment strategies that take individual variability into account) is the way to the future. Adopting global disease assessment, radiotherapy fractionation, imaging hypoxia, adaptive radiotherapy as part of quantifiable methodologies and standardization of FDG-PET, it can become a powerful tool for the diagnosis, individual treatment planning and subsequent treatment strategy. The absolute potential of FDG-PET in various malignancies including musculoskeletal tumors is still a work in progress and is evolving at a rapid pace with the recent development of radiopharmaceuticals and technological advancements..
References
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11. Pring ME, Weber KL, Unni KK, Sim FH. Chondrosarcoma of the pelvis. A review of sixty-four cases. J Bone Joint Surg Am. 2001;83-A(11):1630-42.
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16. Watanabe H, Shinozaki T, Yanagawa T, Aoki J, Tokunaga M, Inoue T, et al. Glucose metabolic analysis of musculoskeletal tumours using 18fluorine-FDG PET as an aid to preoperative planning. J Bone Joint Surg Br. 2000;82(5):760-7.
17. Schulte M, Brecht-Krauss D, Heymer B, Guhlmann A, Hartwig E, Sarkar MR, et al. Grading of tumors and tumorlike lesions of bone: evaluation by FDG PET. J Nucl Med. 2000;41(10):1695-701.
18. Meyer JS, Nadel HR, Marina N, Womer RB, Brown KL, Eary JF, et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr Blood Cancer. 2008;51(2):163-70.
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20. Kong CB, Byun BH, Lim I, Choi CW, Lim SM, Song WS, et al. ¹⁸F-FDG PET SUVmax as an indicator of histopathologic response after neoadjuvant chemotherapy in extremity osteosarcoma. Eur J Nucl Med Mol Imaging. 2013;40(5):728-36.
21. Cheon GJ, Kim MS, Lee JA, Lee SY, Cho WH, Song WS, et al. Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI. J Nucl Med. 2009;50(9):1435-40.
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24. Rakheja R, Makis W, Skamene S, Nahal A, Brimo F, Azoulay L, et al. Correlating metabolic activity on 18F-FDG PET/CT with histopathologic characteristics of osseous and soft-tissue sarcomas: a retrospective review of 136 patients. AJR Am J Roentgenol. 2012;198(6):1409-16.
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27. Denecke T, Hundsdörfer P, Misch D, Steffen IG, Schönberger S, Furth C, et al. Assessment of histological response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters. Eur J Nucl Med Mol Imaging. 2010;37(10):1842-53.
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Re implantation of Sterilised tumour bone by Extra Corporeal Radiotherapy
Vol 1 | Issue 1 | May – August 2015 | page:37-39 | Subin Sugath[1*].
Author: Subin Sugath[1*].
[1]Department of Aster Orthopaedics, Aster DM Healthcare Pvt Ltd., Kochi 682 027, Kerala, India.
Address of Correspondence
Dr. Subin Sugath MS Orth.
Department of Ortho Oncology. Aster DM Healthcare Pvt Ltd. Kuttisahib Road, Near Kothad Bridge, South Chittoor PO, Cheranallor, Kochi 682 027, Kerala, India.
Email: drsubin.sugath@dmhealthcare.com
Abstract
With the use of potent chemotherapeutic drugs, newer imaging modalities and improved surgical techniques limb preserving surgeries for malignant bone tumours have become the norm. Endoprosthesis still remains the commonest method of reconstruction after tumour resection. But when one is able to an oncologically safe intercalary resection for malignant bone tumours one method of reconstruction is reimplanting the resected tumour bone after sterilisation. Radiation given outside the body to sterilise the tumour bone is called Extra Corporeal Radiotherapy (ECRT). After resection the bone is cleaned of all its soft tissue and marrow contents and sent in a plastic container to the Radiotherapy department where it is subjected to 50 Gy of radiation which kills all cells including the tumour cells. The bone is brought back to the theatre and reimplanted after augmenting it with either bone cement or fibular grafts and stabilised by appropriate fixation devices. The advantage of reimplanting the same bone is that you get an exact match to the resected bone which is tumour free. Post operatively the joint is mobilised immediately and weight bearing started as appropriate to the fixation used. The diaphyseal end takes more time to unite than the metaphyseal end. In our series of 16 patients who had undergone ECRT and reimplantation for malignant bone tumours of the extremity and had completed two year follow up, the metaphyseal end took an average of 6.2 months (4 – 12 months) for union while the diaphyseal end united in 10.6 months (5 – 15 months). If the tumour has caused extensive destruction of the bone or has a pathological fracture, it may be mechanically not sound to reimplant it after ECRT. ECRT is an oncologically safe and mechanically stable procedure in biologically reconstructing bony defects after tumour resection.
