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Effect of Combination Chemotherapy and Radiotherapy in the Management of a Pathological Fracture in High-grade Osteosarcoma with Limb Salvage Procedure – A Case Report

Original Article | Volume 6 | Issue 3 | JBST September – December 2020 | Page 9-12 | V.R.Ganesan, T.C.Prem Kumar, Sanjay.C, Roopesh Kumar.S DOI: 10.13107/jbst.2020.v06i03.32

Author: V.R.Ganesan[1], T.C.Prem Kumar[1], Sanjay.C[1], Roopesh Kumar.S[1]

[1]Department of Orthopaedic Surgery & Traumatology,
Madurai Medical College & GRH, Madurai, Tamilnadu. India.

Address of Correspondence
Dr. V R Ganesan,
Department of Orthopaedic Surgery & Traumatology,
Madurai Medical College & GRH , Madurai, Tamilnadu. India.
E-mail: sphospital@hotmail.com


Introduction: Osteosarcoma (OS), the most common primary bone tumor, is known to be relatively a radioresistant tumor. Pathological fracture in OS denotes its aggressive biological response and so it was considered a contraindication to limb salvage in earlier days. Radiotherapy has its role only in cases that are inoperable or have poor prognostic factors. In recent years, there have been major advances in the management of pathological fractures in high-grade OS (HGOS). This case report is about the effect of combination chemotherapy and radiotherapy in the management of pathological fracture in HGOS with limb salvage procedure.
Case Report: A 19-year-old male with pain and swelling in his right lower third of thigh and inability to walk for 3 months was diagnosed as a case of OS right distal femur with a pathological fracture. Open biopsy was done which confirmed the diagnosis as HGOS, staged Enneking IIb. He was treated with a combination of chemotherapy, external beam radiotherapy, tumor resection, and modular resection prosthesis.
Results: There were no immediate, early, and late complications. At the end of 1½ years, his functional recovery is good and he has reached more than 70% of the right knee functions. He has no signs of recurrence at present. He has got a better quality of life and functional activity with the prosthesis compared to what an amputated limb can produce.
Conclusion: Pathological fracture in OS is not a contraindication to limb salvage. Radiotherapy can be used in combination with chemotherapy and limb salvage surgery in HGOS with a pathological fracture. This combination treatment helps in increasing the chances of limb sparing surgery with good local control and tumor necrosis rate. The new knowledge that radiotherapy can be effective when used with chemotherapy has shown good result in our case.
Keywords: Osteosarcoma, pathological fracture, external beam radiotherapy, limb salvage, custom modular prosthesis.


Reference:
1. Abudu A, Sferopoulos NK, Tillman RM, Carter SR, Grimer RJ. The surgical treatment and outcome of pathological fractures in localized osteosarcoma. J Bone Joint Surg Br 1996;78:694-8.
2. Ferguson PC, McLaughlin CE, Griffin AM, Bell RS, Deheshi BM, Wunder JS. Clinical and functional outcomes of patients with a pathologic fracture in high-grade osteosarcoma. J Surg Oncol 2010;102:120-4.
3. Scully SP, Ghert MA, Zurakowski D, Thompson RC, Gebhardt MC. Pathologic fracture in osteosarcoma: Prognostic importance and treatment implications. J Bone Joint Surg Am 2002;84:49-57.
4. Glasser DB, Lane JM, Huvos AG, Marcove RC, Rosen G. Survival, prognosis and therapeutic response in osteogenic sarcoma: The Memorial Hospital experience. Cancer 1992;69:698-708.
5. Finn HA, Simon MA. Limb-salvage surgery in the treatment of osteosarcoma in skeletally immature individuals. Clin Orthop Relat Res 1991;262:108-18.
6. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited: Members of the Musculoskeletal Tumor Society. J Bone Joint Surg 1996;78:656-63.
7. Bacci G, Ferrari S, Longhi A, Donati D, Manfrini M, Giacomini S, et al. Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: Local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 2003;74:449 54.
8. Kim MS, Lee SY, Lee TR, Cho WH, Song WS, Cho SH, et al. Prognostic effect of pathologic fracture in localized osteosarcoma: A cohort/case controlled study at a single institute. J Surg Oncol 2009;100:233 9.
9. Jaffe N, Spears R, Eftekhari F, Robertson R, Cangir A, Takaue Y, et al. Pathologic fracture in osteosarcoma. Impact of chemotherapy on primary tumor and survival. Cancer 1987;59:701-9.
10. Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G. Primary bone osteosarcoma in the pediatric age: State of the art. Cancer Treat Rev 2006;32:423-36.
11. Jeon DG, Lee SY, Kim JW. Bone primary sarcomas undergone unplanned intralesional procedures the possibility of limb salvage and their oncologic results. J Surg Oncol 2006;94:592-8.
12. Xie J, Diener M, Sorg R, Wu EQ, Namjoshi M. Cost-effectiveness of denosumab compared with zoledronic acid in patients with breast cancer and bone metastases. Clin Breast Cancer 2012;12:247-58.
13. Ebeid W, Amin S, Abdelmegid A. Limb salvage management of pathologic fractures of primary malignant bone tumors. Cancer Control 2005;12:57-61.
14. Natarajan MV, Govardhan RH, Williams S, Raja GT. Limb salvage surgery for pathological fractures in osteosarcoma. Int Orthop 2000;24:170-2.
15. Cui Q, Li DF, Liu C, Guo J, Liu SB, Liu YS, et al. Two case-reports of the limb salvage treatment of osteosarcoma consolidated with obvious pathological fractures. Pathol Oncol Res 2011;17:973-9.
16. Godley K, Watts AC, Robb JE. Pathological femoral fracture caused by primary bone tumour: A population-based study. Scott Med J 2011;56:5-9.
17. Chandrasekar CR, Grimer RJ, Carter SR, Tillman RM, Abudu AT, Jeys LM. Outcome of pathologic fractures of the proximal femur in nonosteogenic primary bone sarcoma. Eur J Surg Oncol 2011;37:532-6.
18. Yin K, Liao Q, Zhong D, Ding J, Niu B, Long Q, et al. Metaanalysis of limb salvage versusamputation for treating high grade and localized osteosarcoma in patients with pathological fracture. Exp Ther Med 2012;4:889-94.
19. Scully SP, Temple HT, O’Keefe RJ, Mankin HJ, Gebhardt M. The surgical treatment of patients with osteosarcoma who sustain a pathological fracture. Clin Orthop 1996;324:227-32.
20. Machak GN, Tkachev SI, Solovyev YN, Sinyukov PA, Ivanov SM, Kochergina NV, et al. Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the extremities. Mayo Clin Proc 2003;78:147-55.
21. Caceres E, Zaharia M, Valdivia S, Hilsenbeck S. Tejada F. Local control of osteogenic sarcoma by radiation and chemotherapy. Int J Radiat Oncol Biol Phys 1984;10:35-9.
22. Dincbas FO, Koca S, Mandel NM, Hiz M, Dervişoğlu S, Seçmezacar H, et al. The role of preoperative radiotherapy in non-metastatic high-grade osteosarcoma of the extremities for limb-sparing surgery. Int J Radiat Oncol Biol Phys 2005;62:820-8.


How to Cite this article: Ganesan VR, Kumar TCP, Sanjay C, Kumar SR| Effect of Combination Chemotherapy and Radiotherapy in the Management of a Pathological Fracture in High-grade Osteosarcoma with Limb Salvage Procedure – A Case Report | Journal of Bone and Soft Tissue Tumors | September-December 2020; 6(3): 9-12.

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Osteosarcoma of the Rib: A Case Report

Original Article | Volume 6 | Issue 2 | JBST May-August 2020 | Page 17-20 | Kanu Priya Bhatia, Sameer Rastogi, Ekta Dhamija, Adarsh Barwad, Nishant Bhatia, Jyoutishman Saika. DOI: 10.13107/jbst.2020.v06i02.26

Author: Kanu Priya Bhatia[1], Sameer Rastogi[1], Ekta Dhamija[2], Adarsh Barwad[3], Nishant Bhatia[4], Jyoutishman Saika[5]

[1]Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India,
[2]Department of Radiodiagnosis, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India,
[3]Department of Pathology, All India Institute of Medical Sciences, New Delhi, India,
[4]Department of Orthopaedics, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India,
[5]Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India.

Address of Correspondence
Dr. Kanu Priya Bhatia,
Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
E-mail: bhatiakanu13@gmail.com


Abstract

Introduction: Osteosarcoma (OS) is the most common primary malignancy of bone in children and adolescents. OS has a predilection for the metaphyseal region of the long bones. The most common site of involvement is the distal femur followed by proximal tibia, proximal humerus, middle and proximal femur, and other bones. Primary OS of chest wall is a very rare entity.
Case Report: We, here, describe a case of a 14-year-old boy who presented to our center with a chest wall swelling and pleural effusion, which was subsequently diagnosed as chest wall OS originating from the rib. We treated him with neoadjuvant chemotherapy (Ifosfamide, Adriamycin, and Carboplatin). He showed an excellent transient response to the chemotherapy, after which he underwent an en bloc resection of the tumor. He was then started on adjuvant chemotherapy, but unfortunately, he relapsed soon after the last cycle and later on succumbed to the disease.
Conclusion: Chest wall OS is an infrequent malignancy. Pathological diagnosis is difficult and requires a high index of suspicion. Data regarding the prognostic factors are scarce, and no concrete guidelines are available for the management of such patients.
Keywords: Chest wall, osteosarcoma, rib.


Reference:
1. Moghazy K, Al-Jehani Y, El-Baz A, El-Ghoneimy Y. Incidental finding of a large chest wall osteosarcoma–a case report. Gulf J Oncolog 2007;1:93-7.
2. Sabatier R, Bouvier C, de Pinieux G, Sarran A, Brenot-Rossi I, Pedeutour F, et al. Low-grade extraskeletal osteosarcoma of the chest wall: Case report and review of literature. BMC Cancer 2010;10:645.
3. Qian J, Zhang XY, Gu P, Shao JC, Han BH, Wang HM. Primary thoracic extraskeletal osteosarcoma: A case report and literature review. J Thorac Dis 2017;9:E1088-95.
4. Bathurst N, Sanerkin N. Osteoclast-rich osteosarcoma. Br J Radiol 1986;59:667-73.
5. Chow LT. Giant cell rich osteosarcoma revisited-diagnostic criteria and histopathologic patterns, Ki67, CDK4, and MDM2 expression, changes in response to bisphosphonate and denosumab treatment. Virchows Arch 2016;468:741-55.
6. Daw N, Neel M, Rao B, Billups C, Wu J, Jenkins J, et al. Frontline treatment of localized osteosarcoma without methotrexate. Cancer 2011;117:2770-8.
7. Baez JC, Lee EY, Restrepo R, Eisenberg RL. Chest wall lesions in children. Am J Roentgenol 2013;200:W402-19.
8. Burt M, Fulton M, Wessner-Dunlap S, Karpeh M, Huvos AG, Bains MS, et al. Primary bony and cartilaginous sarcomas of chest wall: Results of therapy. Ann Thorac Surg 1992;54:226-32.
9. Ikeda H, Takeo M, Kayata H, Mikami R, Nakamoto Y, Yamamoto M. A case of rapidly growing osteosarcoma of the rib. Ann Thorac Cardiovasc Surg 2014;20:521-4.
10. Inchara Y, Crasta J, Ananthamurthy A, Mohanty S. An unusual case of primary osteosarcoma of the rib in an adult. Indian J Med Paediatr Oncol 2010;31:18.
11. Rad MP, Masoum SF, Layegh P, Rad MS. Primary osteosarcoma of the sternum: A case report and review of the literature. Arch Bone Joint Surg 2014;2:272-5.
12. Lim W, Sarji SA, Yik Y, Ramanujam T. Osteosarcoma of the rib. Biomed Imaging Interv J 2008;4:e7.
13. Masoud S. Scapula osteosarcoma. Biomed J Sci Tech Res 2017;1:739-42.
14. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20:776-90.


