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.


References

1. Fletcher C, Bridge J, Hogendoorn P, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. Fourth Edition ed.; 2013. p. 247.
2. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res 2009;152:3-13.
3. Dorfman HD, Czerniak B. Bone cancers. Cancer 1995 Jan 1;75(1 Suppl):203-210.
4. Allison DC, Carney SC, Ahlmann ER, Hendifar A, Chawla S, Fedenko A, et al. A meta-analysis of osteosarcoma outcomes in the modern medical era. Sarcoma 2012;2012:704872.
5. Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 2006 Mar 1;106(5):1154-1161.
6. 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 Feb 1;20(3):776-790.
7. Picci P, Sangiorgi L, Rougraff BT, Neff JR, Casadei R, Campanacci M. Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma. J Clin Oncol 1994 Dec;12(12):2699-2705.
8. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980 Nov-Dec;(153)(153):106-120.
9. Kawaguchi N, Ahmed AR, Matsumoto S, Manabe J, Matsushita Y. The concept of curative margin in surgery for bone and soft tissue sarcoma. Clin Orthop Relat Res 2004 Feb;(419)(419):165-172.
10. Li X, Moretti VM, Ashana AO, Lackman RD. Impact of close surgical margin on local recurrence and survival in osteosarcoma. Int Orthop 2012 Jan;36(1):131-137.
11. Bispo Junior RZ, Camargo OP. Prognostic factors in the survival of patients diagnosed with primary non-metastatic osteosarcoma with a poor response to neoadjuvant chemotherapy. Clinics (Sao Paulo) 2009;64(12):1177-1186.
12. Bertrand TE, Cruz A, Binitie O, Cheong D, Letson GD. Do Surgical Margins Affect Local Recurrence and Survival in Extremity, Nonmetastatic, High-grade Osteosarcoma? Clin Orthop Relat Res 2015 May 27.
13. Ayerza MA, Farfalli GL, Aponte-Tinao L, Muscolo DL. Does increased rate of limb-sparing surgery affect survival in osteosarcoma? Clin Orthop Relat Res 2010 Nov;468(11):2854-2859.
14. Kotz R, Dominkus M, Zettl T, Ritschl P, Windhager R, Gadner H, et al. Advances in bone tumour treatment in 30 years with respect to survival and limb salvage. A single institution experience. Int Orthop 2002;26(4):197-202.
15. Tsuchiya H, Tomita K. Prognosis of osteosarcoma treated by limb-salvage surgery: the ten-year intergroup study in Japan. Jpn J Clin Oncol 1992 Oct;22(5):347-353.
16. Brosjo O. Surgical procedure and local recurrence in 223 patients treated 1982-1997 according to two osteosarcoma chemotherapy protocols. The Scandinavian Sarcoma Group experience. Acta Orthop Scand Suppl 1999 Jun;285:58-61.
17. Rougraff BT, Simon MA, Kneisl JS, Greenberg DB, Mankin HJ. Limb salvage compared with amputation for osteosarcoma of the distal end of the femur. A long-term oncological, functional, and quality-of-life study. J Bone Joint Surg Am 1994 May;76(5):649-656.
18. Sluga M, Windhager R, Lang S, Heinzl H, Bielack S, Kotz R. Local and systemic control after ablative and limb sparing surgery in patients with osteosarcoma. Clin Orthop Relat Res 1999 Jan;(358)(358):120-127.
19. Simon MA, Aschliman MA, Thomas N, Mankin HJ. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. 1986. J Bone Joint Surg Am 2005 Dec;87(12):2822.
20. Bacci G, Ferrari S, Lari S, Mercuri M, Donati D, Longhi A, et al. Osteosarcoma of the limb. Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg Br 2002 Jan;84(1):88-92.
21. Mavrogenis AF, Abati CN, Romagnoli C, Ruggieri P. Similar survival but better function for patients after limb salvage versus amputation for distal tibia osteosarcoma. Clin Orthop Relat Res 2012 Jun;470(6):1735-1748.
22. Lindner NJ, Ramm O, Hillmann A, Roedl R, Gosheger G, Brinkschmidt C, et al. Limb salvage and outcome of osteosarcoma. The University of Muenster experience. Clin Orthop Relat Res 1999 Jan;(358)(358):83-89.
23. Bacci G, Ruggieri P, Bertoni F, Ferrari S, Longhi A, Biagini R, et al. Local and systemic control for osteosarcoma of the extremity treated with neoadjuvant chemotherapy and limb salvage surgery: the Rizzoli experience. Oncol Rep 2000 Sep-Oct;7(5):1129-1133.
24. Eilber FR, Mirra JJ, Grant TT, Weisenburger T, Morton DL. Is amputation necessary for sarcomas? A seven-year experience with limb salvage. Ann Surg 1980;192(4):431-438.
25. Jiang F, Shi Y, Li GJ, Zhou F. A meta-analysis of limb-salvage versus amputation in the treatment of patients with Ennekingdouble daggerU pathologic fracture osteosarcoma. Indian J Cancer 2015 Feb;51 Suppl 2:e21-4.
26. Yin K, Liao Q, Zhong D, Ding J, Niu B, Long Q, et al. Meta-analysis of limb salvage versus amputation for treating high-grade and localized osteosarcoma in patients with pathological fracture. Exp Ther Med 2012 Nov;4(5):889-894.
27. Schrager J, Patzer RE, Mink PJ, Ward KC, Goodman M. Survival outcomes of pediatric osteosarcoma and Ewing’s sarcoma: a comparison of surgery type within the SEER database, 1988-2007. J Registry Manag 2011 Autumn;38(3):153-161.
28. Reddy KI, Wafa H, Gaston CL, Grimer RJ, Abudu AT, Jeys LM, et al. Does amputation offer any survival benefit over limb salvage in osteosarcoma patients with poor chemonecrosis and close margins? Bone Joint J 2015 Jan;97-B(1):115-120.
29. Bekkering WP, Vliet Vlieland TP, Koopman HM, Schaap GR, Schreuder HW, Beishuizen A, et al. Quality of life in young patients after bone tumor surgery around the knee joint and comparison with healthy controls. Pediatr Blood Cancer 2010 May;54(5):738-745.
30. Eiser C, Darlington AS, Stride CB, Grimer R. Quality of life implications as a consequence of surgery: limb salvage, primary and secondary amputation. Sarcoma 2001;5(4):189-195.
31. Rosen G, Murphy ML, Huvos AG, Gutierrez M, Marcove RC. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 1976 Jan;37(1):1-11.
32. Anninga JK, Gelderblom H, Fiocco M, Kroep JR, Taminiau AH, Hogendoorn PC, et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer 2011 Nov;47(16):2431-2445.
33. Winkler K, Beron G, Delling G, Heise U, Kabisch H, Purfurst C, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 1988 Feb;6(2):329-337.
34. Goorin AM, Schwartzentruber DJ, Devidas M, Gebhardt MC, Ayala AG, Harris MB, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 2003 Apr 15;21(8):1574-1580.
35. Fuchs N, Bielack SS, Epler D, Bieling P, Delling G, Korholz D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998 Aug;9(8):893-899
36. Smeland S, Muller C, Alvegard TA, Wiklund T, Wiebe T, Bjork O, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 2003 Mar;39(4):488-494.
37. Winkler K, Bielack SS, Delling G, Jurgens H, Kotz R, Salzer-Kuntschik M. Treatment of osteosarcoma: experience of the Cooperative Osteosarcoma Study Group (COSS). Cancer Treat Res 1993;62:269-277.
38. Fuchs N, Bielack SS, Epler D, Bieling P, Delling G, Korholz D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998 Aug;9(8):893-899
39. Ferrari S, Mercuri M, Picci P, Bertoni F, Brach del Prever A, Tienghi A, et al. Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic tumor response. Tumori 1999 Nov-Dec;85(6):458-464.
40. Bacci G, Ferrari S, Bertoni F, Ruggieri P, Picci P, Longhi A, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report.J Clin Oncol 2000 Dec 15;18(24):4016-4027.
41. Ferrari S, Smeland S, Mercuri M, Bertoni F, Longhi A, Ruggieri P, et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and ScandinavianSarcoma Groups. J Clin Oncol 2005 Dec 1;23(34):8845-8852.
42. Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007Jan 17;99(2):112-128.
43. Meyers PA, Gorlick R, Heller G, Casper E, Lane J, Huvos AG, et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J Clin Oncol 1998 Jul;16(7):2452-2458.
44. Eselgrim M, Grunert H, Kuhne T, Zoubek A, Kevric M, Burger H, et al. Dose intensity of chemotherapy for osteosarcoma and outcome in the Cooperative Osteosarcoma Study Group (COSS) trials. Pediatr Blood Cancer 2006 Jul;47(1):42-50.
45. Whelan JS, Bielack SS, Marina N, Smeland S, Jovic G, Hook JM, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol 2015 Feb;26(2):407-414.
46. Wellings RM, Davies AM, Pynsent PB, Carter SR, Grimer RJ. The value of computed tomographic measurements in osteosarcoma as a predictor of response to adjuvant chemotherapy. Clin Radiol 1994 Jan;49(1):19-23.
47. Bajpai J, Gamnagatti S, Kumar R, Sreenivas V, Sharma MC, Khan SA, et al. Role of MRI in osteosarcoma for evaluation and prediction of chemotherapy response: correlation with histological necrosis. Pediatr Radiol 2011 Apr;41(4):441-450.
48. Uhl M, Saueressig U, Koehler G, Kontny U, Niemeyer C, Reichardt W, et al. Evaluation of tumour necrosis during chemotherapy with diffusion-weighted MR imaging: preliminary results in osteosarcomas. Pediatr Radiol 2006 Dec;36(12):1306-1311.
49. Hayashida Y, Yakushiji T, Awai K, Katahira K, Nakayama Y, Shimomura O, et al. Monitoring therapeutic responses of primary bone tumors by diffusion-weighted image: Initial results. Eur Radiol 2006 Dec;16(12):2637-2643.
50. Im HJ, Kim TS, Park SY, Min HS, Kim JH, Kang HG, et al. Prediction of tumour necrosis fractions using metabolic and volumetric 18F-FDG PET/CT indices, after one course and at the completion of neoadjuvant chemotherapy, in children and young adults with osteosarcoma. Eur J Nucl MedMol Imaging 2012 Jan;39(1):39-49.
51. Cheon GJ, Kim MS, Lee JA, Lee SY, Cho WH, Song WS, et al. Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI. J Nucl Med 2009 Sep;50(9):1435-1440.
52. Hongtao L, Hui Z, Bingshun W, Xiaojin W, Zhiyu W, Shuier Z, et al. 18F-FDG positron emission tomography for the assessment of histological response to neoadjuvant chemotherapy in osteosarcomas: a meta-analysis. Surg Oncol 2012 Dec;21(4):e165-70.
53. Duchman KR, Gao Y, Miller BJ. Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Results (SEER) Program database. Cancer Epidemiol 2015 Aug;39(4):593-599.
54. Ferrari S, Bertoni F, Mercuri M, Picci P, Giacomini S, Longhi A, et al. Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001 Aug;12(8):1145-1150.