Keywords: Extra Corporeal Radiotherapy, Bone tumour, intercalary resection.
Introduction
With the use of potent chemotherapeutic drugs, newer imaging modalities and improved surgical techniques limb preserving surgeries for malignant bone tumours have become the norm. Endoprosthetic replacement is the most commonest method used to bridge the bone defect after tumour resection [1]. Such resection commonly involve resection of the growth physis across the joint leading to limb length disparity as the child grows. To overcome this, one will have to use a growing prosthesis which can be lengthened post operatively either by invasive or non invasive techniques to compensate for the growth of the normal limb [2] These implants are expensive and are not affordable to majority of patients who undergo limb salvage surgery in our country
At times, especially in young children where the open physis can be taken as a wide margin the tumour can be resected with wide margins sparing the joint ant the physis. The bone defects after these resection can be bridged by intercalary implants or size matched allografts if one has access to good tissue bank. Biological method of reconstruction has the advantage that once it incorporates with the host bone it is a life long procedure and is not associated with the complications of using a prosthesis [3,4]. Alternative technique of biological reconstruction if one does not have access to a tissue bank would be to use a vacularised or non vascularised autograft like fibula. But at times it would be impossible to harvest enough autografts to bridge large bony defects [5]. Sterilising and reimplanting the resected tumour bone is a viable option in these situations.
The advantage of reimplanting the same bone is that you get an exact match to the resected bone which is tumour free. The different methods used to sterilise tumour bone are autoclaving, pasteurisation, liquid nitrogen and radiotherapy [6]. Autoclaving involves sterilising the bone at 1210 C for 20 minutes which kills all tumour cells. But it has got the disadvantage that it reduces the bone strength as well as destroys the Bone Morphogenic Protein (BMP) [7]. Sterilising the specimen in a water bath at 650 C for 30 minutes is called pasteurisation. It has the advantage it retains the bone strength and BMP but has the practical difficulty of maintain the sterility during the procedure [6,8]. The most common method of sterilisation technique used is radiotherapy. 50 Gy of single shot high dose radiotherapy is used to sterilise the tumor bone. The procedure of giving radiotherapy outside the human body is called Extra Corporeal Radiotherapy (ECRT). The dose of radiotherapy given is so high that it destroys all cells including the tumour cells which necessitates this dose to be given outside the human body. The mechanical strength of the bone is least affected by this procedure and there are enough publications in literature which show this to be an oncological safe procedure in sterilising tumour bone. 50 Gy of radiotherapy is sufficient in attain tumour kill [9,10,11] and any higher dose of radiation decreases the mechanical strength and revascularisation and delays graft union and incorporation. The resection is made as per the pre operative imagings (Fig 1a). Marrow curettings from both the proximal and distal cut ends are send for frozen study to ensure adequacy of tumour clearance. Intercalary resected specimen with soft tissue cover over the tumour. Now the bone is completely stripped of all its soft tissue, periosteum and medullary contents (Fig 1b). The soft tissue removed is oriented with suture tags so that adequacy of tumour clearance can be assessed by histopathological examination. The bone is thoroughly washed with Vacomycin saline using a pulse lavage (Fig 1c).
Care is taken to eliminate free space in the container with saline and cotton pads to eliminate air as air causes dispersion of radiation. Specimen is taken to the radiotherapy department and as described earlier 50 Gy of single shot radiotherapy is given to the specimen after planning CT scan (Fig 2b,2c). This procedure takes between 30 – 90 minutes depending on the radiation machine used. The specimen is then brought back to the theatre and cleaned and washed with Vancomycin saline (Fig 2d).