How to Cite this article: Bhatia KP, Rastogi S, Dhamija E, Barwad A, Bhatia N, Saika J | Osteosarcoma of the Rib: A Case Report | Journal of Bone and Soft Tissue Tumors | May-August 2020; 6(2): 17-20.

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Health-Related Quality of Life in Patients with Bone Tumor around the Knee after Resection Arthrodesis

Vol 5 | Issue 1 | Jan-April 2019 | page: 17-20 | Wilasinee Sirichativapee, Weerachai Kosuwon, Winai Sirichativapee.


Authors: Wilasinee Sirichativapee [1], Weerachai Kosuwon [1], Winai Sirichativapee [1].

[1] Department of Orthopaedics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.

Address of Correspondence
Dr. Winai Sirichativapee,
Department of Orthopaedics, Srinagarind Hospital, 123 Khon Kaen University, Nai Mueang Sub-District, Mueang District, Khon Kaen Province – 40002, Thailand.
E-mail: winaisiri@yahoo.com


Abstract

Background: This study aimed to compare the health-related quality of life (HRQoL) of patient with bone tumor around the knee after resection arthrodesis.
Methods: Patients between 15 and 70 years of age who underwent resection arthrodesis in Srinagarind Hospital >1 year were recruited. Patients were interviewed using a short form-36 questionnaire (social functioning-36 [SF-36] Ver2.0 Thai version) regarding their daily life problems.
Results: Eighteen patients with the mean age of 36.6 years (15–63 years) were included (15 females) in the study. Histological diagnoses were giant cell tumor 10 cases, osteosarcoma seven cases, and low-grade chondrosarcoma one case. Site of lesions was distal femur 15 cases and proximal tibia 3 cases. According to HRQoL, patients have good quality of life (score SF-36 >70) in all domains: Mean score: Physical functioning 75.55 ± 21.88, role physical 71.18 ± 22.70, bodily pain 85.41 ± 22.51, vitality 77.43 ± 16.76, general health 74.44 ± 19.16, SF 83.05 ± 26.40, role emotional 80.09 ± 22.89, and mental health 77.77 ± 21.29. Complications post-operative are broken implants (3 cases, 16.7%) and infections (4 cases, 22.2%).
Conclusion: In patients with bone tumor around the knee after resection, arthrodesis has a good quality of life in all domains in SF-36 version 2.0 questionnaire including function, pain, and mentality.
Keywords: Limb salvage, Arthrodesis, Quality of life, social functioning-36 version 2.0, Osteosarcoma, Giant cell tumor.


References

1. Tarnawska-Pierścińska M, Hołody Ł, Braziewicz J, Królicki L. Bone metastases diagnosis possibilities in studies with the use of 18F-NaF and 18F-FDG. Nucl Med Rev Cent East Eur 2011;14:105-8.
2. Sampath SC, Sampath SC, Mosci C, Lutz AM, Willmann JK, Mittra ES, et al. Detection of osseous metastasis by 18F-NaF/18F-FDG PET/CT versus CT alone. Clin Nucl Med 2015;40:e173-7.
3. Harisankar CN, Agrawal K, Bhattacharya A, Mittal BR. F-18 fluoro-deoxy-glucose and F-18 sodium fluoride cocktail PET/CT scan in patients with breast cancer having equivocal bone SPECT/CT. Indian J Nucl Med 2014;29:81-6.
4. Roop MJ, Singh B, Singh H, Watts A, Kohli PS, Mittal BR, et al. Incremental value of cocktail 18F-FDG and 18F-NaF PET/CT over 18F-FDG PET/CT alone for characterization of skeletal metastasesin breast cancer. Clin Nucl Med 2017;42:335-40.
5. Chan HP, Hu C, Yu CC, Huang TC, Peng NJ. Added value of using a cocktail of F-18 sodium fluoride and F-18 fluorodeoxyglucose in positron emission tomography/computed tomography for detecting bony metastasis: A case report. Medicine (Baltimore) 2015;94:e687.
6. Iagaru A, Mittra E, Mosci C, Dick DW, Sathekge M, Prakash V, et al. Combined 18F-fluoride and 18F-FDG PET/CT scanning for evaluation of malignancy: Results of an international multicenter trial. J Nucl Med 2013;54:176-83.
7. Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, et al. NCCN Clinical Practice Guidelines in Oncology Breast Cancer Version 2; 2016. Available from: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. [Last accessed on 2016 Oct 19].
8. Yoon SH, Kim KS, Kang SY, Song HS, Jo KS, Choi BH, et al. Usefulness of (18)F-fluoride PET/CT in breast cancer patients with osteosclerotic bone metastases. Nucl Med Mol Imaging 2013;47:27-35.
9. Israel O, Goldberg A, Nachtigal A, Militianu D, Bar-Shalom R, Keidar Z, et al. FDG-PET and CT patterns of bone metastases and their relationship to previously administered anti-cancer therapy. Eur J Nucl Med Mol Imaging 2006;33:1280-4.
10. Lapa P, Saraiva T, Silva R, Marques M, Costa G, Lima JP. Superiority of 18F-Fna PET/CT for detecting bone metastases in comparison with other diagnostic ımaging modalities. Acta Med Port 2017;30:53-60.
11. Araz M, Aras G, Küçük ÖN. The role of 18F-NaF PET/CT in metastatic bone disease. J Bone Oncol 2015;4:92-7.
12. Schirrmeister H, Glatting G, Hetzel J, Nüssle K, Arslandemir C, Buck AK. Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J Nucl Med 2001;42:1800-4.
13. Piccardo A, Puntoni M, Morbelli S, Massollo M, Bongioanni F, Paparo F, et al. 18F-FDG PET/CT is a prognostic biomarker in patients affected by bone metastases from breast cancer in comparison with 18F-naF PET/CT. Nuklearmedizin 2015;54:163-72.
14. Iagaru A, Young P, Mittra E, Dick DW, Herfkens R, Gambhir SS. Pilot prospective evaluation of 99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases. Clin Nucl Med 2013;38:e290-6.
15. Hillner BE, Siegel BA, Hanna L, Duan F, Quinn B, Shields AF. 18F-fluoride PET used for treatment monitoring of systemic cancer therapy: Results from the national oncologic PET registry. J Nucl Med 2015;56:222-8.
16. Iagaru A, Mittra E, Dick DW, Gambhir SS. Prospective evaluation of (99m)Tc MDP scintigraphy, (18)F NaF PET/CT, and (18)F FDG PET/CTfor detection of skeletal metastases. Mol Imaging Biol 2012;14:252-9.


How to Cite this article: Koç Z P, Kara P Ö, Sezer E, Erçolak V.Diagnostic Comparison of F-18 Sodium FluorideNaF, Bone Scintigraphy, and F-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Detection of Bone Metastasis. Journal of Bone and Soft Tissue Tumors Jan-Apr 2019;5(1): 17-20.

               


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Is Limb Salvage Surgery a Contra Indication in Pathological Fractures Secondary to Osteosarcoma? Do We Know The Answer?

Volume 2 | Issue 2 | May-Aug 2016 | Page 10-12 | Zeeshan Khan, Shakir Hussain, Simon Carter.


Authors: Zeeshan Khan [1], Shakir Hussain [1], Simon Carter[1].

1Orthopedic Oncology Services, Department of Surgical Oncology, Tata Memorial Hospital, Mumbai.

Address of Correspondence
Dr. Ashish Gulia
Associate Professor, Orthopedic oncology, Department of Surgical Oncology, Tata Memorial Hospital, Mumbai.
Email: aashishgulia@gmail.com


Abstract

 Osteosarcoma is the commonest primary bone tumour with a bimodal age distribution. The survivorship of patients with osteosarcoma has improved with advances in chemotherapy making limb salvage surgery the commonest surgical procedure. Pathological fractures associated with osteosarcoma, however are rare and suggests the aggressiveness of the tumour. These patients are considered as a special group due to the variable outcomes reported in the literature due to some special characteristics, prompting the discussion between limb salvage surgery versus ablative surgery.
This article reviews the reasons why this group of patients are considered challenging and also the various outcomes reported in the literature.
Keywords: Pathological fracture, osteosarcoma, outcomes


Introduction

Primary bone and soft tissue sarcomas are rare tumours. Osteosarcoma is the commonest primary bone tumour with a bimodal age distribution and with a reported incidence of 2-3 per million population per year [1, 2]. With advances in chemotherapy, the survivorship of patients with osteosarcoma has improved significantly with various studies revealing similar results with limb salvage surgery when compared with amputation [5]. Contra indications to limb salvage surgery may include involvement of the neurovascular bundle, joint involvement, progression of disease whilst on treatment, patient choice, infection and a pathological fracture (Fig. 1).
A pathological fractureassociated with osteosarcoma at presentation or during treatment is even rarer with a reported incidence of 5-10% [3, 4]. A pathological fracture can be the mode of presentation for osteosarcomas in certain cases whereas it can occur during treatment in others. This is generally considered to be an aggressive biological behaviour of the disease which in turn, historically, has been considered as a poor prognostic factor in the outcome of this special group of patients [6].

Why is this group of patients special?
This select group of patients poses a challenge to the treating orthopaedic surgeon about the modality of surgical procedure. There has been a debate over the years whether these patients should have ablative or limb salvage surgery and if there is a difference in the outcome of both with varying results reported by different authors [8].

What makes these patients special is the associated hematoma with the pathological fracture which is considered to have tumour cells which spreads locally in the tissues [7]. The extent of spread also depends on the anatomic location of fracture and whether it is intra or extra capsular. The disruption of local microvasculature is also considered to be a risk factor for development of metastasis [7]. Understandably, extra articular resection for intra articular extension of tumours is a more challenging procedure particularly when limb salvage surgery is attempted with the reported outcomes of extra articular resections in limb salvage surgery considered to be compromised as well [9]. The local contamination of soft tissues with the tumour cells is also considered to be a risk factor for local recurrence. This prompted the thought that early and aggressive surgery in the form of ablative surgery will halt the progression and spread of disease any further. The presence of a pathological fracture in osteosarcoma, therefore, has been considered as a poor prognostic factor by some authors but not by all [8, 10, 11].

Initial treatment& work up
Perhaps the most important step in the management of this select group of patients is the early recognition of the aggressiveness of the lesion and prompt referral to a specialist unit. Failure of recognition of these fractures as being pathological can lead to inappropriate treatment and potentially worse outcomes (Fig. 2) [14]. The rest of the management in a multidisciplinary team setting involves a detailed history, examination of the involved limb and joints for any effusion, local and systemic staging, biopsy and neoadjuvant chemotherapy after confirmation of diagnosis of osteosarcoma.
It is also important to note that one of the most challenging issues with this group of patients is pain management and immobilisation during the pre-operative period whilst they wait for surgery and have neoadjuvant chemotherapy. 

Immobilisation
Immobilisation for pain relief can be challenging as this depends on the location of the fracture and may involve a plaster cast, simple sling, skin traction or in some cases external fixators [15]. Significant attention should be paid to the placement of the schanz pins if an external fixator is used due to the risk of tumour spread into non-involved compartments and risk of infection which would compromise limb sparing surgery.

Prognostic factors
A pathological fracture is independently considered a poor prognostic factor in osteosarcoma but was not considered one in cases of chondrosarcoma and Ewing’s sarcoma [8, 10]. A poor response to chemotherapy and local recurrence are also considered to be poor prognostic factors for survivorship [8, 10-13]. It is however, important to note that the efficacy of chemotherapy and healing of fracturesin these special cases are considered as supportive factors for limb salvage surgery [20].