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


 (Abstract    Full Text HTML)      (Download PDF)


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.


References

1. Francis K, Worcester JJ. Radical resection for tumors of the shoulder with preservation of a functional extremity. J Bone Joint Surg Am 1962;44:1423
2. Marcove RC, Miké V, Hajek JV, Levin AG, Hutter RV. Osteogenic sarcoma under the age of twenty-one: A review of one hundred and forty-five operative cases. J Bone Joint Surg Am 1970;52(3):411
3. Friedman MA, Carter SK. The therapy of osteogenic sarcoma: current status and thoughts for the future. J SurgOncol, 1972;4:482–510
4. Link MP, Gebhardt MC, Meyers PA. Osteosarcoma. In: Pizzo A, Poplack G (eds), Principles and Practice of Pediatric Oncology, 4th edition, Philadelphia: Lippincott Williams and Wilkins. 2002;1051–89.
5. Meyers P, Osteosarcoma. In: Pappo A (ed.), Pediatric Bone and Soft Tissue Sarcomas, Berlin: Springer-Verlag. 2006;219–33
6. Sutow WW. Combination Chemotherapy with Adria- mycin (NSC-123127) in Primary Treatment of Osteogen- icsarcoma (Part III) Cancer Chemotherapy Reports. 1975;6: 315-317
7. Sutow WW, Gehan EA, Dyment PC. Multi- Drug Adjuvant Chemotherapy in Osteosarcoma. Interim Report of the Southwest Oncology Group Studies. Cancer Chemotherapy Reports 1962; 62:265-269
8. Herson J, Sutow WW, Elder K. Adjuvant chemotherapy in nonmetastatic osteosarcoma: a Southwest Oncology Group study. Medical and Pediatric Oncology 1980;8:343– 352
9. Edmonson JH, Creagan ET, Gilchrist GS. Phase II study of high-dose methotrexate in patients with unresectable metastatic osteosarcoma. Cancer Treat Rep 1981; 65:538
10. Link MP, Goorin AM, Miser AW et al. The effect of adjuvant chemotherapy on relapse free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986; 314: 1600-1606
11. Eilber F, Giuliano A, Eckardt J, Patterson K, Moseley S, Goodnight J. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J.Clin.Oncol 1987; 5: 21-26.
12. Rosen G, Nirenberg A, Caparros B et al. Osteogenic sarcoma: eight-percent, three-year, disease-free survival with combination chemotherapy (T-7). Natl Cancer Inst Monogr 1981;56:213-20
13. Rosen G, Caparros B, Huvos AG et al Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy Cancer. 1982;49:1221-30
14. Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istitutoortopedicorizzoli according to the istitutoortopedicorizzoli/osteosarcoma-2 protocol: an updated report. J ClinOncol 2000;18:4016–27
15. Bacci G, Briccoli A, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli’s 4th protocol. Eur J Cancer 2001;37:2030–9
16. Souhami RL, Craft AW, EijkenJWvd, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997;350:911–7
17. Lewis IJ, Nooij MA, Whelan J, et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007;99:112–28
18. Fuchs N, Bielack SS, Epler D, et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998;9:893–9
19. Seter G, Alvegård TA, Elomaa I et al. Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study. J ClinOncol 1991;9:1766-75
20. Provisor AJ, Ettinger LJ, Nachman JB, et al. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children’s Cancer Group. J ClinOncol 1997;15:76
21. Meyers PA, Schwartz CL, Krailo M et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyltripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J ClinOncol 2005;23(9):2004-11
22. Bielack SS, Smeland S, Whelan JS, et al. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomized controlled trial. J ClinOncol 33:2279-2287, 2015
23. Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer 43:2163-2177, 1979
24. Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J ClinOncol 2003;21:1574–80
25. Bacci G, Bertoni F, Longhi A, et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity: Histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer 2003;97):3068
26. Bielack SS, Nishida Y, Nakashima H, Shimoyama Y, Nakamura S, Ishiguro N. 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 ClinOncol 2002;20:77
27. Hauben EI, Weeden S, Pringle J, Van Marck EA, Hogendoorn PC. Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup. Eur J Cancer 2002;38:1218
28. Meyers PA, Gorlick R, Heller G, et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J ClinOncol 1998;16:2452–8
29. Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J ClinOncol 1988;6:329
30. Bielack S, Ertman R, Looft G, Purfürst C, Delling G, Winkler K, Landbeck G. Platinum disposition after intraarterial and intravenous infusion of cisplatinum for osteosarcoma. Cancer ChemotherPharmacol 1988;24:376-80
31. Daw NC, Neel MD, Rao BN, et al. Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children’s Research Hospital OS99 trial. Cancer 2011; 117:2770
32. Delepine N, Delepine G, Jasmin C, et al. Importance of age and methotrexate dosage: prognosis in children and young adults with high-grade osteosarcomas. Biomed Pharmacother 1988; 42:257
33. Graf N, Winkler K, Betlemovic M, et al. Methotrexate pharmacokinetics and prognosis in osteosarcoma. J ClinOncol 1994; 12:1443
34. Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J ClinOncol. 1992;10:1579–1591
35. Pathak AB, Advani SH, Iyer RS et al. Adjuvant chemotherapy for osteogenic sarcoma of the extremity with sequential adriamycin and cisplatin. J SurgOncol. 1993;52:181-4
36. Bajpai J, Chandrakanth MV, Shetty N et al. s non-HD–MTX based, dose-dense, combination chemotherapy a valid choice in osteosarcoma in developing world? J ClinOncol 2014 ;32:5s, (suppl; abstr 10537)
37. Gelderblom H, Jinks RC, Sydes M, et al. Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials. Eur J Cancer 2011; 47:895
38. Sauerbrey A, Bielack S, Kempf-Bielack B, Zoubek A, Paulussen M, Zintl F. High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma. Bone Marrow Transplant 2001;27:933
39. Fagioli F, Aglietta M, Tienghi A, et al. High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J ClinOncol 2002;20:2150
40. Chawla SP, Staddon AP, Baker LH, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J ClinOncol 30:7884, 2012
41. GrignaniG,PalmeriniE,DileoP,etal. Aphase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: An Italian Sarcoma Group study. Ann Oncol 23:508-516, 2012
42. Kolb EA, Gorlick R, Reynolds CP, et al. Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program. Pediatr Blood Cancer 60:1325-1332, 2013
43. Beristain AG, Narala SR, Di Grappa MA, et al. Homotypic RANK signaling differentially regulates proliferation, motility and cell survival in osteosarcoma and mammary epithelial cells. J Cell Sci 125: 943-955, 2012
44. Roth M, Linkowski M, Tarim J, et al. Ganglioside GD2 as a therapeutic target for antibodymediated therapy in patients with osteosarcoma. Cancer 120:548-554, 2014
45. Longhi A, Ferrari S, Tamburini A, et al. Late effects of chemotherapy and radiotherapy in osteosarcoma and Ewing sarcoma patients: the Italian Sarcoma Group Experience (1983-2006). Cancer. 2012;118:5050-5059.


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 .

Photos


(Abstract    Full Text HTML)      (Download PDF)


The Current Role of Radiation Therapy for Osteogenic Sarcoma

Volume 2 | Issue 1 | Jan-Apr 2016 | Page 33-35  Sangeeta Kakoti, Nehal Khanna, Siddhartha Laskar.


Authers: Sangeeta Kakoti[1] Nehal Khanna[1], Siddhartha Laskar[1]

[1]Department of Radiation Oncology, Tata Memorial Hospital, Mumbai. India

Address of Correspondence
Dr.Siddhartha Laskar
Professor, Department of Radiation Oncology, Tata Memorial Hospital, Dr Ernest Borges Marg, Parel, Mumbai – 400012, India.
Email: laskars2000@yahoo.com


Abstract

Osteosarcomas are known to be relatively radio-resistant, definitive radiotherapy has a role in cases that are unresectable or have poor prognostic factors. Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. New technologies like particle beam therapy using proton and carbon ions and use of high precision radiation therapy techniques have further improved the results of definitive radiation therapy. Current review traces the advent of radiotherapy, its current role in management of osteosarcoma and future trends in the field.
Keywords: Osteogenic Sarcoma, Radiotherapy, Management.