The medullary canal of the sterilised bone can either be filled with bone cement or fibular graft to add on to the osteoconductive property (Fig 3a). The graft is re-implanted and stabilised by appropriate plate and screw fixation (Fig 3b). Care must be taken to put only minimal screws in the re-implanted graft during fixation. In case of tibial lesions an additional medial gastrocnemius flap may be needed for covering the sub cutaneous implants (Fig 3c). Post operatively the joint is mobilised immediately and weight bearing started as appropriate to the the fixation used. Patients are followed up at the routine frequency practised for malignant bone tumours. Radiological, oncological and functional assessment are done at each visit. The diaphyseal end takes more time to unite than the metaphyseal end. In our series of 16 patients who had undergone ECRT and reimplantation for malignant bone tumours of the extremity and had completed two year follow up, the metaphyseal end took an average of 6.2 months (4 – 12 months) for union while the diaphyseal end united in 10.6 months ( 5 – 15 months) (Fig 3c, 3d).
There were two cases of non union at the diaphyseal end for which subsequent bone grafting was required to attain union.
ECRT can also be used in reconstruction of bony defects after Internal Hemipelvectomy for malignant tumours of the pelvis. Here like in the long bones the tumour can be resected with margins as per the pre chemotherapy imagings and reimplanted after ECRT and fixed with appropriate plate and screw fixation (Fig 4a-d).
ECRT and reimplantation is an inexpensive method of reconstruction which can be carried out even in hospitals without radiation facility. The specimen after resection can be transported to the nearby centre having radiation facility where ECRT can be done and brought back and reimplanted. This method eliminates the need to have a tissue bank in hospital for doing biological reconstruction and also is not associated with the complications of using massive allografts. This technique also has the advantage that it provides an exact size matched graft for reconstruction.
If the tumour has caused extensive destruction of the bone or has a pathological fracture, it may be mechanically not sound to reimplant it after ECRT and alternative methods of reconstruction like intercalary implants or allografts would be ideal. Graft fracture is one complication that can occur in this procedure. This can be reduced by using appropriate fixation devices which bridge the whole length of the graft and also augmenting the graft with bone cement or fibular graft.
ECRT is an oncologically safe and mechanically stable procedure in biologically reconstructing bony defects after tumour resection. But the success of the procedure depends on appropriate patient selection, meticulous preoperative planning, implementing these plans intra operatively and the infrastructure backup to support it.
References
1. Gosheger, G.; Gebert, C.; Ahrens, H.; Streitbuerger, A.; Winkelmann, W.; Hardes, J. Endoprosthetic reconstruction in 250 patients with sarcoma. Clin. Orthop. Relat. Res. 2006, 450, 164–171.
2. Kotz, R.I.; Windhager, R.; Dominkus, M.; Robioneck, B.; Muller-Daniels, H. A self-extending paediatric leg implant. Nature 2000, 406, 143–144.
3. Tsuchiya H, Tomita K, Minematsu K, et al. Limb salvage using distraction osteogenesis: a classification of the technique: J Bone Joint Surg [Br] 1997;79-B:403–11.
4. Plotz W, Rechl H, Burgkart R, et al. Limb salvage with tumor endoprostheses for malignant tumors of the knee: Clin Orthop 2002;405:207–15.
5. Ceruso M, Falcone C, Innocenti M, Delcroix L et al. Reconstruction with a free vascularized fibula graft associated to bone allograft after resection of malignant bone tumor of limbs. Handchir. Mikrochir. Plast. Chir. 2001, 33, 277–282.
6. Singh VA, Nagalingam J, Saad M, Pailoor J: Which is the best method of sterilization of tumour bone for reimplantation? A biomechanical and histopathological study : Biomed Engineering OnLine 2010, 9:48.
7.Kok Long Pan, Wai Hoong Chan, Gek Bee Ong, Shanmugam Premsenthil et al. Limb salvage in osteosarcoma using autoclaved tumor-bearing bone: Pan et al. World Journal of Surgical Oncology 2012,10:105
8.Jyoti Kode, Prasad Taur, Ashish Gulia, Nirmala Jambhekar, Manish Agarwal, and Ajay Puri. Pasteurization of bone for tumour eradication prior to reimplantation – An in vitro & pre-clinical efficacy study; Indian J Med Res. 2014 Apr; 139(4): 585–597.