Fracture consolidation
It has been noted that these fractures heal whilst patients are on chemotherapy and in most of the cases these patients have had significant post chemotherapy necrosis(Fig. 3) [8]. On the contrary some fractures might happen whilst patients are on chemo which depicts the aggressive nature of the disease.

What is the verdict?
Limb salvage surgery should be attempted, if possible, in these patients after neoadjuvant treatment but if clear surgical margins cannot be obtained during surgery or limb salvage will result in a poor functioning limb, then ablative surgery should be considered, particularly in the paediatric population where they can adapt to prosthetics earlier than adults [16]. It is however, also important to note that after wide resection of tumour, limb salvage is still a viable option with reconstruction performed with either arthrodesis or rotationplasty where appropriate.
Scully et al, suggested that a pathological was a poor prognostic factor but it is important to note that this study was performed over a 30 year period where some patients in their series had not received any chemortherapy and there have been advances in this field over the study time period [8]. Similarly Finn et al, suggested early amputation due to the risk of local and distant tumour spread [14]. In another study, the 5 year survival in patients with pathological fractures secondary to osteosarcoma was lower than those without a fracture [18]. On the contrary Bacci et al, and Abudu et al, showed that there was no difference in the survivorship of these patients when they were treated with neoadjuvant chemotherapy [7, 11]. In a recent meta-analysis comparing limb salvage with ablative surgery for pathological fractures in high grade osteosarcomas, no significant difference between local recurrence and 5 year survival was noted [19]. Adjuvant radiotherapy in these patients has not been shown to reduce the risk of local recurrence and in fact might increase the risk of these patients undergoing further surgical procedures compromising there outcomes [7].

Future direction
All the studies performed on this select group of patients are retrospective and contain a small number of patients over a prolonged period of time. The results are further effected by variables including the heterogeneity of the patient and fracture characteristics and also the advances in chemotherapy over a period of time. Improvements in surgical techniques have also resulted in improved outcomes. Most of these variables are un avoidable due to the rarity of these cases but in order to come to a definite conclusion, a multi central randomised trial will eradicate all these bias and should guide treatment.


References

1. 1.Bielack S, Carrle D, Jost L. ESMO guidelines working group osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow up. Annals of Oncology.2008; 19, supplement 2: 94-96.
2. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg Am. 2000; 82:667-74.
3. Jaffe N, Spears R, Eftekhari F, Robertson R, Cangir A, Takaue Y, Carrasco H, Wallace S, Ayala A,Raymond K, et al. Pathologic fracture in osteosarcoma. Impact of chemotherapy on primarytumorand survival. Cancer. 1987; 59:701-09.
4. Mulder JO, Schutte HE, Kroon HM, Taconis WK. Radiologic atlas of bone tumors. Amsterdam:Elsevier Science. 1993. Intraosseous osteosarcoma: conventional type: 51-5.
5. Simon MA. Current concepts review. Limb salvage in osteosarcoma. J Bone Joint Surg Am.1988; 70:307-10.
6. Coley BL, Pool JL. Factors influencing the prognosis in osteogenic sarcoma. Ann Surg. 1940; 112:1114-28.
7. Abudu A, Sferopoulos NK, Tillman RM, Carter SR, Grimer RJ. The surgical treatment and outcome of pathological fractures in localised osteosarcoma. J Bone Joint Surg Br. 1996; 78:694-8.
8. Scully SP1, Ghert MA, Zurakowski D, Thompson RC, Gebhardt MC. Pathologic fracture in osteosarcoma: prognostic importance and treatment implications. J Bone Joint Surg Am. 2002 Jan;84-A (1):49-57.
9. Hardes J1, Henrichs MP, Gosheger G, Gebert C, Höll S, Dieckmann R, Hauschild G, Streitbürger A. Endoprosthetic replacement after extra-articular resection of bone and soft-tissue tumours around the knee. Bone Joint J. 2013 Oct; 95-B (10):1425-31.
10. Bramer JAM, Abudu AA, Grimer RJ, Carter SR, Tillman RM. Do pathological fractures influence survival and local recurrence rate in bony sarcomas?. Eur J Cancer. 2007 Sep; 43(13):1944-51.
11. Bacci G1, Ferrari S, Longhi A, Donati D, Manfrini M, Giacomini S, Briccoli A, Forni C, Galletti S.Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local andsystemic control by amputation or limb salvage after preoperative chemotherapy. ActaOrthop Scand. 2003 Aug; 74(4):449-54.
12. Meyers PA, Heller G, Healey J, Huvos A, Lane J, Marcove R, ApplewhiteA, Vlamis V, Rosen G. Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial Sloan-Kettering experience. J ClinOncol. 1992; 10:5-15.
13. Glasser DB, Lane JM, Huvos AG, Marcove RC, Rosen G. Survival, prognosis, and therapeutic response in osteogenic sarcoma. The Memorial Hospital experience. Cancer. 1992; 69:698-708.
14. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited: Members of the Musculoskeletal Tumor Society. J Bone Joint Surg [Am] 1996; 78-A: 656–663.
15. Chandrasekar CR, Grimer RJ, Carter SR, et al. Pathological fracture of the proximal femur in osteosarcoma: need for early radical surgery? ISRN Oncol 2012; 2012:512389.
16. Hosalkar HS, Dormans JP. Limb sparing surgery for pediatric musculoskeletal tumors. Pediatr Blood Cancer 2004; 42:295–310.
17. Finn HA, Simon MA. Limb-salvage surgery in the treatment of osteosarcoma in skeletally immature individuals. ClinOrthopRelat Res 1991; 262:108–118.
18. Ferguson PC, McLaughlin CE, Griffin AM, et al. Clinical and functional outcomesof patients with a pathologic fracture in high-grade osteosarcoma. J SurgOncol2010; 102:120–124.
19. Yin K, Liao Q, Zhong D, Ding J, Niu B, Long Q, Ding D. Meta-analysis of limb salvage versusamputation for treating high-grade and localized osteosarcoma in patients with pathological fracture. ExpTher Med. 2012 Nov; 4(5):889-894.
20. Scully SP, Temple HT, O’Keefe RJ, et al. The surgical treatment of patients with osteosarcoma who sustain a pathological fracture. ClinOrthop. 1996; 324:227-232.


How to Cite this article: Khan Z, Hussain S, Carter S. Is Limb Salvage Surgery a Contra Indication in Pathological Fractures Secondary to Osteosarcoma? Do We Know The Answer? Journal of Bone and Soft Tissue Tumors May- Aug 2016;2(2):10-12 .


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Radiological Review of Extremity Osteosarcoma

 Volume 2 | Issue 1 | Jan-Apr 2016 | Page 13-18  Amit Janu, Nikshita Jain, Shashikant Juvekar, Ashish Gulia.


Author: Amit Janu[1], Nikshita Jain[1], Shashikant Juvekar[1], Ashish Gulia[2].

[1]Dept of Radiodiagnosis, Tata Memorial Hospital, Parel, Mumbai. India.
[2]Orthopedic Oncology, Dept. of Surgical Oncology, Tata Memorial Hospital, Parel, Mumbai, India.

Address of Correspondence
Dr Ashish Gulia, MS (Ortho), Mch (Surgical Oncology)
Associate Professor, Orthopedic Oncology, Dept. of Surgical Oncology, Tata Memorial Hospital,
Mumbai – 400012, India.
Email: aashishgulia@gmail.com


Abstract

The paradigm shift in the overall outcomes of osteosarcoma is multi factorial. Be it introduction of chemotherapy, introduction of better
imaging or advances in the technology to produce better prosthesis, the crux lies in the correct and timely diagnosis. Radiology along with
clinical evaluation and histopathological confirmation is an essential part of the three tier system which leads to an accurate diagnosis
which forms the platform to initiate an ideal treatment to have desired oncological and functional outcomes. Plain radiography has been
the age old diagnostic tool which is still as important as was in yester century. Inclusion of high end cross sectional imaging likeCT and
MRI has not only helped in early and price diagnosis but has also proved to be a boon to operative surgeons to stage the disease locally and
plan complex limb salvage strategies. In the present article we have discussed the radiological features of various sub types of osteosarcoma
to help a clinician to assess these complex varieties of lesions.
Keywords: osteosarcoma, radiological assessment.


Introduction
Osteosarcoma is the most common primary nonhematologic bone malignancy and is the most common primary bone malignancy in children. There are various subtypes of osteosarcoma, each with distinct clinical and imaging characteristics and variable survival and an incidence of 0.2 to 0.3 per 100,000/year. Osteosarcomas can be classified as intramedullary (high grade, telangiectatic, low grade, small cell, osteosarcomatosis, gnathic), juxtacortical (parosteal, periosteal, intracortical, high-grade surface), or secondary lesions [1]. Though majority of cases are of conventional high grade intramedullary osteosarcoma accounting for 75%- 90%, it is important to differentiate them from other low grade and (low grade central and parosteal osteosarcoma) and intermediate grade osteosarcoma (Periosteal osteosarcoma). An understanding of the systematic imaging approach helps to more accurately diagnose these lesions and direct effective treatment. This article provides an organized approach to analyzing and subtyping of osteosarcoma based on radiographs and guiding the referring physician if any further imaging is warranted as there is frequently overlap with other benign and malignant entities, creating substantial diagnostic challenges. For accurate diagnosis, it is important to be aware of radiographic and cross-sectional imaging features that allow differentiation of each subtype of osteogenic sarcoma from its mimics. Osteosarcoma is a malignant tumor that is characterized by production of osteoid matrix (immature bone) and variable amounts of cartilage matrix and fibrous tissue [2]. Each subtype of the osteosarcoma exhibit distinct imaging features mimicking different benign and malignant entities, however with critical evaluation of specific features a correct diagnosis can be made. Furthermore, important prognostic information, as well therapeutic options can be evaluated based on imaging.

Conventional osteosarcoma
Conventional intramedullary osteosarcoma is the most common subtype of osteosarcoma, accounting for 75% of all cases. Conventional osteosarcoma is a high-grade neoplasm produces osteoid matrix by the tumour cells centrally within the bone and eventually involves the entire width of the bone. It is often described as amorphous, fluffy, cloud-like, solid, cotton like or ivory like on the plain radiographs. It appears as homogenously increased density within bone and in soft tissues. Approximately 90 % of the osteosarcomas show some degree of osteoid matrix on radiographs [3]. Histologically osteosarcoma is pleomorphic and can produce variable amounts of cartilage, fibrous tissue, or other components. Some osteosarcomas produce more than one type of matrix and depending on the dominant cell type, they can be further subdivided into osteoblastic (50%–80%), fibroblastic-fibrohistiocytic (7%–25%), chondroblastic (5%–25%), telangiectatic (2.5%–12%), or small cell (1%) (4). Most cases of conventional osteosarcoma are seen in second and third decades of life, peaking when patients are aged 10 to 15 years, while they are unusual in patients younger than 6 years or older than 60 years [5]. The imaging characteristics of the various subtypes of osteosarcoma are summarized in Table 1.