Introduction

Osteosarcoma (OGS), an osteoid-producing malignant mesenchymal tumour, accounts for 20-45% of all skeletal malignancies. It has a bimodal age distribution with peak incidence at 10-19 years and over 60 years (secondary to prior radiotherapy exposure, Paget’s disease etc). Male to female ratio is approximately 1.6:1. The most common sites of involvement are femur (50%), followed by tibia, humerus, pelvis, jaw, fibula and ribs. The major histological variants are conventional osteosarcoma (osteoblastic, fibroblastic or chondroblastic, according to the predominant type of matrix produced), teleangiectatic and small cell osteosarcoma. Patients commonly present with bony pain and local swelling. Patients may also present with symptoms of metastatic disease like dyspnoea, hemoptysis, or bone pain. Diagnostic investigations include Plain radiograph (characteristic ‘Sun burst’ appearance and ‘Çodman’s triangle’), MRI of local part, CT scan of chest, Bone scan (to look for skip lesions) and a histopathological examination. Tumors are staged according to either the AJCC or Enneking (MSTS) systems. Prognostic factors impacting survival [1] include presence of metastasis, response to Neoadjuvant chemotherapy (NACT), histologic type, age (each decade increases mortality rate by 7 fold), tumour location (tumours of tibia fare better than those of femur) and choice of therapy (post operative radiotherapy and amputation was associated with 92% and 76% increased relative risk of death respectively, may be confounded by advanced disease status). Prior to the extensive use of chemotherapy for treating patients with osteosarcoma, aggressive surgery was considered the treatment of choice, resulting in five year overall survival rate of 10-20% [2]. A meta-analysis by Kassir et al [3] on head and neck Osteosarcoma showed that surgical cut margin status was the sole prognostic factor and there was no survival benefit by adding radiation therapy and/or chemotherapy. But subsequently there have been great leaps in the success of osteosarcoma management. Incorporation of highly active chemotherapeutic agents resulted in significant improvement in outcomes to the tune of 60-75% [4]. The MIOS trial [5] reporting 5% versus 65% overall survival rates in patients randomised to surgery versus surgery and chemotherapy respectively, formed the basis for multimodality therapy in these tumours.

Role of Radiotherapy in management of Osteosarcoma
Osteosarcoma was always thought to be a radio-resistant tumour and hence radiotherapy was initially not included in the standard management regimens. Sir Stanford Cade a British surgeon radiotherapist in 1931 treated 133 patients with radiation therapy with an intention to avoid futile amputation in patients developing lung metastases in subsequent 6-9 months [6]. Following completion of therapy (60 Gy over six weeks) the resected specimen revealed 100% tumour necrosis in all patients.

1) Radiotherapy in definitive setting
There are no randomized trials comparing surgery versus radiotherapy (RT) as primary local therapy for osteosarcoma and is unlikely to be one in future due to ethical issues. However there are a few single arm series showing encouraging results. Machak et al [7] treated 31 patients with extremity osteosarcomas with definitive radiotherapy to a median dose of 60 Gy (range, 40–68 Gy). The 5-year local control (LC), metastasis-free and overall survival (OS) rates were 56%, 62%, and 61%, respectively. Similarly, Caceres et al [8] also noted a complete pathological response in 80% patients with limb OGS treated by chemotherapy and 60 Gy of RT. Excellent functional outcomes was noted in 86% of the patients. In 13 patients treated with definitive RT to median dose of 60 Gy, at a median follow up of 161 months, 3 year LC and OS was 70% and 75% respectively [9]. Subsequently, in the COSS registry of 175 patients [10] treated from 1980 to 2007, at a median follow up of 1.5 years (0.2-23 years), the overall survival rates after RT for treatment of primary tumors, local recurrence, and metastases were 55%, 15%, and 0% respectively. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%). Feasibility of Stereotactic body radiotherapy (SBRT) for recurrent OGS lesions was evaluated by Brown et al [11]. Median dose delivered was 40 Gy in 5 fractions (range, 30-60 Gy in 3-10 fractions; total of 14 patients). Two grade 2 and 1 grade 3 late toxicities occurred (in the setting of concurrent chemotherapy and reirradiation); consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy [11]. Efficacy and long term toxicity are yet to be determined. Gaitan-Yanguas showed a dose-response relationship with no lesion controlled at doses of 30 Gy, and all lesions controlled with doses of >90 Gy [12].
Approximately 25% of pelvic and 10% of head and neck osteosarcomas are not resectable and hence are candidates for definitive radiotherapy. In our institute, we prescribe 70.2 Gy in 39 fractions over 8 weeks.

2) Radiotherapy in preoperative setting
Preoperative radiotherapy is gradually evolving to facilitate function preserving less mutilating surgeries. Dincsbas et al [13] treated 44 patients with preoperative RT to a dose of 35 Gy in 10 fractions followed by limb sparing surgery. The tumor necrosis rate was 90% in 87% of the patients. At a median follow-up of 44 months, the 5-year LC and OS were 97.5% and 48.4% respectively. They documented subcutaneous fibrosis in 16%, joint movement restriction in 20%, and osteo-radionecrosis and pathologic fracture in 4% patients. Chambers et al [14] reported an OS of 73% at 5 years of 33 patients treated with preoperative RT and resection for craniofacial OGS.

3) Radiotherapy in adjuvant setting
Delaney et al [15] reported 41 patients with osteosarcoma involving various sites (primary, recurrent as well as metastatic) in different settings to a dose of 10 to 80 Gy (median 66 Gy) preceded by gross total tumor resection in 65.8%, subtotal resection in 21.9% and biopsy only in 12.2%. The local control rates according to the extent of resection were 78.4%, 77.8% and 40% respectively. The overall survival rates in corresponding groups were 74.45%, 74.1% and 25% respectively. The authors concluded that adjuvant RT can help provide local control of osteosarcoma for patients in whom surgical resection with widely negative margins is not possible. Dose response relationship was not found to be significant. Caveat of the study was that the patient population as well as the treatment parameters including dose and timing of radiation (some received preoperative followed by postoperative RT) was very heterogeneous.
Guadagnolo et al [16] reported that the addition of adjuvant RT in head and neck osteosarcoma definitely improves local control for those with positive or uncertain margins. Laskar et al reported the outcomes of patients with head and neck osteosarcomas treated at the Tata Memorial Hospital, Mumbai [17]. The authors highlighted the impact of post-operative adjuvant radiotherapy, even after R0 resection or in patients with adverse prognostic factors (large tumour size, lymphovascular invasion, soft tissue infiltration etc). The patients receiving adjuvant RT at TMH were prescribed a dose of 64.8 Gy in 36 fractions over 7 weeks. The authors reported local control rate of 36%. High dose intra-operative EBRT with kV X rays or electrons is emerging as yet another experimental option. Hong et al reported outcome of extracorporeal irradiation (ECI) in the management of 16 pts with a variety of tumours (OGS being in 4 of them) to a dose of 50 Gy in single fraction. At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis [18]. Puri et al reported the outcomes of patients treated at the Tata Memorial Hospital, Mumbai, using extracorporeal irradiation [19]. Thirty-two patients (16 Ewing’s sarcoma and 16 OGS) with a mean age of 15 years (2 to 35 years) underwent this procedure. There were three local recurrences. All were associated with disseminated disease and the recurrences were in soft- tissue remote from the irradiated graft. There were no local recurrences involving the irradiated bone. The OS for patients with osteosarcoma was 65% with excellent functional outcome.

4) Radiotherapy in palliative setting

There is little data regarding dose fractionation and efficacy of radiotherapy for palliation of advanced osteosarcoma. Considering the similar mechanisms of pain and inflammation like bony metastases, data from the later are often extrapolated [20] and single fraction or protracted fractionation have both been equally used. Oligo-metastatic OGS is treated with curative intent. Metastatectomy is the gold standard as a component of the curative regimen with a documented 5 year OS of approx 22%. Stereotactic body radiotherapy (SBRT) to limited lung metastases is an equally efficacious emerging non invasive option. In a series of 46 patients with oligometastatic disease to lungs from sarcomas, at a median follow up of 22 months after median dose of 10-48 Gy in 1-5 fractions, 31% of patients survived for more than 3 years [21]. In a multicentric phase I/II trial treating 38 patients with oligometastases to a median dose of 38-60 Gy in 3 fractions, LC at two years was 96% and median survival was 19 months. Incidence of grade III-IV toxicity was 8% [22].

5) Particle therapy for osteosarcoma
Ciernik et al, treated 55 patients (42% received definitive RT) with osteosarcoma of all sites [23] using combination of photons and protons to a mean dose of 68.4 Gy. With a median follow-up of 27 months, LC at 3 and 5 years were 82% and 72% respectively. The 5-year DFS and OS was 65% and 67% respectively. Prognostic factors found to have a significant impact on disease control were grade and bulk of the tumour. The extent of surgical resection did not correlate with outcome. Grade 3 to 4 late toxicity was seen in 30.1 % of patients. In another series of 30 patients with unresectable OGS of the trunk treated with definitive Carbon ion therapy to a dose of 52.8–73.6 Gy, the 3 and 5 year LC at a median follow up of 33 months was 62% and 49% respectively. The corresponding OS was 53% and 29%. Severe skin/soft tissue reaction was reported in 5 patients [24]. With neutrons, local control rates of 55% were documented in patients with unresectable OGS of different sites [25]. A median prescribed dose of 66 Gy has been tried in a series to patients with paraspinal osteosarcomas with a resultant LC of 74%. There were no reported late toxicities [26].