9.Mondelaers W, Van Laere K, Uyttendaele D. Treatment of primary tumours ofbone and cartilage by extracorporeal irradiation with a low energy high power electron linac; Nuclear Instruments Methods in Physics Res 1993;70-B:898-900.
10.Hong A, Stevens G, Stalley P, et al. Extracorporeal irradiation for malignant bone tumours. Int J Radiat Oncol Biol Phys 2001;50:441-7
11.Sharma D N, Rastogi S, Bakhshi S, Rath G K, Julka P K, Laviraj M A, Khan S A, Kumar A. Role of extracorporeal irradiation in malignant bone tumors. Indian J Cancer 2013;50:306-9.
Dr.Subin Sugath
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Management of Ewing Sarcoma: Current Management and the Role of Radiation Therapy
Vol 1 | Issue 1 | May – August 2015 | page:18-22 | Monica Malik Irukulla[1,*], Deepa M Joseph[1].
Author: Monica Malik Irukulla[1,*], Deepa M Joseph[1].
[1]Department of Radiation Oncology, Nizam’s Institute of Medical Sciences, Hyderabad. India
Address of Correspondence
Dr. Monica Malik Irukulla, MD.
Department of Radiation Oncology, Nizam’s Institute of Medical Sciences, Hyderabad. India.
Email: dr_monica11@yahoo.com
Abstract
The management of Ewing sarcoma has evolved over the last few decades with successive improvement in survival rates. Multidisciplinary management is the key to successful outcomes. Dose intensity of chemotherapy is of vital importance. Local control can be effectively achieved with surgery, radiation therapy or a combination of the two. The choice of appropriate local therapy should be individualized and depends on various factors such as site, size, resectability, expected morbidity, long term effects etc. Metastatic disease remains a significant challenge and optimal therapeutic strategies still need to be defined. Current management and the role of radiation therapy in Ewing sarcoma are reviewed.
Keywords: Ewing sarcoma, radiation therapy, management.
Introduction
Ewing sarcoma family of tumors (ESFT) are a group of small round cell tumors showing varying degrees of neuroectodermal differentiation with Ewing sarcoma being the least differentiated. Primitive neuroectodermal tumors (PNET) show neuroectodermal differentiation by light microscopy, immune histochemistry (IHC) or electron microscopy [1]. According to WHO classification of bone and soft tissue tumors, Ewings sarcoma/PNET is synonymous with Ewing tumor, peripheral neuroepithelioma, peripheral neuroblastoma and Askin tumor [1]. In most of the patients, a chromosomal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor which is the major oncogene in this pathology [2].
Epidemiology
Ewing sarcoma is the second most common primary bone tumor of childhood and it most commonly occurs in the second decade of life with a slight male preponderance. The incidence of Ewing sarcoma has been reported to be low in Asian population as compared to Caucasians[3]. Data from Indian population show that it is not so uncommon[4]. The common sites of primary Ewing sarcoma are the long bones of the lower extremities (41%), pelvic bones (26%), and bones of the chest wall (16%)[5]. Extraosseous Ewing sarcoma is more commonly axial in location involving the trunk (32%), extremities (26%), head and neck (18%), the retroperitoneum (16%) etc[6]. Approximately 20-25% of patients present with metastasis at diagnosis. Common sites of metastases include lungs, bones and bone marrow.