Table 1
Conventional osteosarcoma most frequently affects long bones (70%–80%), particularly near the knee, in the femur, tibia, and humerus. This lesion originates in the metaphysis, with extension to the epiphysis (seen in up to 80% of MR imaging studies) (Fig. 1C), however initial manifestation in epiphysis alone is extremely rare [6]. Patients with conventional osteosarcoma may present with pathologic fractures. Skip lesions also occur in about 5% of patients. The intraosseous and extraosseous extent of tumor seen in cross sectional imaging should be measured and documented which is vital in preoperative assessment and staging of osteosarcoma. Joint involvement is seen in 19% to 24% of cases and is diagnosed when hyaline cartilage is penetrated and synovial involvement is rarely seen [7]. Radiographic findings are characteristic, osteosarcoma tends to destroy cortex without expanding osseous contours, reflects its aggressive nature with osteoid matrix having a pattern of fluffy opacities, with aggressive periosteal reaction (laminated, hair-on-end, sunburst, or Codman triangle) and with a soft tissue mass in 80-90 % of the cases (Fig.1). Occasionally, the lesions are purely lytic (fibroblastic) or sclerotic (osteoblastic), but most common pattern seen is mixed lytic and sclerotic [8]. MR imaging is the examination of choice for local staging and for planning biopsies or surgery because of superior contrast resolution and multiplanar imaging. The entire involved bone should be scanned to evaluate for skip metastases. The lytic areas appears low signal on T1-weighted images and high signal on T2-weighted images, whereas the mineralized matrix appears low signal on both T1- weighted (see Fig.1C) and T2-weighted images. The T1- weighted images gives vital information regarding the anatomical extent of the marrow involvement, invasion into epiphysis and skip lesions. Treatment includes chemotherapy followed by wide surgical resection and limb salvage or amputation. Local recurrence is high if there has been a pathologic fracture. Staging work-up should include a non contrast chest CT and a whole-body bone scan. Approximately 15% to 20 % of patients present with radiographic metastases. Most common site for metastasis are lungs followed by other bones. All high-grade osteosarcoma are treated with a multimodality management. The standard sequence include a multiagent chemotherapy (Doxorubicin, cisplatin, high-dose methotrexate, etoposide and ifosphamide) followed by wide surgical excision of the primary tumor which is followed by adjuvant chemotherapy. Addition of chemotherapy has dramatically improved the overall outcomes of extremity osteosarcomas from a mere 20% to 60–70%.

Figure 1, 2

Telangiectatic osteosarcoma
Telangiectatic osteosarcoma accounts for 2 %–7% of all osteosarcomas cases and most commonly occurs in the 1st and 2nd decades of life. Telangiectatic osteosarcomas are located in the metaphysis of long bones and show asymmetric expansion, geographic lysis of bone, with an aggressive growth pattern (ill defined margins) with cortical destruction, minimal sclerosis and soft tissue mass [9, 10]. On pathological analysis, it shows dilated cavities filled with blood and septa and a small solid mass or a rim that contains high-grade osteosarcomatous cells. Commonly it appears low attenuation mass on computed tomography (CT), low signal on T1-weighted MR imaging, and high signal on T2-weighted MR imaging with fluid-fluid levels are seen in up to 90% of these lesions (Fig. 2). The imaging and pathologic features of these lesions may be confused with those of aneurysmal bone cysts, giant cell tumor, metastases and chondroblastic conventional osteosarcoma [11, 12]. The presence of thick, nodular, solid tissue within or around the cystic spaces, best seen on contrast-enhanced MR imaging along with aggressive pattern of growth and presence of matrix mineralization, is also helpful in making the diagnosis. Matrix mineralization in these lesions may be subtle on radiographs and it is better seen on CT. Imaging also helps to guide biopsy of the viable tumour areas. It is of utmost importance that these tumors must not be confused with other differentials and a biopsy should be performed before embarking on any form of definitive surgical procedure. The staging work up and management of telangiectatic osteosarcoma is similar to that of a conventional osteosarcoma.

Small-cell osteosarcoma
Small cell osteosarcoma is a distinct but rare subtype of conventional osteosarcoma which represents approximately 1- 4% of osteosarcoma cases. It most often affects patients in the 2nd and 3rd decades of life. The pathologic characteristics may be mistaken for Ewing sarcoma or primitive neuro- ectodermal tumor because its cells are small and have round and hyperchromatic nuclei, but cells of small cell osteosarcoma lack uniformity and consistently produce osteoid [13]. These lesions are most commonly seen in the metaphysis like conventional osteosarcoma, but they can be seen purely in the diaphysis in 15% of cases [14, 15]. Small-cell osteosarcoma is an intramedullary, permeative lytic lesion that is associated with cortical destruction, aggressive periosteal reaction, and soft tissue mass (Fig. 3) [16]. Differential diagnosis includes Ewing sarcoma, lymphoma, and conventional osteosarcoma. Although osteoid matrix is typically seen, purely lytic lesions may occur in up to 40% of cases. The prognosis is poor than that of conventional osteosarcoma. Some centres modify the chemotherapy like that of Ewing sarcoma due to presence of round cells but no standard concensus exist [14]. Over all staging and management of these tumors is also similar to other high grade osteosarcoma.

Low-grade central osteosarcoma
Low-grade central osteosarcoma is uncommon variant of conventional osteosarcoma also referred to as well differentiated or sclerosing osteosarcoma [20]. The mean age of presentation is slightly older and occurs in 3rd or 4th decade of life [21]. The radiologic and pathologic findings simulates those of fibrous dysplasia and benign fibro-osseous lesions often resulting in erroneous radiographic and histologic diagnosis. The presence of aggressive features like cortical destruction, permeative pattern or a soft tissue mass is helpful in differentiation of low-grade central osteosarcoma from benign fibro-osseous lesions which are better seen on CT and MRI. These cases are usually staged with a chest radiograph only. Surgery forms the main cornerstone of the management. Chemotherapy is not warranted and these are treated with wide surgical excision. The outcomes are usually excellent with wide excision, however intra-lesional resection and curettage can result in high local recurrences and transformation of initial lesion into high grade sarcoma as well [22].

Juxtacortical osteosarcoma
Juxtacortical or surface osteosarcoma refers to originating from the surface of bone and accounts for 4% to 10% of all osteosarcomas. It is usually associated with the periosteum and cortex with variable medullary canal involvement. These lesions are further divided into parosteal, periosteal, high grade surface, and intracortical osteosarcomas because of different radiological and histological findings.

Figure 3, 4

Parosteal osteosarcoma
Parosteal osteosarcoma is the most common type of juxtacortical osteosarcoma originates from the outer layer of the periosteum, accounting for 65% of juxtacortical osteosarcomas and typically manifesting in the third and fourth decades [23]. The lesion is slightly more commonly seen in women. The tumor usually occurs in the metaphysis of long bones and posterior aspect of the distal femur is the most frequent site. Pathologically, it is usually a low grade tumour with extensive osteoid matrix and minimal fibroblastic stroma with occasional areas of cartilage are seen. At radiography, the classic appearance is a lobulated, cauliflower like, juxtacortical centrally dense ossific mass, separated by radiolucent cleavage plane with adjacent normal cortex in its early stages (approximately 30% of cases at radiographs and in 65% of cases at MRI) [24, 25]. This cleavage plane refers to the periosteum interposed between the normal cortex and the tumor mass. Cortical thickening with a relative lack of aggressive periosteal reaction may also be seen (Fig.4). The ossified matrix is predominantly low in signal intensity on both T1- and T2-weighted images (Fig.4), while unmineralized soft-tissue mass larger than 1 cm3 is predominantly high in T2 signal intensity. High signal intensity indicates high grade tumour [24]. Medullary cavity invasion may be seen in 8% to 59% of cases on MR imaging, and although the prognosis of these patients of these patients is controversial, knowledge of this invasion helps in complete surgical resection. Prognosis in patients with parosteal osteosarcoma is excellent, with a 10-year survival rate of 80%. High-grade foci warrant adjuvant chemotherapy. The main differential diagnosis includes myositis ossificans, osteochondroma and periosteal chondroma. Apart from trauma history, the gradual ossification of the lesion from the periphery toward the center of the mass and no attachment to the cortex is a characteristic radiographic finding of myositis ossificans [26]. Osteochondroma have corticomedullary continuity between the tumor and the underlying medullary canal which lacks in parosteal osteosarcoma [27].

Periosteal osteosarcoma
Periosteal osteosarcoma is the second most common type of juxtacortical osteosarcoma originates from the inner germinative layer of periosteum, accounts for 25% of juxtacortical osteosarcomas and usually presents in second and third decades with slight male preponderance [28, 29]. Pathologically, it is predominantly cartilaginous with small areas of osteoid, intermediate cytologic grade distinctly lower than that of conventional osteosarcoma but higher than that of parosteal osteosarcoma. Periosteal osteosarcoma characteristically occurs in diaphysis or metadiaphysis and usually involves 50% of the osseous circumference (Fig.5). Common radiographic findings include a broad-based mass on the surface of the bone, with cortical erosions, cortical thickening and periosteal reaction. Though medullary extension can occur, it is still rare and reactive marrow changes can occur in 50% of the cases [28, 29]. Periosteal reaction is seen as perpendicular low signal intensity areas on all MR sequences arising from the inner cortex to the outer margin of the tumor (Fig.5). Pathologically tumours are chondroblastic and they usually appear low attenuation on CT and high signal on T2-weighted images. Perpendicular periosteal reaction is seen as rays of low signal intensity on all MR imaging sequences. Prognosis of patients is better than conventional osteosarcoma but worse than parosteal osteosarcoma. Treatment consists of wide local excision with limb salvage. Perisoteal osteosarcomas are intermediate grade tumors and are staged like high grade osteosarcomas. A wide surgical resection is mandatory but role of chemotherapy is controversial.

Figure 5

High-grade surface osteosarcoma
High-grade surface osteosarcoma is least common type of osteosarcoma and accounts for 10% of juxtacortical osteosarcomas. It usually manifests in second and third decade of life. Pathologically, it is high grade like conventional osteosarcoma. Radiologically, it affects the diaphysis or metadiaphysis of the long bones, involves the entire circumference of the bone and may invade the medullary cavity [30, 31]. These tumors are staged and treated like other high grade osteosarcoma.

Intracortical osteosarcoma
Intracortical osteosarcoma is a rare type of osteosarcoma that arises from the cortex and is most commonly seen in second decade. Radiologically, they affect diaphysis long bones and have a geographic lytic area with variable amounts of mineralized osteoid. The lesions may also have smooth margins and variable cortical thickening with common differential diagnosis for this condition includes osteoid osteoma or osteoblastoma. Medullary invasion is rare.

Secondary osteosarcoma
Although conventional osteosarcoma and secondary osteosarcoma are histologically indistinguishable, diagnosis is made on the basis of typical radiographic appearances in the pre existing lesions such as MFH or paget disease (Fig.7) or secondary to radiation. The prognosis for these patients is usually poor.

Osteosarcomatosis (multifocal osteosarcoma)
Osteosarcomatosis is a condition characterized by multiple intraosseous osteosarcomas believed to represent rapidly progressive multicentric metastatic disease. It accounts for 3% to 4% of all osteosarcomas. Most of these patients have a multiple radiographic lesions and pulmonary metastatic disease. Mean survival for these patients is less than 1 year

Figure 6, 7


Conclusion

Osteosarcoma is the most common primary bony malignancy in children’s. The radiologic appearances vary over a wide spectrum and may be mimicked by various benign and malignant lesions still each subtype have often characteristic radiographic features and are suggestive of the specific diagnosis most of the time. Perhaps more important, additional cross sectional imaging modalities specifically MR imaging, provide vital information for planning biopsies or preoperative staging in surgical management. Recognition of these imaging features is an important guide for the accurate diagnosis which helps our clinical colleagues regarding the often difficult and complex multimodality treatment of patients with osteosarcoma to improve the clinical outcome.


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How to Cite this article:.Janu A, Jain N, Juvekar S, Gulia A. Radiological Review of Extremity Osteosarcoma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 13-18.