6) Role of brachytherapy
There is very limited role of brachytherapy in osteosarcomas. A new treatment strategy based on direct injections of 90Y-hydroxide into the tumor bed is under preclinical trial   [27].


 Conclusion

Neo-adjuvant Chemotherapy followed by local therapy (surgery alone and/or radiotherapy) and maintenance chemotherapy remain the current standard of care for treatment of non-metastatic high grade osteosarcoma. Although osteosarcomas are considered to be relatively radio-resistant, definitive radiation therapy results in significant long term disease control in patients with inoperable disease and postoperatively in patients with poor prognostic factors. The outcomes of definitive treatment using radiation therapy has further been improved by the use of particle beam therapy like protons & carbon ions & escalated doses of photon therapy using modern high precision radiation therapy techniques. Hence, Radiotherapy remains an important option for local treatment of unresectable tumors, following incomplete resection, or as an effective tool for palliation of symptomatic metastases


References

1. Prognostic factors and outcomes for osteosarcoma: An international collaboration. Emil-ios E. Pakos, Andreas D. Nearchou, Robert J. Grimer et al. European Journal of Cancer. 2009; 4 5: 2 3 6 7 –2 3 7 5
2. Osteogenic sarcoma: a study of 600 cases. Dahlin DC, Coventry MBBoneJoint Surg 1967; 49: 101-l 10.
3. Osteosarcoma of the Head and Neck: Meta-analysis of Nonrandomized Studies. Laryn-goscope, 1997; 107: 56-61.
4. Dana-Farber Cancer Institute/The Children’s Hospital adjuvant chemotherapy trials for osteosarcoma: three sequential studies, A. M. Goorin, M. Delorey, and R. D. Gelber, Cancer Treatment Symposia. 1985; 3: 155–159.
5. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosar-coma of the extremity. M. P. Link, A. M. Goorin, and A. W. Miser. The New England Journal of Medicine. 1986; 314: 1513
6. Osteogenic sarcoma. A study based on 133 patients. Cade S. J R Coll Surg Edinb. 1955; 1: 79-111.
7. Neoadjuvant chemotherapy and local radiotherapy for high-grade osteosarcoma of the ex-tremities. Machak GN, Tkachev SI, Solovyev YN et al Mayo Clin Proc. 2003;78:147-155
8. Local control of osteogenic sarcoma by radiation and chemotherapy. Caceres E, Zaharia M, Valdivia S, et al. Int J Radiat Oncol Biol Phys . 1984;10:35-39
9. Patrick Hundsdoerfer et al, European Journal of Cancer 4 5 (2009) 24 47 –2451
10. Craniofacial osteosarcoma Experience of the cooperative German–Austrian– Swiss osteosarcoma study group. Sven Jasnau, Ulrich Meyer, Jenny Potratz et al. Oral Oncology (2008) 44, 286– 294
11. Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosar-coma. Brown LC, Lester RA, Grams MP et al, Sarcoma. 2014:418270
12. A study of the response of osteogenic sarcoma and adjacent normal tissues to radiation. Gaitan-Yanguas M. IJROBP. 1981; 7: 593-595
13. The role of preoperative radiotherapy in non metastatic high-grade osteosarcoma of the extremities for limb-sparing surgery. Dincbas FO, Koca S, Mandel NM et al. Int J Radiat Oncol Biol Phys 2005;62:820-828
14. Osteogenic sarcoma of the mandible, current management. Chambers RG, Mahoney WD. Am Surg . 1970;36:463-471
15. Radiotherapy for local control of osteosarcoma. Thomas F. Delaney, Lily Park, Savelli I Goldberg et al, IJROBP, 2005; 61(2): 492-498.
16. Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Guadagnolo BA, Zagars GK, Raymond AK, et al, Cancer 2009;115: 3262-70.
17. Osteosarcoma of the head and neck region: lessons learnt from a single institutional expe-rience of 50 patients, Siddhartha Laskar, Ayan Basu, Mary Ann Muckaden et al, Head & Neck, 2008: 1020-1026.
18. Extracorporeal irradiation for malignant bone tumors. Hong A, Stevens G, Stalley P, et al. Int J Radiat Oncol Biol Phys . 2001;50:441-447
19. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradia-tion and re-implantation of the host bone. A Puri, A Gulia, N Jambhekar, S Laskar. J Bone Joint Surg Br 2012;94-B:982–8.
20. Randomized trial of short versus long-course radiotherapy for palliation of painful bone metastases. Hartsell WF, Scott CB, Bruner DW, et al. J Natl Cancer Inst 2005;97:798–804
21. A retrospective study of SBRT of metastases in patients with primary sarcoma. Christina Linder Stragliotto, Kristin Karlsson, Ingmar Lax et al. Med Oncol. 2012; 29:3431–3439
22. Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy for Lung Me-tastases, Kyle E. Rusthoven, Brian D. Kavanagh, Stuart H. Burri. J Clin Oncol 2009; 27:1579-1584.
23. Proton-Based Radiotherapy for Unresectable or Incompletely Resected Osteosarcoma: I. Frank Ciernik, MD1,2; Andrzej Niemierko, PhD1,3,4; David C. Harmon et al, cancer 2011; 117: 4522–30.
24. Impact of Carbon Ion Radiotherapy on Outcome in Unresectable High-grade Osteosar-coma of the Trunk, T. Kamada, R. Imai, S. Sugawara et al, I. J. Radiation Oncology d Biology d Physics Volume 75, Number 3, Supplement, 2009
25. Fast neutron radiotherapy for sarcomas of soft tissue, bone, and cartilage: Laramore GE, Griffith JT, Boespflug M et al, Am J Clin Oncol, 1989, vol 12, pp 320-326
26. Image-guided intensity-modulated photon radiotherapy using multifractionated regimen to paraspinalchordomas and rare sarcomas. Terezakis SA, Lovelock DM, Bilsky MH et al. Int J RadiatOncolBiol Phys. 2007;69(5):1502-8
27. Dosimetry of a 90Y-hydroxide liquid brachytherapy treatment approach to ca-nine osteosarcoma using PET/CT. Jien Jie Zhou, Arnulfo Gonzalez, Mark W. Lenox. Ap-plied Radiation and Isotopes. 2015; 95: 193-200.


How to Cite this article:Kakoti S, Khanna N, Laskar S. The Current Role of Radiation Therapy for Osteogenic Sarcoma. Journal of  Bone and Soft Tissue Tumors Jan-Apr 2016;2(1): 33-35.

Photo


 (Abstract    Full Text HTML)      (Download PDF)


OncoMedia Sep-Dec 2015

Vol 1 | Issue 2 | Sep – Dec 2015 | page:34-35 | Dr Ashish Gulia & Dr Ashok Shyam


Author: Dr Ashish Gulia[1] & Dr Ashok Shyam[2, 3]

Dr. Ashish Gulia MS (Ortho), Mch – Surgical Oncology
[1] Fellowship – Musculoskeletal Oncology (TMH – HBNI)
Asst. Professor – Orthopaedic Oncology, Tata Memorial Hospital, Mumbai, India.

Dr Ashok Shyam MS (Ortho)
[2]Indian Orthopaedic Research Group, Thane, India
[3] Sancheti Institute for Orthopaedics &Rehabilitation, Pune, India


ONCOMEDIA will focus on News and Event related to Bone and Soft Tissue Tumors from all across the World. Specific focus will be Industry updares,New Research, Social Impactof tumors, Basic Scinece and developmentsin cytogentics and allied fields. In short OncoMedia is a place for most interesting read in this entire issue 🙂

Bone Tumors on You tube

You tube has revolutionised the information dissemination scenario. From reading text the scenario has now changed of visuals. Medical knowledge dissemination through you tube is started almost from the inceptino of the website. There are many videos and essential details that are available on the you tube website. The problem is selecting a few and finding time to watch them. The JBST Oncomedia team and gone through you tube and found some interesting vedioes that we can recommend to our readers. We will also be psoting links of these videos on jbstjournal.com too. Lets see some details of these videos.
1. Pathology of Bone tumors. Essentially meant for postgraduate students, this video gives pictures of true specimens and their description.


Link: https://www.youtube.com/watch?v=oHfozp2e8zg 


2. Bone Tumor Imaging: is a video of powerpoint lecture by Dr K L Verstraete. Although made in 2012, the lecture is quite informative and will help many to update their knowledge about Bone Tumor imaging.


Link: https://www.youtube.com/watch?v=EsLIUyExEXU


 

 

3. KOC Radiology conference: This KOC talk was given by our editorial board member Dr Bhavin Jhankaria in 2014. This is a very thorough update on imaging of bone tumor and delivered in inimitable style of Dr Bhavin. We highly recommend everyone to watch this video.


Link: https://www.youtube.com/watch?v=g2TGHrYGAvA


 

 

4. MSK Imaging bone tumor: Finally we can complete the update on bone imaging by watching this detailed video. Again presented in format of voice over of a powerpoint presentation, this includes a very good visual appeal to the video.


Link: https://www.youtube.com/watch?v=VcYRoB-qRX0

We will be providing reviews of some more youtube resources in the next issue of Oncomedia. Please provide us with your comments, suggestions and criticism for this feature of JBST.


