Tag Archive for: Osteosarcoma

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.

Figure 1      Fig 2

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).

Figure 3      Figure 4     Figure 5

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)

  Figure 6

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..

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How to Cite this article: Ansari J, Munker R, Takalkar A. Current role of FDG-PET in Bone and Soft tissue tumors. Journal of  Bone and Soft Tissue Tumors May-Aug 2015; 1(1):29-36.
Dr. Junaid Ansari
Dr. Junaid Ansari
Dr. Reinhold Munker
Dr. Reinhold Munker
Dr. Amol Takalkar
Dr. Amol Takalkar

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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).

Fig 1
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.

Fig 2
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.

Fig 3
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.Fig 4The team opted for titanium alloy as the material of choice for the ramedullary stems as a material with no biocompatibility issues given its long history of successful clinical use, the ability of the material to withstand the imposed stresses in this application with an adequate factor of safety and the lower modulus of elasticity which was perceived as a possible advantage.
Titanium alloy is known to have its own difficulties in processing and is not an easy material from a manufacturing standpoint. Fortunately, the engineering and manufacturing teams at Sushrut-Adler had developed strong experience in working with this alloy due to their previous history with successful development and commercialization of spine implants manufactured from titanium alloy and these challenges were not difficult to overcome.
The change of materials and the expected solution to the difficult stem failure issue thus opened the way for the team of surgeons and the Sushrut-Adler engineers to take the next step of modularizing the system paving the way for more widespread use. The difficulties of custom-manufacturing implants by this time were well understood and the constraint imposed on an operating surgeon working with an implant of fixed size was not desirable. Modularity enabled a surgeon to intra-operatively select the most optimum surgical margin for the excision with no concerns about having an implant size that would adapt to the length of the resection.
The surgeons’ need for modularity resulted in many months of manufacturing trials at Sushrut-Adler as the necessary self-locking tapers for the modular components were designed and proven through the manufacturing process.
The final standardized condylar dimensions enabled the team to opt for superior Cobalt Chrome alloy investment castings for the condylar components thus gaining better articulation properties with the UHMWPE components.
The culmination of all these efforts resulted in the first patient implanted with the ResTOR modular resection prosthesis in a limb salvage procedure in late 2006. The modular system was commercialized in early 2007 for distal femur and proximal tibia resections. The addition of an upper limb system and a proximal femur resection system over the next few years enabled a complete portfolio of solutions.
It may be argued, with hindsight, that the inception of this project in 1999-2000 was with a compromised implant. However, as cogently argued by Dr. Agarwal ten years later [9], many patients benefited even with these compromised implants, the failure rate of around 15% was not viewed as catastrophic and was considered acceptable in a situation where an expensive implant was not an option and where amputation or rotationplasty would have been the only alternatives for the patient. The limb salvage procedure allowed many children to continue with education and adults to remain employed. Icing on the cake came in the form of the prestigious Golden Peacock Innovation Award in 2010 which recognized this as a major health-care initiative.
The ResTOR modular resection prosthesis system since 2007 has contributed to cost-effective limb salvage surgery of more than 2000 patients in India and a number of other countries [17] with prosthesis survivorship rates comparable to those reported in literature [15,16]. As a case in point, the Tata Memorial experience of 88% implant survivorship at five years with total femoral replacement [16], a specially challenging procedure with extensive resection does great credit to the team of surgeons and engineers who worked on this project. As implant survivorship improves and a greater number of patients experience disease-free survivorship with continuously improving surgeon experience, the ResTOR team continues to face newer challenges related to the increased demands on the implant.
While many improvements have been made and will continue to be made, as global experience with limb salvage implants has shown, the demands placed on these implants are immense and the way forward promises an abundance of challenges to be faced and problems to be solved.

Note

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

References

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

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

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