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Emerging role of PET/CT in osteosarcoma

Volume 2 | Issue 1 | Jan-Apr 2016 | Page 19-21 |Nilendu C Purandare1, Venkatesh Rangarajan1


Nilendu C Purandare[1], Venkatesh Rangarajan[1]

Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Parel, Mumbai 400012

Address of Correspondence
Dr.Nilendu C Purandare
Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Parel, Mumbai 400012
Email: nilpurandare@gmail.com


Abstract

The role of PET/CT in malignant tumors has grown exponentially in the past few years. Newer methods have been investigated and older methods have been refined. This article is a brief review of its current and potential utility in osteosarcoma.
Keywords: PET/CT radioisotope scans, osteosarcoma.


Introduction:
FDG PET/CT has been used to evaluate various malignancies including those of the musculoskeletal system. It is an imaging technique that provides information about the metabolic changes associated with cancer. PET imaging uses molecules that are labelled with radio nuclides. In clinical PET practice the principal radio-isotope used is the positron emitting 18 F-FDG which is a glucose analogue labelled with radionuclide 18 F. FDG is injected intravenously and is transported from the plasma to the cells by glucose transporters (GLUT 1 & GLUT 4). It then undergoes phosphorylation within the cell by the enzyme hexokinase and is converted to FDG-6-phosphate. FDG-6-phosphate does not get further metabolised and gets trapped in the cell. Cancer cells demonstrate increased anaerobic glycolysis (Warburg effect) which is believed to be due to upregulation of glucose transporters and hexokinase and reduced levels of glucose-6-phosphatase thus limiting further metabolism of the tracer in cancer cells [1]. Thus FDG PET provides unique functional information by taking advantage of the propensity of malignant tumors to demonstrate increased glucose utilization (metabolism) as compared with normal tissue. A semiquantitative measure of the metabolic activity (corrected for the amount of radiotracer injected per kilogram of body weight and for blood glucose level) is known as the standard uptake value (SUV) . Although the degree to which both benign and malignant tumors accumulate FDG can be quite variable, malignant tumors tend to have higher SUV values. In general significant difference is noted in the SUV of benign and malignant primary bone tumors. It should be noted that the interpretation of absolute SUV values can be misleading. No cutoff value of SUV can be established in clinical practice to reliably differentiate benign from malignant primary bone tumors. Osteosarcomas (OGS) and Ewings sarcomas tend to be FDG avid whereas chondrosarcomas and soft tissue sarcomas showing a wide range of uptake depending on the histology and grade of the tumor. Since OGS is FDG concentrating tumor, FDG PET can be used for staging and restaging. FDG PET can also be used to monitor response to neo-adjuvant chemotherapy and as a prognostic and predictive marker.

Use of FDG PET in staging:
Effective treatment stratification in patients with musculoskeletal malignancies requires accurate assessment of the extent of primary tumor and evaluation for the presence of metastatic disease. MRI is the modality of choice in assessing the local extent of the primary lesion for surgical planning and PET plays a limited role. However PET may allow the noninvasive estimation of the histologic grade of tumors. The SUV of bone and soft tissue sarcomas has been used as a prognostic marker to predict patient outcomes. It has been shown that the baseline SUVmax is an independent predictor of overall survival [2]. Also FDG accumulation within a large heterogeneous tumor allows identification of the areas with the highest biologic activity. This can allow targeted biopsy from the most metabolically viable portion of the tumor, which can help in ascertaining the accurate histological grade [3]. Since OGS metastasizes to multiple skeletal sites an accurate whole body bone imaging modality is important for accurate staging. Bone scanning using 99m Tc- methylene diphosphonate(MDP) has been for several years the work horse for detection of skeletal metastases in several cancers including OGS. MDP bone scan seems to be well suited to detect skeletal involvement because of the osteoblastic nature of skeletal metastases in OGS which can be detected by a conventional MDP bone scintigraphy with a high degree of sensitivity. However MDP bone scanning can suffer from limited spatial resolution due to planar imaging. In addition the high tracer uptake in the region of the growth plates can also conceal metastatic lesions. Another limitation of bone scanning is the high number of false positives and indeterminate findings which need further confirmation with anatomical imaging. Recent studies have shown a better sensitivity of FDG PET/CT than MDP bone scan primarily due to its greater ability to detect metastases in the region of the growth plate which are often masked on bone scans [4]. Addition of CT information in an integrated PET/CT scan also reduce the number of false positives leading to better accuracy compared to bone scintigraphy. Volker et al in their study in paediatric sarcomas (Ewings, OGS & RMS) showed a higher sensitivity of FDG PET (88%) over conventional imaging (37%) for skeletal metastases from Ewings sarcoma [5]. The sensitivity however was not much different (90% for PET Vs 81% for conventional imaging) for skeletal metastases in OGS. PET was superior to conventional imaging in the correct detection of lymph node involvement (sensitivity, 95% v 25% respectively). With the availability of integrated PET/CT machines, pulmonary metastases can be diagnosed using the CT component of the PET/CT study with same accuracy as that of a chest CT obviating the need for a separate CT examination of the chest. Thus an integrated FDG PET/CT can serve as a single stop shop modality for metastatic work up of OGS patients (figure 1). Various metabolic parameters can be obtained from the FDG PET/CT study that provide valuable prognostic information. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are indicators of tumor metabolism which are independent prognostic markers and can predict metastases and survival in OGS [6].

Figures 1, 2

Role of FDG PET as a surrogate marker in assessing response to neoadjuvant therapy:
Since functional and biochemical changes in a tumor in response to therapy occur much earlier than morphologic changes, FDG PET has proven to be very useful in looking at tumor viability before the changes are evident on standard morphological imaging techniques. Various studies have found a strong correlation between the degree of tumor necrosis on histology following neo-adjucvant chemotherapy and reduction in FDG concentration in Osteosarcomas [7,8]. In patients classified as having a good response to chemotherapy there is significant reduction in tumor FDG concentration (figure 2). Thus PET using FDG can be potentially used as a non-invasive surrogate to predict response as well for prognostication [9]. A multiparameter analysis technique based on kinetic 18F-FDG data (dynamic PET) of a baseline study and after 2 cycles is helpful for the very early prediction of chemosensitivity in patients with soft-tissue sarcomas receiving neoadjuvant chemotherapy. This can have potential implications on management in the form of whether to change or intensify chemotherapy or to decide whether to salvage or ampute the limb in chemo non-responsive tumors.

Role of FDG PET in detection of disease recurrence:
Conventional imaging modalities such as CT and MR imaging are limited in their ability to differentiate treatment related changes from recurrent tumor. Distortion of normal anatomy, symmetry and tissue planes following surgery or radiation therapy makes detection of tumor recurrence difficult. Also degradation of image quality due to artifiacts produced by metallic prosthesis limits evaluation of local tumor recurrence. The whole body imaging capabilities of FDG PET allow detection of local as well as distant tumor recurrence. FDG PET/CT is useful in detecting recurrence at the primary site and is often complementary to other imaging modalities [9]. It is fairly accurate in detecting sites of distant failure as well. Its potential benefits and limitations compared to conventional imaging modalities will have be studied in larger homogenous patient groups.

18F Sodium fluoride (NaF) PET scan:
18F NaF is a bone seeking radiotracer which was introduced way back in 1962 for skeletal imaging [10]. The availability of integrated PET/CT systems has led to a renewed interest in the use of 18F-NaF for imaging skeletal metastases (Fig. 3). PET/CT imaging allows high-resolution functional imaging of the skeleton with greater sensitivity than that of planar scintigraphy/MDP bone scans. Integrated PET and CT system allows the interpretation of 18FNaF in conjunction with CT images. This enables better morphologic characterization and improved differentiation between benign and malignant lesions reducing the number if false positives and the indeterminate lesions. Studies have shown better accuracy and lesions detectability for 18F NaF PET scans as compared to MDP bone scans in several cancers.(11,12). 18F NaF PET/CT scan can image skeletal as well as lung metastases in a single examination and can be used for metastatic work up of OGS patients. Comparison of the diagnostic accuracy and cost effectiveness of FDG PET/CT and NaF PET/CT in OGS patients has not been investigated in detail and studies addressing the same need to be carried out.

Figure 3


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8. Cheon GJ, Kim MS, Lee JA, et al. Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MR imaging. J Nucl Med. 2009;50:1435–1440.
9.Franzius C, Daldrup-Link HE, Wagner-Bohn A, et al. FDG-PET for detection of recurrences from malignant primary bone tumors: comparison with conventional imaging. Ann Oncol 2002;13:157–16.
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12. Schirrmeister H, Guhlmann A, Elsner K, et al. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J Nucl Med 1999;40:1623–1629.


How to Cite this article:Purandare NC, Rangarajan V. EPurandare NC, Rangarajan V. Emerging role of PET/CT in osteosarcoma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):19-21 .

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How important are surgical margins in Osteosarcoma?

 Volume 2 | Issue 1 | Jan-Apr 2016 | Page 22-26 |Thomas P Cloake, Lee M Jeys.


Authors: Thomas P Cloake[1], Lee M Jeys[2].

[1]The Royal Orthopaedic Hospital, Bristol Road South, Birmingham, B31 2AP, UK.
[2]School of Health and Life Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK.

Address of Correspondence
Professor Lee M. Jeys
Professor of Health and Life Sciences
Aston University, Aston Triangle, Birmingham, B4 7ET, UK.
E-mail: lee.jeys@nhs.net


Abstract

Surgical resection combined with chemotherapy is the mainstay of treatment of osteosarcoma. Traditionally, surgical margins were based upon tumour grade and classified into marginal, wide or radical resection. The definition of these margins, however, remains subjective and recent research has questioned the need for wide or radical margins. Advances in surgical technique and the use of neo-adjuvant chemotherapy have led to an improvement in outcome. By reducing tumour burden, chemotherapy has provided surgeons with the option of limb salvage surgery rather than radical resection. Surgical margins and response to chemotherapy are now considered the two most important predictors of outcome in osteosarcoma. This review focuses on surgical margins with respect to limb salvage surgery and discusses the importance of response to chemotherapy.
Keywords: osteogenic sarcoma, osteosarcoma, surgical margins, chemotherapy, limb salvage surgery.


Introduction
Osteosarcoma is a high grade, primary tumour of bone in which the tumour cells produce osteoid [1]. It is the most common primary bone tumour, with an annual incidence rate of 5.0 per million [2]. Osteosarcoma is predominantly a disease of the young with a peak incidence in the second decade and displays a male predominance which is most pronounced at a younger age [3]. The treatment of osteosarcoma is challenging. The use of neo-adjuvant chemotherapy regimes combined with surgical resection has led to an improvement in outcome. Nevertheless, despite recent advances in surgical technique and chemotherapy agents, the survival rate has plateaued over the last 30 years [4]. There has been much research into prognostic factors that may help predict outcome in osteosarcoma, a number of these have been identified (see Table 1). Authors have suggested the most important, independent risk factors are the response to adjuvant chemotherapy and resection margins [5-7]. This review considers the impact of resection margins with a focus on limb salvage surgery and discusses the significance of response to chemotherapy.

Table 1

Resection margins
There has been much debate around the margin of clearance required for surgical treatment of osteosarcoma.  Enneking et al. were the first group to formally stage osteosarcoma into three distinct grades according to biologic aggressiveness, tumour site and distant metastases [8].  The authors suggested this system be used in surgical planning and inform the use of marginal, wide or radical resection margins. Nonetheless the definition of marginal or wide resection remains subjective and may vary between surgeons or units and has never been objectively defined (Fig 1).  Kawaguchi et al. developed this concept by giving distinct numerical values for desired resection margin according to the grade to tumour suggesting a 2cm margin was required for low-grade tumours and a 3cm margin was needed for high-grade neoplasms such as osteosarcoma [9].More contemporary studies have failed to reach a consensus on a numerical value for an adequate resection margin. Li et al. reported there was no difference in local recurrence when wide (>5mm) margins and close (<5mm) margins were used [10]. Bispo et al. failed to detect a difference in local recurrence using a margin of 2mm [11]. Betrand et al. found surgical margin to be the only independent risk factor for local recurrence and suggested a margin of 1mm may be adequate [12].  These papers suggest resection does not require a strict numerical margin, however efforts should be made to ensure no margins are intralesional. However, international consensus is in equipoise regarding margins, and this has made interpreting research articles very difficult. Even within units, tumour clear margins and ‘wide’ margins have become interchangeable when in reality they may be completely different and may lead to inappropriate treatment for patients. In the oncological world, the concept of patient specific treatment or ‘personalised medicine’ is gaining popularity and what is correct for one patient, may not be suitable for another patient, even with the same tumour type.