 

Orthopaedic Powerpoints is a new presentation of the Orthopaedic Research Group. Although PPT’s are readily available online but many of them are not recent or with medicore content. At OrthoPowerpoints.com we will assure that best quality of material is published and circulated. The website will feature peer reviewed powerpoints and to begin with includes members by invitation only. Few presentations from the editorial board of JBST are available online. Visit www.orthopowerpoints.com for more details.

IMSOS 2016:The second Annual conference of Indian Musculoskeletal Oncology Society is planned on 11-13 March 2016 and will be held in Kochi. Visit the website www.imsos2016.org for more details.

Invitation (1)
IMSOS – Surgeon’s Training Initiative: This will be a travelling fellowship open only to IMSOS members allowing them a 6-8 weeks fellowship at a centre of their choosing. Two fellowships per year will be available. Interested readers can join IMSOS and look for further announcements


 

           Dr. Ashish Gulia
Dr. Ashok Shyam

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


Role of Image Guided Interventions in Orthopaedic Oncology

Vol 1 | Issue 2 | Sep – Dec 2015 | page:25-29 | Himanshu Pendse[1*], Aniruddha Kulkarni[2], Manish Agarwal[2]


Author: Himanshu Pendse[1*], Aniruddha Kulkarni[2], Manish Agarwal[2]

[1]P.D Hinduja Hospital Veer Savarkar Marg, Mahim, Mumbai, India

Address of Correspondence
Dr. Himanshu Pendse
P.D Hinduja Hospital Veer Savarkar Marg, Mahim, Mumbai, India.
Email: himanshu.pendse@gmail.com


Abstract

Interventional radiology has grown in leaps and bounds specifically in field of orthopaedic oncology. The procedures have advantage of being minimally invasive and have a much better postprocedure rehabilitation. These procedures can be broadly classified as Non-vascular and Vascular interventions. Common non-vascular procedures comprise of image guided biopsies, radiofrequency ablations, vertebroplasty and khyphoplasty. Vascular procedures comprise of Embolotherapy and Sclerotherapy. Isolated Limb Infusion (ILI), MR-HIFU (MRI-guided High Intensity Focused Ultrasound), Cryoablation are few of the more recent advances in the field of interventional radiology. Each procedure has its own indications, contraindications and safety profile. The current article provides an overview of these procedures and there clinical importance.
Keywords: Interventional radiology, orthopaedic oncology.


Introduction

Image guided interventions or otherwise popular as the field of interventional radiology comprise of procedures which are performed with the help of an imaging modality such as fluoroscopy, USG, CT or MRI. With the rising preference for minimal invasive therapies, these procedures enjoy an increasing scope in the patient management. Other than elective procedures, interventional radiology proves invaluable for managing medical and surgical emergencies. In recent years, interventional radiology is playing a vital role in the field of orthopedics and orthopedic oncology. This article will give an outline of the common procedures performed by an interventional radiologist in orthopedic oncology. These procedures can be broadly classified as Non-vascular and Vascular interventions.

Fig 1 2

Non-Vascular Interventions
Common non-vascular procedures comprise of image guided biopsies, radiofrequency ablations, vertebroplasty and khyphoplasty.
Image guided biopsies and fine needle aspiration cytology (Fig 1A and B, 2A and B, 3A and B and Fig 4):
This is emerged as a safe, faster and accurate tool for getting a diagnosis from a musculoskeletal lesion. It has safer and has better patient tolerance as compared to conventional open biopsy [1].

Fig 3 4

Indications
1. Determine whether lesion is benign or malignant
2. Obtain material for microbiological examination in a suspected infective lesion
3. Determine status of a lesion in a patient with known primary
Contraindications:
Known coagulopathy, Pregnancy (for CT-guided procedures)

Fig 5

Special considerations
It is imperative to determine a safe route for biopsy, which comes in the excision and/or radiation field for treating the primary lesion. Classic “no-touch” lesions like myositis ossificans in evolving stage; subchondral geodes etc should be identified on imaging and prevented from being biopsied. These lesions appear aggressive on histology, causing radiological and pathological discrepancies.

Fig 6

Equipment and Techniques
Fluoroscopy, USG, CT or MRI have been used for image guidance for a biopsy. CT scan is most often used for biopsy of bone lesions [2]. The main advantage of CT being precise visualization of trajectory of the needle. thus preventing damage to the important structures like the neurovascular bundle.
USG is preferred for superficial bone lesions with a targetable soft tissue component. It is preferred in patients where radiation exposure has to be avoided [3].

Fig 7

Fluoroscopy is a good modality for biopsy of large lesions. In some cases, the lesion is visible only on MRI. In such cases, MRI-guided biopsy is indicated.
The procedure is generally performed under local anaesthesia with light sedation when necessary. The patient lies prone for vertebral biopsy. For any other bone, the position depends on the site of the lesion. Compartmental anatomy greatly influences the needle approach, and such knowledge is critical for preventing unnecessary surgery and loss of limb function. It is important to stress that the biopsy trajectory should be through the tissues that would be excised or comes in the radiation field to prevent recurrence along the biopsy tract.

Fig 8
Generally, an 11-15G Trephine Bone Biopsy Needle is used to target bone lesions without significant soft tissue component. For a FNAC, a 22 G needle is generally used. The yield is better for a larger needle. In case of vertebral biopsy of the dorsal vertebrae, it is advisable to use a 13G needle instead of an 11G needle due to the thinner pedicles of the dorsal vertebrae. In lesions with a significant soft tissue component, an 18G co-axial biopsy set with a co-axial needle and a semi-automated or automated gun would be a good choice. In a circumscribed lytic lesion, it is prudent to use an 11/13G bone biopsy needle as an anchor. Through this, the 18G biopsy needle is passed to obtain soft tissue cores. MRI guided biopsies need special MRI compatible needles. Sampling should be performed by fine-needle aspiration (FNA) along with Core Needle Biopsy as many interventional radiologists feel that both the techniques have a complementary role.

Fig 9

Complications
Pain, bleeding, infection, biopsy tract recurrence and bone fracture are the common complications. Instilling gelfoam torpedos in the biopsy tract can arrest bleeding from biopsy of hypervascular metastasis. Post-procedural Care: Patient may be advised to take painkillers if pain is significant Antibiotic cover is not necessary post-biopsy. Biopsy Yield and Outcomes: This is an important issue for bone biopsies. It is important to take enough samples, especially when benign disease is suspected. Several studies have shown higher accuracy of core needle biopsy (89.7%-96%) to fine needle aspiration cytology (64%-88%) [4]. Biopsy of bone lesions with soft-tissue components (93%, 89%) has higher diagnostic accuracy than biopsy of lytic lesions (85%, 71%) [5]. Also, in case of cystic lesions, biopsy from the wall of the cystic lesion has better yield than aspirating fluid [6]. Infections have been reported to have a high diagnostic yield of 80% to 90% on aspiration [7]. Diagnostic yield has been attributed to larger lesion size and larger specimen length [8].

Fig 10

Cementoplasty
This involves injecting bone cement in the weakened weight-bearing bones to relieve pain. The procedure is usually named after the bone, which is treated. For example, acetabuloplasty when acetabular cementoplasty is done and sacroplasty (Fig 5A, B and C) when sacrum is treated.

Fig 11

Vertebroplasty and Khyphoplasty
Vertebroplasty and khyphoplasty, also know of vertebral augmentation techniques, involve injection of bone cement in the vertebral body to relieve pain and restore the height of the vertebral body [9]. Indications: Main indication of this procedure is to treat painful vertebral compression fractures which have failed conventional medical therapy. Most common cause is fracture due to primary osteoporotic disease. Others causes like steroid-induced osteoporosis (Fig 6A- C), metastatic disease, compression due to myeloma, hemangioma (Fig A-F) etc are also an indiction for these procedures [10].

Fig 12
Contraindications: Absolute contraindications are uncorrectable coagulopathy, spinal infection, vertebral infection and allergy to bone cement.
Special Considerations: Few of the following situations when present, should alert the interventional radiologist to take extra care during the procedure [11]-
1. Disruption of posterior cortex- increased risk of cement leaking into the spinal cord
2. Vertebra plana or marked loss in the height of the vertebral body
3. Epidural extrusion of tumor
4. Narrow central canal
Pre-procedure assessment and Imaging-
Pre-procedure history and clinical assessment is very important. Pain score before the procedure should be recorded.
Point tenderness at the spinous process should be elicited and correlated with the collapsed vertebra on imaging. A conventional spinal radiograph would be sufficient for this preliminary assessment. A lower limb neurological exam should also be performed. Routine laboratory investigations like complete blood count and coagulation profile should be done.
MRI is the test of choice for pre-procedure evaluation. It shows the exact site of marrow edema, the size of the spinal canal, the course of the exiting nerve roots and allows evaluation of epidural extension of tumor. At the same time, it will also help to make a definitive diagnosis on the etiology of the lesion. CT proves useful to evaluate the integrity of the posterior vertebral cortex.
Technique: Procedure is generally done in prone or oblique position. This position will facilitate extension of the fractured segments [12]. Local anesthesia with or without sedation is required. General anesthesia should be avoided as a conscious patient can alert the clinician about any new symptoms during the procedure.