Diagnostic Evaluation
Typical presenting symptoms include pain and swelling with occasional constitutional symptoms like fever, fatigue and loss of weight. Patients should be evaluated and managed by a multidisciplinary team of experts including pediatric oncologists, orthopedic surgeons, radiologists, pathologists and rehabilitation specialists. A biopsy should be performed in a way such that the track and scar can be included in the subsequent resection or radiation portal. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture and should be through rather than between muscle compartments avoiding the neurovascular bundles. A skilled pathologist should be available onsite to confirm adequacy of the material and review the frozen sections. A needle biopsy may be adequate if sufficient tissue can be obtained for histological, cytogenetic and molecular studies. The risk of diagnostic errors and complications increases by as much as 12-fold when the biopsy is improperly done [7]. Ewing sarcoma/PNETs usually strongly express the cell surface glycoprotein MIC2 (CD99) and this can be helpful in diagnosis of small blue round cell tumors. CD99 is however not exclusively specific for ES/PNET and is found in other tumors such as synovial sarcoma, NHL, GIST etc [8]. Approximately 85% patients have expression of EWS-FLI1 chimeric transcription factor resulting from translocation between EWS and FLI-1 gene t(11;22)(q24;q12) [9]. In most of the remaining patients, alternative translocations between EWS and another ETS- family member (ERG, FEV, ETV1, E1AF) are detected [2]. Molecular analysis for EWS-FLI 1 should be considered. The prognostic value of the same remains inconclusive until now[10]. This is being evaluated as potential therapeutic target [11]. Local imaging with MRI with or without CT scan is recommended. Conventional staging evaluation includes bilateral bone marrow aspiration and biopsy or MRI of spine and pelvis, bone scan and CT scan of the chest. Serum LDH is an important prognostic marker. Positron emission tomography (PET) combined with conventional imaging is a valuable tool in staging and restaging ESFT with a sensitivity of 96% and specificity of 92% [12]. FDG-PET can also serve as a non-invasive method to predict response to chemotherapy which is a useful prognostic marker.13 Whole-body MRI can be a useful radiation-free modality to detect metastatic lesions with a higher sensitivity than bone scintigraphy [14,15]. Fertility consultation should be done for patients desiring future child bearing before starting therapy.
Prognostic factors
5-year event free survival approaches around 70% with standard multimodality approach in localized disease [16]. Favorable prognostic factors include extremity tumors, tumor volume <100ml, normal LDH and absence of metastases at presentation. Common adverse prognostic factors include metastatic disease at presentation, extra skeletal presentation, pelvis as the primary site and poor response to induction chemotherapy. Metastatic disease is the most significant adverse prognostic factor. Those with isolated pulmonary metastasis have a slightly better outcome than those with bone or bone marrow metastasis [17]. Survival depends on the site and number of metastases and the tumor burden with 5 year survival rates ranging from approximately 30% with isolated lung metastasis to less than 20% with multiple bone metastases. Older patients do worse than patients younger than 15 years.18 Poor histologic response to chemotherapy is associated with worse outcomes in patients with localized disease [19].
Treatment
Treatment of Ewing sarcoma has evolved following evidence from large multinational trials over the past few decades with successive improvement in outcomes. Multimodality approach is the key in the management of nonmetastatic Ewing sarcoma.
Chemotherapy
The prognosis in Ewing sarcoma remained very poor until 1960s in spite of good initial response to local treatment. The introduction of chemotherapy into the treatment regimen dramatically improved the response rates and thus the cure rates. Patients are started on induction chemotherapy for 3-4 cycles followed by local therapy at 12weeks. Restaging should be done with a chest imaging and MRI of the local part before local therapy. Further adjuvant chemotherapy is continued for total treatment duration of about 10-12 months. Chemotherapy with Vincristine, Adriamycin/Actinomycin D, cyclophosphamide, (VAC) alternating with Ifosfamide and Etoposide (IE) administered at a three weekly fashion is the standard regimen. Maintaining adequate dose intensity of chemotherapy is of utmost importance. Interval compressed or dose dense chemotherapy improves DFS and has the potential to improve overall survival [20].
Local therapy
Local therapy is delivered at the completion of 3-4 cycles of chemotherapy at 12 weeks and comprises of surgery or radiotherapy or both. There are no randomized trials comparing the two modalities. The choice of local therapy depends on the site of the disease, age of the patient, expected functional outcomes and concern over the late morbidities. Although retrospective institutional series suggest superior local control and survival with surgery rather than radiation therapy, most of these studies are compromised by selection bias. A North American intergroup trial showed no difference in local control or survival based on local treatment modality – surgery, radiation therapy, or both [21]. In patients with localized Ewing sarcoma treated in cooperative intergroup studies there was no significant effect of local control modality (surgery, RT, or surgery plus RT) on OS or EFS rates. In the CESS 86 trial, although radical surgery and resection plus RT resulted in better local control rates (100% and 95%, respectively) than definitive RT (86%), there was no improvement in relapse free survival and overall survival [22]. Preoperative radiation therapy can achieve tumor shrinkage and surgical resection with negative margins in cases with borderline resectability and can potentially allow smaller fields and lower radiation doses [23].