Figure 1

Limb salvage surgery

Prior to the advent of effective chemotherapy, the surgical treatment for osteosarcoma involved early radical amputation or disarticulation of the affected limb. Whilst ensuring complete removal of the tumour, performing this radical surgery on young patients caused loss of function and permanent disability, without improving patient survival. Limb salvage surgery (LSS) aims to resect the tumour, whilst maintaining function of the preserved limb, all with minimal risk to the patient (Fig 2).


Figure 2 Figure 3

 

The emergence of efficacious chemotherapy regimes, which acted to reduce tumour burden and reduce metastatic spread, and enhanced imaging techniques such as CT and MRI have led to the increased use of LSS [13-15]. By definition, the use of LSS requires preservation of limb neurovascular structures and narrower surgical margins when compared to amputation. Preservation of tissue during tumour resection has led to the inevitable decrease in resection margins, which potentially risks causing an increase in local recurrence (Fig 3). There are conflicting reports on the rate of local recurrence in LSS with some studies reporting an increase [15-17] and others a decrease [18], when compared to amputation. Considering local recurrence is associated with poor outcome, much work has been done to examine the impact of LSS on survival. Simon et al. were one of the first groups to investigate outcomes following LSS in a multi-centre retrospective review of 227 patients. They reported LSS had a comparable survival rate with amputation at 5 years follow up [19] and provided the impetus for increased uptake of LSS amongst surgeons. A large study by Bacci et al. retrospectively compared the outcome in patients who underwent LSS to amputation. The authors report that whilst LSS was associated with reduced resection margins, local recurrence and 5-year disease free survival were comparable to amputation [20]. These results are confirmed by a number of other groups, with each describing a survival rate equal to or better than that of amputation [15,17,18,21-27].It is important to consider, however, these studies are limited by their retrospective nature. Without robust methods of randomisation, treatment decisions have been based on individual patient and tumour characteristics, local practice and patient choice, leaving them open to the influence of selection bias. Postoperative quality of life is an important outcome measure in osteosarcoma. As patients with osteosarcoma are young and can expect a prolonged period of survival following treatment, the demands put upon a salvaged limb or prosthesis can be great. It is essential, therefore to ensure there is minimal risk of technical failure, the limb provides adequate function for the individual patient and has an acceptable cosmesis for both the patient and their care givers. Measurement of quality of life in children is difficult and there have been relatively few studies assessing this outcome measure. Using objective quality of life scores, LSS and amputation groups report reduced quality of life compared to population norms [29,30]. A meta-analysis comparing quality of life in patients who underwent LSS and amputation found there was no significant difference between the 2 groups. Taking into consideration all the above evidence LSS remains a safe and effective management option and when used in combination with adjuvant chemotherapy offers a good survival outcome.

Chemotherapy/chemonecrosis

The introduction of chemotherapy regimes alongside surgical resection has led to a dramatic improvement in survival. The use of chemotherapy in the treatment of osteosarcoma began in the 1970s with the use of doxorubicin and high dose methotrexate regimens [31]. Administration of chemotherapy agents before surgical resection as neo-adjuvant therapy enhanced survival from10 – 20% to 70% [32].Current modern chemotherapy regimes are based on combination therapy using methotrexate, adriamycin/doxirubicin and cisplatin. Poor response to chemotherapy has been identified as an important independent risk factor for poor prognosis. Histological evaluation of surgical resection specimens permits the classification of response to chemotherapy as good (>90% tumour necrosis) and poor (<90% tumour necrosis). Patients who display poor response are consistently reported to have worse outcome [33,34]. A number of strategies have been employed to improve results in poor responders. Evidence suggests modification of chemotherapy regime may improve results. Several groups have showed intensification of pre-operative chemotherapy enhances tumour response [35-37] and may improve survival [38-40]. This benefit however, is limited and intensification of chemotherapy beyond a certain level does not improve outcome [36,41-43]. The use of high dose, intensive treatment to induce a good response early in the disease process has also been shown not to convey overall survival benefit [38,42-44]. Further work is therefore required to optimize tumour response and improve outcome in patients with poor chemotherapy response. A recent, large, multi-national study EURAMOS-1 investigated the effect of adding the additional agents, ifosfamide and etoposide, to salvage poor response to chemotherapy, as well as evaluating the addition of pegylated interferon for good responding tumours [45]. The published initial results suggest that the addition of interferon for good responding tumours appears beneficial, however, it was poorly tolerated and frequently refused by patients. Current practice involves assessing tumour response using resection specimens following surgery, after the completion of neo-adjuvant chemotherapy, to advise further treatment[45]. Considering tumour response to chemotherapy is such a significant prognostic factor, measuring response early in the disease process may inform further management choices. Non-invasive imaging techniques such as CT [46], MRI [47-49] and F-FDG PET [50,51] have all be used to investigate response to neo-adjuvant chemotherapy. A combination of F-FDG PET and CT (F-FDG PET-CT) scanning is widely used for the detection of many cancers. Meta-analysis of the current evidence for its use in osteosarcoma has shown F-FDG PET-CT to be a valuable modality to assess chemotherapy-induced necrosis [52]. Newer techniques for evaluating response to chemotherapy prior to surgery, such as functional MRI (fMRI) are also promising and may inform surgeon’s decisions in planning surgical margins.
Patients with poor response to chemotherapy present a complex management challenge. There have been few studies presenting evidence to guide the surgical management of these patients. Bacci et al. suggested that amputation should be considered in the setting of poor response to chemotherapy due to its significant correlation with local recurrence rates [20]. Recent work in Birmingham investigated the influence of resection margins on survival in patients with poor response to chemotherapy [28]. The authors showed there was no survival benefit gained from amputation when compared to LSS with close margins, irrespective of the risk of developing local recurrence [28]. These data demonstrate resection with preservation of the limb to be a safe surgical option even in patients with poor chemonecrosis.

Predicting outcome
The current classification systems used to grade osteosarcoma, pioneered by Enneking, incorporate tumour characteristics including the presence of metastases to guide surgical management and predict prognosis [8]. However, despite the widely accepted importance of response to chemotherapy in prognosis, the current classification fails to reflect this.  In a recent presentation at International Society of Limb Salvage (ISOLS 2015), Jeys et al introduced The Birmingham Classification, which uses numerically defined tumour margins and response to chemotherapy to predict both local recurrence and survival. In this series, chemotherapy response was reported to show a significant effect on the rate of local recurrence and overall survival. It was also reported that a margin of 2mm was a statistically significant cut off value for predicting local recurrence.  Furthermore, combining resection margins (greater or lesser then 2mm) with response to chemotherapy (good, >90% or poor, <90%) was more effective in predicting local recurrence and survival than other staging systems.  This classification, however, requires further validation on a multi-centre basis.


Conclusion

Osteosarcoma continues to present a number to treatment challenges. Although surgical resection margins are an important predictor of outcome, limb salvage surgery with close margins has been shown to be a safe and effective surgical option.  Response to chemotherapy is an important independent predictor of survival.  A distinct group of poor responders exist, who despite modification to chemotherapy regimes and complete surgical excision of the tumour continue to have a poor outcome.  Current classification systems have so far failed to reflect important prognostic indicators, the Birmingham Classification represents a new, robust system for classifying osteosarcoma and predicting outcome.


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How to Cite this article: Cloake T, Jeys L.How important are surgical margins in Osteosarcoma? . Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):22-26.

Dr. Thomas P Cloake

Dr. Thomas P Cloake

Prof Lee M Jeys

Prof Lee M Jeys


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Chemotherapy in Osteosarcoma: Current Strategies

Volume 2 | Issue 1 | Jan-Apr 2016 | Page 27-32 | Sandeep Jain, Gauri Kapoor.


Authers: Sandeep Jain[1], Gauri Kapoor[1]

[1]Department of Pediatric Hematology and Oncology, Rajiv Gandhi Cancer Institute & Research Centre, Delhi.

Address of Correspondence
Dr. Gauri Kapoor MD, PhD
Director Department of Pediatric Hematology and Oncology,
Rajiv Gandhi Cancer Institute & Research Centre, Delhi.
Email: kapoor.gauri@gmail.com


Abstract

Incorporation of chemotherapy to multi-modality management of high grade osteosarcoma has led to remarkable improvement in survival rates. Its use in the neoadjuvant setting is now accepted as standard of care and has the added advantage of providing important information on histologic response. Survival rates for non-metastatic disease are nearly 70%. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups. The current review focusses on evolution of chemotherapy, controversies in its use and current standard of care for osteosarcoma.
Keywords: Osteosarcoma, chemotherapy, neoadjuvant chemotherapy.


Introduction
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents accounting for 4% of all pediatric malignancies. Approximately 20% of children present with metastatic disease at diagnosis and it remains, unquestionably the most important factor affecting long term survival. Prior to 1970, the prognosis of patients with osteosarcoma was dismal, with a 10–20 % overall survival despite being treated with radical surgeries [1-3]. Outcome of patients with osteosarcoma has improved in the past three decades with the addition of effective systemic polychemotherapy and advances in surgical resection. These have led to improvements in overall survival of patients with localized disease to the tune of 70% [4-5]. Various well coordinated systemic trials by different co-operative groups in North America and Europe have identified high-dose methotrexate (HD-MTX), cisplatin, doxorubicin, ifosfamide and etoposide as active cytotoxic agents and combinations of these drugs make up the cornerstone of treatment. Chemotherapy not only takes care of micrometastatic disease at diagnosis but also facilitates limb salvage surgery. The choice of regimen and optimal schedule of chemotherapy is somewhat controversial. In this review we focus on evolution of chemotherapy, controversies in chemotherapy use and current standard of care.

Evolution of chemotherapy
Before the introduction of chemotherapy, the outcome of patients with osteosarcoma was only 15-20%, despite adequate local control. Most patients succumbed to metastatic lung disease. These findings led to the conclusion that patients with osteosarcoma have microscopic metastatic disease at the time of diagnosis and this prompted investigators to identify active agents to target it. Initial studies to demonstrate chemosensitivity of osteosarcoma were done in the early 1970s by Sutow et al [6]. He developed a regimen called “Conpadri”which included cyclophosphamide, Oncovin (vincristine), doxorubicin (adriamycin), and L-phenylalaninemustard. Later on with the inclusion of HD-MTX, the acronym was changed to “Compadri’ [6-7]. These regimes were the first rational attempt at confirming the role of adjuvant combination chemotherapy using drugs with non-overlapping toxicities in osteosarcoma. Compadri I–III yielded a 41% 18-month disease-free survival [8]. These results suggested that addition of chemotherapy improved survival in patients with osteosarcoma. However, in the absence of randomized trials, it was not clear, to what extent improvement in surgical techniques and radiological studies contributed to achieving these results. These observations were further supported by the first randomized trial from Mayo clinic wherein patients were randomized to receive adjuvant vincristine and HD-MTX versus surgery alone[9]. This trial did not show any difference between the two arms. All these concerns were put to rest by two subsequent randomized controlled trials from North America that clearly established the survival benefit of adjuvant chemotherapy. In both these trials patients receiving no adjuvant treatment had a 2 year event free survival of just 20% compared to 66% and 55% in patients who received adjuvant chemotherapy [10-11]. These trials also established adriamycin, cisplatin, HD-MTX and alkylating drugs like ifosfamide and etoposide as active agents in the treatment of osteosarcoma. The various trials showing benefit of chemotherapy in osteosarcoma are listed in Table 1[12-22].