Table 1
Routine pre-procedure antibiotic coverage in form of 1gm Cefazolin is given.
Approach: Generally, an 11 G needle is preferred for lower dorsal and lumbar vertebrae while a 13 G needle may be used for upper dorsal vertebrae. It is important to remember the orientation of the vertebral pedicles as one goes down the spine. Generally, two approaches are used to enter the vertebral body- the transpedicular approach and the parapedicular approach. The transpedicular approach has an advantage of protecting the nerve roots and the paravertebral tissue due to the long intraosseous course. The first step is to align the affected vertebral body in such a way that the spinous process is in the midline, the vertebral edges overlap and the pedicle is in the centre of that half of the vertebral body. The entry point is marked on the skin at about 10O’Clock position with respect to the pedicle that will be traversed. Lignocaine is infiltrated at that site and a small skin nick given with an 11 No blade. Needle is inserted from the planned entry point. For transpedicular approach, it is most important to keep the needle, lateral to the medial margin and superior to the inferior margin of the pedicle. This takes care that the needle is in the confines of the pedicle. The needle position could be checked on AP and lateral view on fluoroscopy. Once the needle reaches the posterior margin of the vertebral body, it should be further advanced till the anterior third of the vertebral body in lateral view and till the midline on AP view. Unipedicular approach would suffice if the cement crosses to the opposite side. Otherwise, a bipedicular approach is required [13]. For parapedicular approach, the vertebral body is directly entered and thus the needle is kept lateral to the lateral margin of the pedicle.

Table 2
Cement Injection for Vertebroplasty:
The cement commonly used is Polymethyl Methacrylate (PMMA). It comes in powder form with a solvent. The powder and solvent are mixed and left for few minutes. The cement is instilled through the needle when it has toothpaste like consistency. It is important to closely monitor leakage of cement in the spinal canal or along the nerve roots. The endpoints for cement injection include passage of cement beyond the marrow space and cement reaching the posterior quarter of the vertebral body. Mathis and Wong have recommended cement filling to 50-70 percent of the residual volume of the vertebral body [14].
Kyphoplasty: Before injecting cement, khyphoplasty involves an additional step of increasing the size of the vertebral body. This is achieved with a khyphoplasty balloon. Later, a dedicated Vertebroplasty injector system can be used to inject PMMA for khyphoplasty. It is recommended to treat up to 3 vertebral levels at a sitting to prevent the complications arising due to marrow fat embolizations [15].
When fractures with Intraosseous vacuum phenomenon (Kummell disease) is noted, it is important to place the needle as close as possible to the cleft in order to allow the cement to fill the cleft.
Complications: Common complications are pain, hematoma, cement extravasation along the nerve roots. Small amount of extraosseous passage of cement is seen in two-thirds of vertebroplasty. As against this, khyphoplasty has a lower rate since the cavity fills first with subsequent hardening of the cement. Other possible complications are paraspinal abscess, hypotension due to cement and fat emboli, pneumothorax, spinal cord damage due to cement extravasation and worsened pain [16]. The risk of complication is more while treating malignancy-related fractures.
Post-procedure monitoring and Follow-up:
The patient should lie supine for an hour after the procedure. Ideally, patient’s can be discharged later on the same day. NSAID’s can be prescribed for the procedure related pain. Many patients have significant relief of symptoms immediately after the procedure. Patient should be informed to report any sudden onset backache as this may indicate a new fracture. 3-week follow-up post-procedure is generally advised. At every follow-up, clinical and pain score assessment is important.
Radiofrequency Ablation: It involves ablating tissues by sending radiofrequency waves in the patient. Basic mode of killing cells involves generation of thermal energy around the electrode.
Principles [17,18]: The radiofrequency wave consists of an alternating current at high frequency (200 –1,200 kHz).
A closed loop circuit consisting of the RF generator, electrode, patient and ground pads (acting as a large dispersing electrode) in series is required. The electrode and the ground pads are active. The RF generator generates the RF current, which enters the tissue to be ablated through the electrode. This current leads to rapid oscillation of the molecules. The patient acts as a resistor. The friction generates heat, which kills the cells. The marked discrepancy between the surface area of the needle electrode and the dispersive electrode causes the generated heat to be tightly focused and concentrated around the needle electrode. The response of the tissue to heat depends on the temperature and the time for which heat was applied (Table 1).
Types of Electrodes: Major categories include monopolar devices, bipolar devices, and coblation devices.
1. Monopolar systems are most commonly used. These require a grounding pad placed on the patient. Their main disadvantage is the formation of aberrant currents, which do not always allow for uniform energy deposition inside the lesion.
They can be divided into single electrode and multi-tined. Single electrodes have the advantage of small caliber but have smaller ablation radius. They can feature hot, cooled-tip, and water-perfused. Multi- tined electrodes increase energy deposition by creating larger zones of ablation and produce better lesion destruction.
2. Bipolar devices do not require a grounding pad, because the current passes through the same or neighboring needles. Advantage is lesser aberrant currents.
Application of Radiofrequency Ablation in Orthopaedic Oncology:
A host of benign and malignant lesions can be treated with radiofrequency ablation. This include- Benign tumors like Osteoid Osteoma, Chondroblastoma, Aneurysmal Bone Cysts and Vertebral hemangiomas
Malignant tumors like spinal metastasis, ablation of soft tissue sarcoma’s to achieve local control.
Other non-oncology applications like radiofrequency neurotomy to treat backache are also practiced.
General Contraindications:
Absolute contraindications to ablation include coagulopathy disorders, skin infection, immunosuppression, and absence of a safe path to the lesion without harming vital organs or structures.
Radiofrequency Ablation for Benign tumors: Among the benign tumors, osteoid osteoma is the commonest benign bone lesion treated with RFA.
RFA of Osteoid Osteoma [18] (Fig 8A and B): It is a benign lesion, commoner in males (male: female = 4:1). It usually presents in the second decade with nocturnal pain, which is relieved by aspirin or other NSAID’s.
Imaging features: CT is the modality of choice. Typical lesion is seen in the cortex of a long bone with a centrally placed radiolucent nidus and a surrounding sclerotic rim. On contrast enhanced CT study, the nidus shows enhancement.
General technique: Percutaneous radiofrequency ablation is a reliable and effective technique that provides fast, long-lasting pain relief. Bourgault C et al recently published a paper treating 87 patients with osteoid osteoma. In this study, with mean follow-up of 34 months, the success rate for first-line treatment was 89.6% and it was 97.5% for second-line treatment. The recurrence rate was 10.4%.
RFA is generally done under CT guidance. Typically, the skin entry is achieved with a bone biopsy needle, which is advanced till the cortex. In cases where there is significant sclerosis, this thick bone is drilled using a bone drill. Once the lesion enters the lesion nidus, biopsy of the lesion is taken. Further, the RF electrode is inserted through the bore of the biopsy lesion into the lesion nidus. Before, ablation is commenced; the biopsy needle is withdrawn to prevent inadvertent heating of the surrounding tissues due to heat propagation via the needle. Otherwise, the biopsy needle can be exchanged for a hard introducer with a distal insulated tip over a K-wire. The presence of intact cortex around the lesion produces oven effect which leads to better ablation of the lesion.
RFA of other benign tumors: Condroblastoma, an epiphyseal tumor has been treated with RFA as an alternative to surgery. Rybak et al describes 17 patients with chondroblastoma for whom RFA was used as the primary treatment modality. On median follow-up of 41.3 months, 12 out of 17 patients showed complete relief of pain [19].
Aneurysmal bone cyst (ABC) has been treated by RFA of the epithelial lining followed by cementoplasty analogous to curettage and bone grafting. There have been reports where ablation of the ABC wall has been achieved using radioactive material [20].
There are some published reports on the treatment of other benign bone conditions such as enchondroma, eosinophilic granuloma, bone haemangioma and giant cell tumors.
RFA of Malignant tumors: This is usually done for pain relief with a palliative intent. In case of large tumors, compressing nerves, RFA can be performed to debulk the tumors. As RFA destroys cells and theoretically forms a cavity, cementoplasty can be performed along with the RFA to provide tensile strength [21, 22].

Embolotherapy for Musculoskeletal tumors
Transarterial embolization has been practiced for many years in both benign and malignant musculoskeletal tumors. The main purpose of these procedures is to reduce blood supply of the tumor, avoiding non-target embolization [23]. Embolization can be pre-operative embolization, serial embolization or palliative embolization. Pre-operative embolization aims to occlude as a much as possible, helping the surgeon to have a relatively bloodless field. Serial embolization aims to decrease to size of the tumor. This can relieve the patients of the symptoms like pain and in some, can make the patient fir for surgery. Palliative, as the name suggests aims to relive the patients of the symptoms and to improve the quality of life.
Technique: Generally, a pre-procedure cross-sectional imaging is helpful to see the extent and overall vascularity of the neoplasm. A pre-procedure assessment of platelet count, International Normalized Ratio (INR) and creatinine levels is necessary. Initially, a diagnostic angiogram is done to define the supplying vessels following which embolization is performed.
Gelfoam is the embolization material of choice for pre-operative embolization. In cases where serial embolization is required, particulate agents like polyvinyl alcohol (PVA) or embospheres is used. Coils are used where parent vessel occlusion is required or when protection of distal vasculature is necessary.
Embolotherapy in Benign Musculoskeletal Tumors: Embolization is generally performed for benign tumors like Giant Cell Tumor, Aneurysmal Bone Cyst, Vertebral Hemangiomas, Osteoblastomas and arteriovenous malformations.
Giant Cell Tumors (GCT’s)(Fig 9 A – D):
GCT’s radiographically appear as expansile lytic lesions in the metaphyseal region reaching the endplate. These have significant vascularity and are associated with significant blood loss.
Sacral GCT’s are especially associated with significant peri-procedure blood loss and post-surgical morbidity. In small operable GCT’s , embolotherapy aims to pre-operatively devascularize the tumor while in cases large sacral GCT’s, it aims to reduce the bulk of the lesion. It can also decrease the associated pain due to compression of the nerve roots [24].
Post-procedure increase in ossification of the lesion is a sign of favourable response to embolization.
In a series of 18 patients of GCT’s, managed with embolization, follow of 26 years showed durable response in 50% of patients with local recurrence rates of 31% in 10 years and 43% in 15-20 years [25].
Aneurysmal Bone Cyst (ABC) (Figure 10A and B): Though, curettage and resection are the primary treatment modalities of choice, embolization has been performed in recurrent ABC’s and as a pre-operative measure to reduce blood loss [26].
Vertebral Hemangiomas: Surgery is the modality of choice to treat vertebral hemangiomas causing cord compression or any neurogenic deficit. In these cases, pre-operative embolization serves as an adjuvant to surgery by reducing blood loss[27].
Arteriovenous Malformation of Bone:
Tranarterial embolization can prove as a useful treatment for AVM’s of bone. Direct puncture of the hemangioma with percutaneous embolization has also been attempted to control hemorrhage [28].
Other benign tumors like cervical spine osteoblastomas have been treated by embolization as a adjuvant to surgery.