Definitive Radiotherapy
Ewing sarcoma was described by James Ewing in 1921 as “diffuse endothelioma of bone”, a distinct entity from osteosarcoma due to its high response to radiation therapy. In the current scenario, definitive radiotherapy remains an effective local therapy strategy for patients with tumors in sites not amenable for surgical resection and in cases where resection is likely to result in unacceptable morbidity. Advances in imaging, tumor delineation, treatment planning and delivery is now allowing greater precision and sparing of normal tissues. Historically, patients were treated with whole bone irradiation. With the POG 8346 trial, adequate involved field RT with MRI based planning became the standard. Current guidelines recommend 1.5 to 2 cm margin from the gross tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2 cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS [24]. Initial treatment volume include the pre-chemotherapy volume with margin up to a dose of 45Gy, further boost is delivered to the post chemotherapy volume upto a total dose of 55.8Gy to 60Gy. Tumor size and RT dose have been shown to be predictive of local control rates in patients with non-metastatic Ewing sarcoma treated with chemotherapy and definitive RT [25]. Role of hyperfractionated radiotherapy in management of Ewing sarcoma has been evaluated in the CESS 86 trial [22]. No significant advantage has been demonstrated over the standard fractionation and dose. Recent reports suggest that Proton beam therapy can potentially spare more amount of normal tissue but longer follow up is needed to determine its impact on morbidity and cure rates [26]. Radiation therapy is associated with the development of second malignant neoplasms. In a retrospective analysis, the incidence of second malignancy was 20% in patients who received doses of 60 Gy or more and 5% in those who received 48 Gy to 60 Gy. Those who received < 48 Gy did not develop a second malignancy [27]
Postoperative RT
Postoperative radiation (PORT) is recommended in cases of intralesional or marginal resection, intraoperative spill and poor pathological response to chemotherapy and is usually initiated at 6-8 weeks following surgery. Current Children’s Oncology Group (COG) protocols have more specifically defined adequate margin status. Complete resection is defined as a minimum of 1 cm margin and ideally 2–5 cm around the involved bone. The minimum soft tissue margin for fat or muscle planes is at least 5 mm and for fascial planes at least 2 mm. The Intergroup Ewing Sarcoma Study (INT-0091) recommends 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy boost for patients with microscopic residual disease. In the absence of gross residual disease there seems to be no clear benefit to doses over 45 Gy [28]. No radiation therapy is recommended for those who have no evidence of microscopic residual disease following surgical resection. Although not statistically significant, local relapse was least in the combined arm (10.5%) compared with 25% for either surgery or radiotherapy alone [21]. EICESS 92 evaluated the role of postoperative RT in patients with poor pathological response to induction chemotherapy (<90% necrosis). In their analysis there was reduction in local failures (5% vs.12%) in the poor responders if they received PORT [29 In the CESS and EICESS trials, the local failure rate for central primaries was reduced by 50% with PORT. However the role of adjuvant radiotherapy in poor responders and central tumors needs to be clearly defined and the benefits need to be balanced against potential risks of long term effects and second malignancies. For extraskeletal ES, PORT is generally recommended except in good prognosis superficial tumors [30].
Management of metastatic disease
Standard treatment guidelines for metastatic Ewing sarcoma recommend treatment similar to localized disease [30]. Different chemotherapy agents used are Vincristine, Adriamycin, Cyclophosphamide, Ifosphamide and Etoposide. Addition of IE to VAC does not seem to have additional benefit in this subset of patients [31]. Dose-intense treatment approach with high dose chemotherapy and autologous stem cell transplantation (HDT/SCT) was evaluated in the nonrandomized Euro-EWING 99 R3 study [32]. Even though this may have a potential to improve outcome, it has not become the standard of therapy.