Table 1

Role of neoadjuvant chemotherapy
The concept of neoadjuvant chemotherapy (NACT) was first introduced at Memorial Sloan-Kettering Cancer Center (MSKCC) in their T-10 protocol [23]. Preoperative chemotherapy was administered in an effort to increase the number of patients who could undergo limb salvage as the surgeons needed time to order the prosthetic devices. Administration of NACT also had the theoretical advantage of treating presumed microscopic metastatic disease. The outcome of the T-10 trial was similar to that of the Multi Institutional Osteosarcoma Study (MIOS), with a 65% survival rate at 5 years. Importantly, the results of this trial laid the foundation for the subsequent important association between histologic necrosis and prognosis. However, there were concerns regarding the impact of delayed surgery among patients with chemo-resistant disease as well as the probability of development of resistant clone in those with high volume disease. To answer this concern Pediatric Oncology Group conducted a randomized clinical trial (POG 8651) between 1986 and 1993, comparing NACT with adjuvant chemotherapy. This trial compared immediate surgery followed by postoperative adjuvant chemotherapy with 10 weeks of the NACT (same drugs) followed by surgery in 100 patients under the age of 30 years with non-metastatic,high grade osteosarcoma. Chemotherapy consisted of alternating courses of HD-MTX with leucovorin rescue, cisplatin, doxorubicin, and bleomycin, cyclophosphamide,dactinomycin (BCD). The five-year relapse-free survival rates were similar between the two groups, 65% versus 61% for adjuvant and neoadjuvant arms respectively. There was also no difference in the number of patients who underwent limb salvage procedures (55% and 50 % for immediate and delayed surgery, respectively) [24]. On the basis of these results, the use of preoperative chemotherapy has become standard of care, given its advantages, as it allows sufficient time for surgical planning, potentially facilitates tumor removal, and permits evaluation of response to therapy. Several investigators in single and multi-institutional studies in the United States and across Europe, support this general strategy [13,14,16,18].

Histological response to chemotherapy
Most trials reveal that patients with greater than 90% necrosis following NACT have significantly better event free survival (EFS) compared to those with less than 90% necrosis. Several grading systems have been developed for assessing the effect of preoperative chemotherapy on the tumor. The two most commonly used classification systems are the Picci and Huvos classifications[Table 2]. The Institute of Rizzoli (IOR) reviewed data on localized extremity osteosarcoma in more than 1000 patients over the 19-year period from 1983 to 2002 [25]. Fifty-nine percent of all patients had good response to chemotherapy (Picci), and had a 5-year survival of 76%, compared to 56% for poor responders. The Cooperative Osteosarcoma Study group (COSS) database analyzed 1,700 patients between 1980 and 1998 that included all sites, ages, and presence or absence of metastases [26]. The data revealed that 55.6% of patients had good response to therapy. The 5-year survival rate for good and poor responders was 77.8% and 55.5% respectively. The European Osteosarcoma Intergroup (EOI) analyzed data of two consecutive studies between 1983 and 1986 and 1986 and 1991 [27]. A total of 570 patients were analyzed in the report. This analysis is notable for several differences compared to the COSS and IOR analyses. Only 28% of patients had a good histologic response, whereas 72% of patients had a poor histologic response. Their 5-year survival rate was 75% and 45% respectively. Interestingly, many of the patients included in the analysis did not receive HD-MTX as they were randomized to receive either doxorubicin and cisplatin or more intensive therapy including doxorubicin and HD-MTX. This data clearly established that histological response to chemotherapy is an important prognostic factor.

Table 2

Intensification of neoadjuvant and adjuvant chemotherapy
As it became clear that the degree of histological necrosis after pre-operative chemotherapy predicts survival, efforts were directed to intensify chemotherapy so as to achieve maximum therapeutic response. This strategy of preoperative chemotherapy intensification has been tested in COSS-86 and MSKCC T-12 study [14,28]. Although this strategy resulted in increased proportion of good responders achieving >90% necrosis, it did not translate into improved overall survival (OS) or EFS rates. Till date only INT-0133 study has shown benefit of NACT intensification [19]. The next group of trials focused to alter or intensify chemotherapy for patients with sub-optimal response to preoperative chemotherapy. In the early 1980s at Memorial Sloan-Kettering Cancer Center, poor responders had cisplatin substituted for HD-MTX in addition to continuing BCD (bleomycin, cyclophosphamide, and dactinomycin) and doxorubicin [13]. Survival of patients with intensified adjuvant treatment was similar to others. Several other reports have also failed to demonstrate benefit of intensification of therapy for poor responders[20,29]. Thus, till date it has not been possible to improve the outcome of poor responders by altering postoperative chemotherapy. An explanation for this may be that the NACT response is a surrogate measure of chemo-sensitivity of tumor and an inherently biologic unresponsive tumor is not modifiable by currently available therapies.

Table 3

Role of intra-arterial chemotherapy
The intra-arterial route was introduced in an attempt to enhance the efficacy of drugs by increasing the local concentration of chemotherapy. Alkylating agents like ifosfamide and cyclophosphamide could not be used as they required phosphorylation in liver for activation. Doxorubicin was not a suitable agent as it is associated with skin and subcutaneous necrosis. MTX achieved high tumoricidal concentrations intra-arterially but similar concentrations could also be attained via the intravenous route. Intra-arterial cisplatin was therefore, selected and found to be highly effective. Response rates with the intra-arterial route were better when compared to the intravenous route[30]. It has been used extensively at the MD Anderson Cancer Center in the TIOS pediatric trials. It was highly effective in patients with pathological fractures and neurovascular involvement. Unfortunately, intra-arterial route is labor intensive and requires general anaesthesia or conscious sedation in a radiological suite. It also requires intensive monitoring of the distal arterial vascular status during and after the infusion. Moreover, similar results could be achieved with multiple courses of combination chemotherapy administered by the intravenous route over a more prolonged period. Therefore, intra-arterial route is generally not preferred.

High Dose Methotrexate
High dose methotrexate is one of the oldest drugs used in the treatment of osteosarcoma. It is generally administered over 4-6 hours and requires aggressive hydration, leucovorin rescue, serum level monitoring and adequate infrastructure to safeguard delivery and manage toxicity. Moreover, it adds substantially to the overall cost of treatment. In addition, there are no randomized studies to compare the efficacy of higher versus intermediate doses of HD-MTX plus doxorubicin and cisplatin versus doxorubicin/cisplatin alone. Furthermore, investigators at St. Jude Children’s Research Hospital have demonstrated good outcomes with five-year EFS and OS of 66% and 75% respectively with non-methotrexate-containing chemotherapy regimen consisting of carboplatin, ifosfamide and doxorubicin [31]. All of this has led to considerable controversy regarding the optimum role of HD-MTX. Methotrexate is the only active agent that has been subjected to a comparative trial of efficacy with another active agent i.e. cisplatin. Compared to 5-20% survival of historical controls in pre-chemotherapy era, HD-MTX increased survival to 40% – 60% as a single agent. When combined with other active agents like cisplatin and doxorubicin the long term survival of 65% – 75% was reported [12-15]. Many studies have shown a favorable correlation between peak serum levels and outcome [19,32-33]. Therefore, optimum doses and administration schedule is crucial to derive optimum benefit from HD-MTX therapy. Chemotherapy regimes devoid of HD-MTX were considered, among the “major poor prognostic factors” in the treatment of osteosarcoma by Graf et al. [33]. Despite the absence of randomized trials evaluating osteosarcoma treatment with and without HD-MTX, it is generally acknowledged that methotrexate is a standard component of almost all contemporary osteosarcoma protocols in children and adolescents.

Current standard of care for patients with osteosarcoma
It is well established that chemotherapy is an integral component of osteosarcoma treatment and is essential in addition to local surgery in order to achieve a reasonable expectation of cure. Therefore, optimum treatment for osteosarcoma demands a multidisciplinary strategy. The treatment generally consists of three stages: initial cytoreduction with chemotherapy to eradicate micro metastatic disease and facilitate effective local control measures with wide negative margins; and consolidation therapy for eradication of occult residual disease to reduce the likelihood of tumor recurrence. Importantly, NACT not only helps to achieve optimal cytoreduction in facilitating limb salvage procedures but also provides a chance to assess the histologic response to chemotherapy. Most treatment protocols include cisplatin, doxorubicin and HD-MTX with or without ifosfamide plus etoposide(IE). In the recently concluded EURAMOS study, all patients received NACT: 2 blocks of MAP (methotrexate, doxorubicin and cisplatin) chemotherapy for 10 weeks followed by surgery (wide excision). Surgical excision of tumor with oncologically safe margins was the best means of local control. Post surgery, poor responders were randomized to receive MAP for 28 weeks with or without IE. All good responders continued on MAP for 28 weeks and then were randomized to no further therapy and maintenance therapy with pegylated interferon. This is the largest international trial in the history of osteosarcoma treatment and its results show that intensification of adjuvant chemotherapy by addition of IE in poor responders did not improve survival. Furthermore, in good responders addition of pegylated interferon maintenance was not useful [22]. Schema of this treatment is shown in [Figure 1] and most of the study groups endorse this strategy as current standard of care.

Figure 1

Non-methotrexate based chemotherapy for countries with limited resources
There is paucity of published data on osteosarcoma from India. Historically, the role of high dose methotrexate in the treatment of osteosarcoma has always been debatable. From the practical perspective, it requires rigorous pharmacokinetic monitoring and often the infrastructure required for monitoring is not available in many centers with limited resources. Therefore, most of the centers in India use cispaltin, doxorubicin and ifosfamide based chemotherapy. Pathak et al have reported relapse-free survival was 72% nonmetastatic osteogenic sarcoma of the extremities using cisplatin and doxorubicin as adjuvant therapy [35]. Recently, results from a single center study from India have revealed 2yr progression free survival of 70 % for patients with non-metastatic osteosarcoma [36]. In light of these results use of non methotrexate based therapy in resource constraint setting seems justified. In addition, it is desirable to focus on developing infrastructure to provide limb salvage procedures and direct resources to develop indigenous affordable prosthesis.

Treatment of relapsed osteosarcoma
Treatment of relapsed osteosarcoma has not been tested in randomized clinical trials, and thus, there is no single standard approach. Prognosis of patients with relapse depends on duration of off therapy and site of relapse. In a large database of 565 osteosarcoma patients who relapsed after being treated with one of three different NACT protocols within the European Osteosarcoma Intergroup, five year survival post relapse in those whose disease recurred after two years versus within two years of randomization was 35 versus 14 percent, respectively[37]. There is no reasonable chance of cure without complete surgical resection of all sites of disease. Choice of chemotherapy depends on agents used in front line therapy. In most of contemporary studies, most of the patients receive cisplatin and doxorubicin in front line therapy. Therefore, ifosfamide, etoposide and HD-MTX are the most commonly used drugs in relapse setting. In general, patients should be treated with any of the four most active agents that were not included in front line therapy. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue has been applied to salvage therapy. However, at least two small pilot studies failed to demonstrate significant advantage of standard salvage therapy approaches [38-39].