Embolotherapy in Malignant Musculoskeletal Tumors
Metastases: Hypervascular metastases especially from thyroid and renal carcinomas are treated with embolization. The main intent is palliative and aims to reduce pain and other symptoms that may arise due to compression of the surrounding structures [7]. In 16 cases of renal cell carcinoma metastases bleeding was significantly reduced post embolization [29].
Metastatic spinal tumors (Fig 11A, B and C): Hypervascular spinal and pelvic tumors are treated with embolization as a pre-operative measure to decrease blood loss or as a palliative procedure to relieve symptoms.

Sclerotherapy of Bone Lesions
This involves instilling a scleroscent inside a bone tumor (especially a cystic bone tumor) to damage the lining endothelium, which eventually results in thrombosis.
Sclerotherapy using polidocanol has been attempted in treating Aneurysmal bone cysts (ABC) with encouraging results. In a paper written by Rastogi et al, the author has treated 72 cases of ABC’s with sclerotherapy with satisfactory result in more than 97% [70] of patients [31]. Significant reduction in size of the lesions has been documented. In hypervascular ABC’s, sclerotherapy can be preceded by embolization.

Percutaneous treatment of Vascular Malformation
Though congenital vascular anomalies are not bone lesions, these commonly present as a swelling and are referred to an orthopedic surgeon.
International Society for the Study of Vascular Anomalies (ISSVA) classifies congenital vascular anomalies into vascular tumors and vascular malformations.
Vascular tumors are hemangiomas, which are seen in infancy and childhood. They are further classified into infantile hemangioma, congenital hemangiona, Kaposiform hemangioendothelioma and tufted angiomas. Congenital hemangiomas are classified as Rapidly Involuting Congenital hemangiomas (RICH) and Non- Involuting Congenital hemangiomas (NICH) [32].
Vascular malformations can present anytime in life. They are classified as low-flow vascular malformations and high-flow vascular malformations.
Low-flow vascular malformations are namely venous malformations, lymphatic malformations or mixed while high flow vascular malformations are arterio-venous malformations and arterio-venous fistulas.
Diagnosis: These conditions are diagnosed on the age of presentation, the changes in the lesion over time (progression or regression) and some key imaging features.
Dyanamic Contrast MR Angiography (DCE_MRA) is the investigation of choice (33). Table 2 provides a review on the imaging features of few of the common vascular anomalies-

Treatment of Vascular tumors
Vascular tumors generally involute over time and eventually regress on follow-up. In cases of high flow lesions, endovascular angioembolization can be attempted to relieve symptoms or to decrease the vascularity before surgery.
Treatment of Vascular Malformations:
Low-flow vascular malformations are most commonly treated by percutaneous sclerotherapy.

Percutaneous Sclerotherapy (Fig 12A, B, C, D, E and F)
This involves injecting a scleroscent in the malformation, which leads to necrosis of the endothelium and subsequent thrombosis.
Contraindications: Atrial septal defects and pulmonary hypertension are absolute contraindications [34].

Technique for venous malformation
The procedure is performed under high quality digital subtraction angiography imaging with road-mapping technique.
The method of sclerotherapy depends on the angioarchitecture of the lesion. Vascular malformations are classified into sequestrated, non-sequestrated and mixed varieties. Sequestrated lesions do not have any communication with the deep venous system, making injecting scleroscent in the lesion safe. The non-sequestrated lesions have communication with the deep venous system while mixed lesions have both the features [35].
Procedure is generally performed under local anaesthesia. General anaesthesia with endotracheal intubation is required for lesions involving the oro-naso-laryngeal pathway or when severe pain is expected during scleroscent injection. Torniquent may be tied to decrease the venous outflow for malformations involving the extremities. Good hydration is necessary to counter scleroscent induced hemolysis.
Procedure: The lesion is punctured using 22G scalp vein needle or 22G spinal needle. Contrast injection is done to evaluate the angioarchitecture. In non-sequestrated lesions, scleroscent is injected into the lesion. For non-sequestrated lesions, outflow tract is occluded with a balloon catheter or glue or ablated with Nd-YAG Laser [36,37].
The commonest used scleorscent is sodium tetradecyl sulphate (Setrol). It is injected as foam. For radioopacity, it is mixed with oil-based solution like Lipiodol or non-ionic contrast. Not more than 0.5ml/kg should be injected at a time with a maximum permissible dose of 20ml [38].
Other scleroscents used are sodium morrhuate, bleomycin, doxyclycine, OKT-432 and ethanol.

Treatment for lymphatic malformation
These are classified as cystic or channel type. Cystic type is further classified as macrocystic, microcystic or mixed. These lesions present as large collections of lymph, commonly in the neck and the axillary lesions.
Lymphatic malformation is punctured with a needle under ultrasound (USG) guidance and fluid is aspirated with or without a pigtail catheter. Later, the scleroscent is instilled in the lesion. Doxycycline is the scleroscent of choice as it can be injected in large quantities [39].
Post-procedure monitoring:
Tight dressing and painkillers are given post-procedure. The lesion tends to increase in size for a few days due to imflammation. This generally settles with painkillers.
Complications: Pain, infection, hematoma and skin blistering are the general complications. Neuropathy may be seen after ethanol injection. Compartment syndrome is a dreadful complication seen when sclerotherapy is done in closed spaces like the orbit. Hemolysis and hemoglobinuria is seen when large amount of scleroscent is used. Other rare complications are pulmonary edema and acute cardiovascular collapse [40].

Advances in Interventional Orthopediac Oncology
Isolated Limb Infusion (ILI) for Malignant Extremity Bone Tumors:
This is a comparatively new approach of delivering high dose of a chemotherapeutic agent in the limb in which the tumor is present. The main advantage is larger quantity of dose of the chemotherapeutic agent can be administered with less systemic side-effects.
ILB has been attempted for melanoma using Actinomycin-D and for soft tissue sarcoma’s using melphalan and tumor necrosis factor [41].
MR-HIFU (MRI-guided High Intensity Focused Ultrasound) [42]:
This involves focusing high intensity ultrasound beam in the desired tissue to be treated. The ultrasound waves cause heat generation in the tissue with coagulative necrosis. MRI is used to guide the treatment. In orthopedic oncology, MR-HIFU can be used for ablation of painful bone metastasis and local tumor control in infiltrative tumors.
Cryoablation [43]: Like radiofrequecy ablation destroys tissue by heat, cryoablation damages tissue by extreme cooling to sub-zero temperatures. It is indicated for painful bone metastasis and for local tumor control. Use of thermocouples to measure temperature is sometimes indicated to prevent damage to surrounding nerves is some cases.

Conclusion

Interventional Radiology has an ever increasing role in the diagnosis and management of bone and soft tissues tumors. Close co-operation and discussions with the orthopedic oncologist and interventional radiologist is the cornerstone for selection of correct treatment modality and optimizing response.