Following induction chemotherapy, patients are reassessed with local and chest imaging and previously abnormal investigations are repeated. A progressive disease is treated with palliative intent and the good responders are managed with treatment of primary disease and metastatic sites. Timing of local therapy for both primary site and metastatic sites remain unclear.
Radiotherapy in metastatic disease
Whole lung irradiation (WLI) in patients with lung-only metastases has shown improved disease free and overall survival in various trials. Patients with lung metastasis should be considered for whole lung irradiation even after complete resolution following chemotherapy [33] Doses of 12 to 21 Gy have been used and are usually well tolerated [34]. Hemithoracic irradiation is recommended in patients with chest wall tumor with pleural nodules, pleural effusion or positive pleural cytology.
Bone metastases in Ewing sarcoma should be treated with similar doses as the primary site. They may be treated simultaneously or following completion of chemotherapy depending on the risk of marrow suppression. In the phase II POG/CCG trial which evaluated the role of intensive chemotherapy, local treatment for primary disease was done after completion of 21weeks of chemotherapy and that of metastatic disease was done after week 39 chemotherapy [35]. With the emergence of stereotactic body radiotherapy (SBRT), it is now possible to deliver ablative doses to sites of bone metastases with excellent sparing of normal tissues. SBRT delivered in one to five fractions can also minimize interruptions of systemic therapy.
Treatment of relapse
Outlook of patients who relapse remain unfavorable. Late onset relapse (>2years) and strictly localized disease has a favorable outcome [36]. Chemotherapy regimens in relapse settings are not standard. Two phase II studies have demonstrated upto 33% partial responses in relapsed refractory Ewing’s sarcoma with the combination of Topotecan and Cyclophosphamide [37]. The combination of Irinotecan and Temozolomide has demonstrated clinical responses.38 Gemcitabine in combination with Docetaxel has shown modest activity [39]. Newer drugs and targeted therapies are being evaluated. Radiotherapy and/or surgery may play a role in improving control rates.
Indian Data
There is paucity of data from Indian population. In a retrospective analysis, symptom duration >4 months, tumor diameter >8cm and baseline WBC >11×10(9)/L were predictive of poorer outcomes [40]. Optimal surgical margin in extra skeletal Ewing sarcoma in children was evaluated by Laskar et al who concluded that clear margins of resection correlated with local control irrespective of margin size[41] Survival rates in India remain dismal in spite of the advancement seen in the western world [42]. Patients tend to present with advanced stage disease and often default treatment due to socioeconomic factors.
Conclusion
The management of Ewing sarcoma has significantly evolved over the last few decades with consequent improvements in survival and functional outcomes. Treatment mandates multidisciplinary co-ordination involving Medical, Surgical and Radiation Oncologists, Orthopedic surgeons, Rehabilitation specialists, Pediatricians and others. Dose intensity of chemotherapy and optimal timing and modality of local therapy appear to significantly influence outcomes and survival rates. Metastatic disease represents a major challenge and optimal treatment strategies still need to be defined.
References
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3.Parkin DM, Stiller CA, Nectoux J. International variations in the incidence of childhood bone tumours. International journal of cancer Journal international du cancer 1993;53:371-6.
4.Rao VS, Pai MR, Rao RC, Adhikary MM. Incidence of primary bone tumours and tumour like lesions in and around Dakshina Kannada district of Karnataka. Journal of the Indian Medical Association 1996;94:103-4, 21.
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7. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor Society. The Journal of bone and joint surgery American volume 1996;78:656-63.
8. Perlman EJ, Dickman PS, Askin FB, Grier HE, Miser JS, Link MP. Ewing’s sarcoma–routine diagnostic utilization of MIC2 analysis: a Pediatric Oncology Group/Children’s Cancer Group Intergroup Study. Human pathology 1994;25:304-7.
9. Delattre O, Zucman J, Plougastel B, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 1992;359:162-5.
10. Le Deley MC, Delattre O, Schaefer KL, et al. Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:1982-8.
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.
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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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