Newer therapies
There has been significant progress in the management of patients with osteosarcoma from 1970 to 1990. However, thereafter, progress has been stalled due to limited options available for patients with poor histologic response and those with metastatic and recurrent disease. It is clear that intensification of available chemotherapeutic agents has not translated into survival benefit for these group of patients and novel agents are required. Some of the agents being tested include mTOR inhibitor (ridaforolimus), inhibitors of insulin-like growth factor I receptor, tyrosine kinase inhibitor (sorafenib), microtubule inhibitor (oferibulin), human monoclonal antibody against RANKL (Denosumab) and anti-disialoganglioside antibody (theuseofan) [40-44]. Some of these agents have demonstrated promising results in preclinical data and may offer a potential role in adjuvant therapy in the future.

Acute toxicities and Late Effects
The most frequent acute toxicities due to chemotherapy are infections secondary to myelosuppression and mucositis. Renal dysfunction may lead to hypomagnesemia and other electrolyte abnormalities from tubular and glomerular damage induced by ifosfamide and cisplatin respectively. Ototoxicity from cisplatin and cardiac dysfunction related to anthracyclines are the other commonly observed side effects. Late effects in osteosarcoma may be attributed to local therapy i.e. surgery or to systemic chemotherapy. Those related to chemotherapy are usually agent specific. Doxorubicin is known to cause chronic cardiomyopathy which is dependent on the total cumulative dose. Longhi et al reported 2% incidence of symptomatic cardiomyoathy at a median follow up of 10 years [45]. In general, cumulative dose of doxorubicin is usually limited to less than 450 mg/m2. Anthracycline and alkylating agents may also result in second malignant neoplasm (SMN). The same authors report a 10-year and 20-year cumulative incidence of SMN of 4.9% and 6.1% respectively in osteosarcoma survivors. The alkylating agent, ifosfamide is associated with infertility, especially male infertility, so sperm cryopreservation should be offered to postpubertal boys if treatment plan includes alkylating agents. In addition, ifosfamide can cause a persistent renal tubular electrolyte loss and, less commonly, a decrease in glomerular function, in a dose-dependent fashion.


 Conclusion

Inclusion of chemotherapy in the multimodality treatment of osteosarcoma has undoubtedly improved survival from a dismal 20% to the present 60%. NACT has enabled limb salvage rates to the tune of 90-95% in most advanced centers. Outcome of patients with poor histological response and those with metastatic and recurrent disease continues to be unsatisfactory and an ongoing challenge. Therefore, there is a need to develop novel agents and biologically driven strategies to target these disease subgroups.


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How to Cite this article:Jain S, Kapoor G. Chemotherapy in Osteosarcoma: Current Strategies. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1):27-32 .

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High dose Methotrexate in Paediatric Osteosarcoma – a brief overview

Vol 1 | Issue 2 | Sep – Dec 2015 | page:22-24 | Reghu K S[1], Vivek S Radhakrishnan[1]


Author: Reghu K S[1], Vivek S Radhakrishnan[1]

[1]Aster Medicity Cheranallur Cochin, India.

Address of Correspondence
Dr. Reghu KS
Aster Medicity Cheranallur Cochin, India.
Email: reghuks@gmail.com


Abstract

Systemic combination chemotherapy protocols have significantly impacted the survival rates in paediatric osteosarcoma. A number of drugs have been found effective and high dose methotrexate (HDMtx) is of them. The clinical data available on use of HDMtx is still not clear about the effectiveness and metanalysis have found that evidence is still inadequate to recommend routine use. Few studies have strongly reported improved survival rates with high dose methotrexate and this led to more trials using the drug in standard treatment arm. However there are other studies that have failed to show any survival advantage. In this review we discuss the biology of osteosarcoma with relevance to Methotrexate, clinical trials evaluating the use of High dose Mtx in treatment of OS and recommendations based on available evidence.
Keywords: Methotrexate, Osteosarcoma, Evidence.


Introduction

The introduction of systemic combination chemotherapy has dramatically improved the survival of pediatric osteosarcoma (OS). Various combinations of chemotherapeutic agents have been tried by different study groups and centres and the common agents that have emerged as effective are Adriamycin, cisplatin, Ifosfamide, Etoposide and High does Methotrexate. The overall survival using various combinations of these agents have more or less been similar. The role of methotrexate in treatment of pediatric OS has been a contentious issue even after decades of its use. Methotrexate (Mtx) was introduced in the 1960s by for treatment of osteosarcoma by Norman Jaffe and has been a standard component of chemotherapy for pediatric OS. However evidence for high dose Mtx having an independent impact on survival is controversial. In this review we discuss the biology of ostesarcoma with relevance to Mtx, clinical trials evaluating the use of High dose Mtx in treatment of OS and recommendations based on available evidence.

Biological rationale for the use of High dose Methotrexate (HDMtx)
Methotrexate is a structural analog of folic acid that binds to dihydrofolate reductase (DHFR), and inhibits the folate metabolism in tumor cells. Polyglutamylated form of Mtx is retained in the cells better and it effectively blocks DHFR. Methotrexate is transported into the cell by the folate receptors, the reduced folate carrier (RFC), and the proton coupled folate transporter, out of which the RFC is the most relevant. Osteosarcoma tumor cells show one or more sequence alteration in the RFC gene or decreased RFC mRNA expression. Increased DHFR mRNA expression is also common ,especially in metastatic disease. These mechanisms cause OS tumor cells to be inherently resistant to standard doses of Mtx [1]. However this resistance can be overcome with higher than standard dose of Mtx which may allow transport through alternative means, such as passive diffusion and by prolonged drug exposure. Doses of 8gm/sq.m to 12gm/sq.m of Mtx are usually used in most protocols.

Evidence from Clinical trials
The data from clinical trials regarding the effect of HDMtx on survival have been ambiguous. HDMtx was incorporated as a standard component of therapy without the rigorous evidence from randomized control trials, mostly based on experience from single centre cohorts. Bacci et al demonstrated that patients receiving HDMtx had higher overall survival rates at 5 years. For patients receiving HDMTX therapy a rate of 58% was reached versus 42% for patients treated with intermediate dose MTX. MTX levels after HDMtx administration had a significant effect on survival [2]. Complete remission rate at surgery was related to serum levels and at levels below 700 micromole/liter complete remission rates were 9.9% while it was 28% at higher levels. Another randomized trial compared doxorubicin/ Cisplatin versus HDMtx with reduced dose doxorubicin and cisplatin. Disease-free survival was inferior in patients who received the 3 drug arm but overall survival was not significantly different between both treatment arms. However, the intensity of administration of MTX was compromised by the design of the study [3]. Non-methotrexate containing chemotherapy was found to be a poor prognostic factor in some studies [4]. There also have been studies which failed to show any survival benefit with HDMtx containing regimes. A randomized study conducted by the Children’s Cancer Study Group comparing HDMTX and intermediate dose Mtx in combination with doxorubicin and vincristine as adjuvant therapy did not show any benefit of HD- Mtx [5]. The results from St.Judes OS99 trial in which all patients were treated with a 3 drug non-methotrexate regimen consisting of carboplatin ,doxorubicin and Ifosfamide had favorable outcomes compared to HDMTx regime used previously by the same group [6]. The European Osteosarcoma Intergroup (EOI) compared a 2-drug regimen (doxorubicin, cisplatin) with a multi-drug regimen (HDMtx, doxorubicin, bleomycin, cyclophosphamide, dactinomycin, vincristine, cisplatin) and no difference in survival between the 2 arms was seen [7]. The frequency of MTX dosing was decreased to allow the administration of doxorubicin when compared with the multi-drug scheme similar to the T-10 Rosen scheme and with the presence of other active drugs the contribution of HDMtx was difficult to demonstrate. Attempts to enhance the efficacy of MTX-L in osteosarcoma by extending the period of administration from 4 or 6 hours to 24 hours or prolonging the interval before initiating the rescue program have not been successful. Administering a high Mtx dose by the intra-arterial route, which produces a higher local concentration, also did not enhance the efficacy.

Considerations for the Clinic Administration of High dose Methotrexate
HDMtx administration when done in centres with adequate expertise has a good safety profile. Diligent monitoring of hydration, urine pH, renal function and serum methotrexate level monitoring are absolutely needed for HDMTx administration. Protocols have to be written down, staff should be well trained and supervised in such centres. Leucovorin rescue by administering folinic acid intravenously based on serum methotrexate level monitoring is the key to successful HDMtx therapy. Algorithms to calculate leucovorin dose based on serum methotrexate levels and time interval following Mtx administration must be used. Hydration also has to be continued till the serum Mtx levels have decreased to less than 0.1 micromol/L to 0.3 micromol/L. Drugs like penicillins , NSAIDs which interfere with Mtx excretion must not be used concomitantly. Use of carboxypeptidase should be considered if serum methotrexate concentration is >10 micromol/L more than 48 hours after methotrexate administration or if there is a rise in creatinine of 100% or more within 24 hours of methotrexate. It reduces mtx levels dramatically within minutes of administration. Access to Glucarpidase when required is recommended.
HDMtx must be avoided in case of pleural effusion or ascites due to retention and slow release of Mtx .
Complications that can occur with HDMtx are renal failure, severe mucositis, myelosuppression and encephalopathy.

Mechanisms of Methotrexate Resistance in Osteosarcoma
DHFR gene amplification and impaired transport of Mtx are two common mechanisms of acquired resistance observed. Decreased RFC expression was associated with a worse histological response to preoperative chemotherapy that includes HDMtx treatment. Increased DHFR expression represents acquired MTX resistance and is an uncommon mechanism for intrinsic resistance [8]. Emergence of a resistant clone or acquisition of DHFR gene mutations could be the underlying causes. Rb gene mutations which are common in OS cause elevated E2F expression and is proposed to elevate the DHFR levels [9].

Challenges in developing nations
The scenario in developing nations like India has been gradually improving. But the survival rates are still low compared to the developed nations. There is a lack of data regarding treatment details and survival outcomes in pediatric OS. Most centres in India use Cisplatin/doxorubicin based regimes which do not contain HDMtx. In a yet to be published study from a high volume cancer centre in India, survival figures of pediatric OS treated with cisplatin/Adriamycin/Ifosfamide chemotherapy the overall OS and DFS were 54.6 and 43.4 respectively at 3 years (personal communication). The DFS was 0% at 3 years for patients with metastatic disease at presentation. Similar experience is shared by other centres in the country using non-methotrexate regimes.
Though it is tempting to consider addition of HDMtx in such a scenario , the limited resources in developing nations precludes its routine use for pediatric OS. Lack of facilities for Mtx level monitoring, high infection rates , underlying malnutrition, inadequate supportive care facilities makes it difficult to administer HDMtx to most of the pediatric OS patients in India.

Current recommendation
Based on available studies a Cochrane meta-analysis concluded that data is inadequate to make a definite recommendation for HDMtx [10]. It seems unlikely that there will be in the future any large RCTs to unequivocally establish the superiority of HDMtx. Despite this, HDMtx is an essential component of standard arms of ongoing trials. The recent EURAMOS trial has 12gm/sq.m of Mtx in the neoadjuvant chemotherapy phase for all patients [11]. Absence of RCTs should not dissuade the addition of HDMtx, especially in centres which have poor outcomes with non-methotrexate chemotherapy regimes. Addition of HDMtx may provide an edge over existing chemotherapy and should be attempted , provided that the prerequisites for HDMtx therapy as discussed above are available. One approach could be to try HDMtx for high risk OS patients first and based on the experience gathered, treatment may be extended to standard risk patients as well.


References

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How to Cite this article: Reghu KS, Radhakrishnan VS. High dose Methotrexate in Paediatric Osteosarcoma – a brief overview. Journal of  Bone and Soft Tissue Tumors Sep-Dec 2015;1(2): 22-24 .

R  
              Dr. K S Reghu
V

Dr. Vivek S Radhakrishnan


     


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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