References

1. Mankin HJ, Mankin CJ, Simon MA. The hazard of biopsy revisited. 
J Bone Joint SurgAm 1996;78:656–63.
2. Choi JJ, Davis KW, Blankenbaker DG. Percutaneous musculoskeletal biopsy. Semin Roentgenol 2004;39:114–28.
3. Ahrar K, Himmerich JH, Herzog CE, et al. Percutaneous ultrasound- guided biopsy in definitive diagnosis of osteosarcoma. J Vasc Interv Radiol 2004;15:1329–33.
4. Kasraeian S, Allison DC, Ahlmann E, et al. A comparison of fine- needle aspiration, core biopsy, and surgical biopsy in the diagnosis of extremity soft tissue masses. Clin Orthop Relat Res 2010;468: 2992–3002.
5. Logan PM, Connell DG, O’Connell JX, et al. Image-guided percutane- 
ous biopsy of musculoskeletal tumor: an algorithm for selection of 
specific biopsy techniques. AJR Am J Roentgenol 1996;166:137–41.
6. Jelinek JS, Murphey MD, Welker JA, et al. Diagnosis of primary bone tumors with image-guided percutaneous biopsy: experience with 110 
tumors. Radiology 2002;223:731–7.
7. White LM, Schweitzer ME, Deely DM, et al. Study of osteomyelitis: utility of combined histologic and microbiologic evaluation of percutaneous biopsy samples. Radiology 1995;197:840–2.
8. Wu JS, Goldsmith JD, Horwich PJ, et al. Bone and soft tissue lesions: what factors affect diagnostic yield of image-guided core-needle biopsy. Radiology 2008;248:962–71.
9. Phillips FM. Minimally invasive treatments of osteoporotic vertebral compression fractures. Spine 2003;28:S45-53.
10. Stallmeyer MJB, Zoarski GH, Obuchowski AM. Optimizing patient selection in percutaneous vertebroplasty. J Vasc Interv Radiol 2003; 14:683–96.
11. Laredo JD, Hamze B. Complications of percutaneous vertebroplasty 
and their prevention. Skeletal Radiol 2004;33:493–505.
12. Teng MM, Wei CJ, Wei LC, et al. Kyphosis correction and height restoration effects of percutaneous vertebroplasty. AJNR Am J Neuro- radiol 2003;24:1893–900.
13. Hu MM, Eskey CJ, Tong SC, et al. Kyphoplasty for vertebral compression fracture via a uni-pedicular approach. Pain Physician 2005;8: 363–7
14. Mathis JM, Wong W. Percutaneous vertebroplasty: technical considerations. J Vasc Interv Radiol 2003;14:953–60.
15. Mathis JM, Barr JD, Belkoff SM, et al. Percutaneous vertebroplasty: a developing standard of care for vertebral compression fractures. AJNR Am J Neuroradiol 2001;22:373–81.
16. Nussbaum DA, Gailloud P, Murphy K. A review of complications asso- ciated with vertebroplasty and kyphoplasty as reported to the Food and Drug Administration medical device related web site. J Vasc Interv Radiol 2004;15:1185–92.
17. Rhim H, Goldberg SN, Dodd GD 3rd, Solbiati L, Lim HK, Tonolini M, Cho OK. Essential techniques for successful radio-frequency thermal ablation of malignant hepatic tumors. Radiographics. 2001 Oct;21 Spec No:S17-35; discussion S36-9.
18. Motamedi D, Learch TJ, Ishimitsu DN, Motamedi K, Katz MD, Brien EW, Menendez L. Thermal ablation of osteoid osteoma: overview and step-by-step guide. Radiographics. 2009 Nov;29(7):2127-41.
19. Rybak LD, Rosenthal DI, Wittig JC. Chondroblastoma: radiofrequency ablation–alternative to surgical resection in selected cases. Radiology. 2009 May;251(2):599-604.
20. Charles H. Bush Walter E. Drane Treatment of an Aneurysmal Bone Cyst of the Spine by Radionuclide Ablation AJNR 2000 21: 592-594
21. Callstrom MR, Charboneau JW, Goetz MP, et al. Image-guided ablation of painful metastatic bone tumors: a new an effective approach to a difficult problem. Skeletal Radiol. 2006;35:1–15.
22. Fernando Ruiz Santiago, María del Mar Castellano García et al Treatment of bone tumours by radiofrequency thermal ablation Curr Rev Musculoskelet Med. Mar 2009; 2(1): 43–50.
23. Bucheler E, Hupe W, Hertel EU et al. Catheter embolization of Renal Tumors. Rofo 1976;124(2): 134-38.
24. Turcotte RE, Sim FH, Unni KK. Giant cell tumor of the sacrum. Clin Orthop Relat Res 1993;291: 215-21
25. Lin PP, Guzel VB, MouraMF, at al Long-term follow up of patients with giant cell tumor of sacrum treated with selective arterial embolization Cancer 2002;95(6): 1317-25.
26. Guzey FK, Emel , Aycan A, et al Paediatric vertebral and spinal epidural tumors: a retrospective review of twelve cases. Pediatr Neurosurg 2008;44((1): 14-21.
27. Fox MW, Onofrio BM. The natural history and management of symptomatic and asymptomatic vertebral hemangiomas . J Neurosurg 1993;78:36-45
28. Resnick SA, Russel EJ, Hanson DH, et al. Embolization of a life-threatening vascular malformation by direct percutaneous transmandibular puncture Head Neck 1992;14(5): 372-9.
29. Van Tol KM, Hew JM, Jager PL, et al. Embolization in combination with radio-iodine therapy for bone metastases from primary differentiated thyroid carcinoma. Clin Endocrinol 2000; 52: 653-9.
30. Sun S, Lang EV. Bone metastases from renal cell carcinoma: pre-operative embolization J Vas Interv Radiol 1998;9: 263-69.
31. S. Rastogi, M. K. Varshney, V. Trikha, S. A. Khan, B. Choudhury, R. Safaya, J Bone Joint Surg Br September 2006 vol. 88-B no. 9 1212-1216
32. Mulliken JB, Glowacki J. Classification of pediatric vascular lesions. Plast Reconstr Surg 1982;70(1):120–1.
33. Dubois J, Alison M. Vascular anomalies: what a radiologist needs to know. Pediatr Radiol 2010;40(6):895–905.
34. Dompmartin A, Blaizot X, Theron J, et al. Radio-opaque ethylcellulose- ethanol is a safe and efficient sclerosing agent for venous malforma- tions. Eur Radiol 2011.
35. Mendonca DA, McCafferty I, Nishikawa H, et al. Venous malformations of the limbs: the Birmingham experience, comparisons and classification in children. J Plast Reconstr Aesthet Surg 2010;63(3): 383–9.
36. Holt P, Burrows P. Interventional radiology in the treatment of vascular lesions. Facial Plast Surg Clin North Am 2001;9(4):585–99.
37. Siniluoto TM, Svendsen PA, Wikholm GM, Fogdestam I, Edström S. Percutaneous sclerotherapy of venous malformations of the head and neck using sodium tetradecyl sulphate (sotradecol). Scand J Plast Reconstr Surg Hand Surg. 1997 Jun;31(2):145-50.
38. Burrows PE, Mason KP. Percutaneous treatment of low flow vascular malformations. J Vasc Interv Radiol 2004;15(5):431–45.
39. Burrows PE, Mitri RK, Alomari A, et al. Percutaneous sclerotherapy of lymphatic malformations with doxycycline. Lymphat Res Biol 2008;6(3–4):209–16.
40. Rimon U, Garniek A, Galili Y, et al. Ethanol sclerotherapy of peripheral venous malformations. Eur J Radiol 2004;52(3):283–7.
41. Wray, C. J., Benjamin, R. S., Hunt, K. K., Cormier, J. N., Ross, M. I. and Feig, B. W. (2011), Isolated limb perfusion for unresectable extremity sarcoma. Cancer, 117: 3235–3241.
42. Bio Joo, Park M-S, Lee SH, et al. Pain Palliation in Patients with Bone Metastases Using Magnetic Resonance-Guided Focused Ultrasound with Conformal Bone System: A Preliminary Report. Yonsei Medical Journal. 2015;56(2):503-509.
43. Callstrom, M. R., Dupuy, D. E., Solomon, S. B., Beres, R. A., Littrup, P. J., Davis, K. W., et al (2013), Percutaneous image-guided cryoablation of painful metastases involving bone. Cancer, 119: 1033–1041.


How to Cite this article: Pendse H, Kulkarni A, Agarwal M. Role of Image Guided Interventions in Orthopaedic Oncology. Journal of  Bone and Soft Tissue Tumors Sep-Dec 2015;1(2):  25-33.

h A 

Dr. Aniruddha Kulkarni

m 

Dr. Manish Agarwal


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


 

 

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

1.Posthuma De Boer J, van Royen BJ and Helder MN. Mechanisms of therapy resistance in osteosarcoma: a review. Oncol Discov. 2013; 1:8
2.Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer. 2006 Mar 1;106(5):1154–61.
3.Gelderblom H.Survival after recurrent osteosarcoma: data from 3 European Osteosarcoma Intergroup (EOI) randomized controlled trials.Eur J Cancer. 2011 Apr;47(6):895-902.
4.Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment – where do we stand? A state of the art review. Cancer Treat Rev. 2014 May;40(4):523–32.
5.Krailo M.A randomized study comparing high-dose methotrexate with moderate-dose methotrexate as components of adjuvant chemotherapy in childhood nonmetastatic osteosarcoma: a report from the Childrens Cancer Study Group. Med Pediatr Oncol. 1987;15(2):69-77.
6.Daw NC, Neel MD, Rao BN, et al. Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children’s Research Hospital OS99 trial. Cancer. 2011;117:2770–8.
7.Craft AW .Osteosarcoma: the European Osteosarcoma Intergroup (EOI) perspective.Cancer Treat Res. 2009;152:263-74.
8.Wang J, Li GJ .Relationship between RFC gene expression and intracellular drug concentration in methotrexate-resistant osteosarcoma cells Genet Mol Res. 2014 Jul 24;13(3):5313-21.
9.Sowers R.mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma.Mol Cancer Ther. 2003 Jun;2(6):535-41.
10. van Dalen EC, van As JW, de Camargo B. Methotrexate for high-grade osteosarcoma in children and young adults. Cochrane Database of Systematic Reviews 2011, Issue 5. Art. No.: CD006325
11.Whelan JS, Bielack SS, Marina N, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Annals of Oncology. 2015;26(2):407-414.
12. Xu M,Xu SF,Yu XC.Clinical analysis of Osteosarcoma patients treated with high-dose methotrexate-free neoadjuvant chemotherapy. Current Oncology. 2014;21(5):e678-e684


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