Advances of Treatment in Atypical Cartilaginous Tumours - Edwin F

Advances of treatment in atypical cartilaginous tumours - Edwin F. Dierselhuis 2019

Advances of treatment in atypical cartilaginous tumours

Edwin F. Dierselhuis ADVANCES OF TREATMENT IN ATYPICAL CARTILAGINOUS TUMOURS Financial support for printing and distribution of this thesis was kindly provided by:

Implantcast Link & Lima Nederland Smith & Nephew Research institute SHARE Nederlandse Orthopaedische Vereniging

COLOFON

Author: Edwin F. Dierselhuis Cover design en lay-out: Miranda Dood, Mirakels Ontwerp Printing: Gildeprint - The Netherlands ISBN: 978-90-9031884-4

All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means without prior permission of the author, or when appropriate, of the publisher of the publications. Advances of treatment in atypical cartilaginous tumours

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.

De openbare verdediging zal plaatsvinden op

woensdag 10 juli 2019 om 12.45 uur

door

Edwin Frank Dierselhuis

geboren op 4 november 1983 te Rotterdam Promotores Prof. dr. S.K. Bulstra Prof. dr. A.J.H. Suurmeijer

Copromotores Dr. P.C. Jutte Dr. M. Stevens

Beoordelingscommissie Prof. dr. P.D.S. Dijkstra Prof. dr. P.C.W. Hogendoorn Prof. dr. R.A.J.O. Dierckx

TABLE OF CONTENTS

I General introduction 08

PART I 22 II Cochrane review: Intralesional treatment versus wide resection for central low grade chondrosarcoma of the long bones

III Local treatment of atypical cartilaginous tumors in the long bones: 94 results in 108 patients with a minimum follow-up of two years

IV Computer assisted surgery for curettage of atypical cartilaginous 114 tumors / chondrosarcoma grade I in the long bones compared to fluoroscopic guidance

PART II

V Radiofrequency ablation as a new treatment modality in 136 cartilaginous lesions in the long bones: results of a pilot study

VI Radiofrequency ablation in the treatment of atypical cartilaginous 152 tumours in the long bones: Lessons learned from our experience VII General discussion, implications and future perspectives 170

VIII Summary 180

IX Nederlandse samenvatting 186

Dankwoord 194 List of publications 198 Research Institute SHARE 200 Curriculum Vitae 202

CHAPTER I

General introduction 10 | Advances of treatment in atypical cartilaginous tumours

INTRODUCTION 1 CHONDROSARCOMA

Sarcomas are malignant tumours of mesenchymal origin that arise in soft tissue and bone. They differ from common types of cancer, such as breast cancer, which derive from epithelial cells and are called carcinomas. Sarcomas are relatively uncommon, representing about 1% of all new cancer diagnoses in the United States.1 In the Netherlands, about 150 cases of primary bone malignancies are diagnosed each year.2 Chondrosarcomas (CS) are a very heterogeneous group of cartilage matrix-producing tumours. They are most commonly seen in patients aged 40-70 and are the third most common primary bone malignancy.3 The majority of cases (85%) are de novo central tumours, inside of the bone,3 yet can also arise secondarily from the surface of the bone from an osteochondroma – peripheral CS – or in the presence of Ollier disease or Maffucci syndrome. All these tumours form a wide range of malignant potential. The benign counterpart – enchondroma – is often an asymptomatic, locally non-aggressive tumour. On the other side of the spectrum, dedifferentiated CS is a very high-grade tumour with very poor survival4 (Figure 1). In general, chondroid tumours are poorly vascularised and have a low percentage of dividing cells. This makes them relatively insensitive to radiation and/or chemotherapy, and the mainstay of treatment for malignant cartilaginous tumours is surgery.3,4

enchondroma ACT CS grade II CS grade III dedifferentiated CS

excellent prognosis very poor prognosis

FIGURE 1. The spectrum of cartilaginous tumours, ranging from benign enchondroma to dedifferentiated chondrosarcoma General introduction | 11

ATYPICAL CARTILAGINOUS TUMOUR An atypical cartilaginous tumour (ACT) is a cartilage-producing tumour located in 1 the bone with intermediate malignant potential – also known as low-grade or grade I chondrosarcoma5 (Figure 2). Most cases are incidental findings, when patients come for evaluation of other joint- or bone-related complaints. With increased usage of MRI and CT-scanning, incidence of the disease has risen in recent decades.6-8 This is why it is important for orthopaedic surgeons to be aware of this entity and its possible treatment options.

FIGURE 2. Typical MRI image of an FIGURE 3. Tumour in the diaphysis atypical cartilaginous tumour (ACT) in of the femur, treated by intercalary the proximal humerus, showing a large resection, and reconstructed by allograft lesion and wall-to-wall filling but no signs with plate and nail fixation. of higher-grade aggressiveness

ACTs tend to be only locally aggressive, although incidental metastasising has been reported in literature.9,10 Historically a correct diagnosis has been notoriously difficult to make, since histology and imaging alone are not always conclusive and have shown high inter-observer variability.11 In some cases the tumour evolved to a high grade after local recurrence.12 This clearly has a negative impact on patient survival, and wide resection has long been advocated in order to achieve adequate surgical margins.13 However, nowadays 12 | Advances of treatment in atypical cartilaginous tumours

a paradigm shift has taken place in literature towards more local (intralesional) surgery.14 1 It may be that more aggressive tumour biology after local recurrence is the result of an undertreated high-grade tumour, rather than a direct consequence of the local recurrence in itself. With improved imaging modalities and a better understanding of the natural behaviour of these tumours, case series have been published that show excellent survival after intralesional surgery by curettage of the tumour.15-23 Given the seemingly relatively mild nature of ACT but the potential morbidity of the current surgical strategies, one can wonder whether the cure is not worse than the disease. Minimally invasive treatment might thus be a step towards an ideal treatment regime: local control leading to excellent oncological outcome, no compromise on functional results, and ideally performed in day care. This concept was developed by our group after an apparently benign lesion treated by RFA turned out to be a cartilaginous malignancy.24

SURGICAL TECHNIQUES AND THEIR CONSEQUENCES

As described above, different surgical techniques have been applied for treatment of ACT, every single one with its specific characteristics and advantages/disadvantages. More details are provided below for each particular technique.

WIDE RESECTION

In this technique whole segments of bone (including joints) are removed in order to attain extensive surgical margins. This will sometimes lead to amputation if neurovascular bundles cannot be saved, reconstruction is not feasible, or soft-tissue coverage cannot be achieved. If limbs can be salvaged but joints are lost, endoprosthesis such as total knee arthroplasty (TKA) or total hip arthroplasty (THA) is needed. This often requires specially designed tumour prostheses rather than conventional arthroplasties. If segments of bone between joints are removed (intercalary resection), reconstruction is done with autologous bone (e.g. vascularised fibula) and/or allograft (Figure 3). Wide resection, regardless of the reconstructive possibilities, often leads to functional deficiencies. Amputees will not be the only ones suffering from functional loss, as in reconstructive surgery too muscle function is often (temporarily) lost and weight bearing is prohibited for several months.25,26 Finally, due to the scope of the surgery, operating time and large wound bed there is a considerable risk of postoperative infection, nerve damage, fracture and thromboembolic events.26-28 General introduction | 13

INTRALESIONAL SURGERY (CURETTAGE) In curettage the tumour is removed while leaving the surrounding bone virtually intact. 1 Only a small cortical window is created to have access to the tumour. The lesion is removed using a curette, traditionally under fluoroscopy guidance (Figure 4). To improve surgical margins, several local adjuvants are available. Most common are the application of phenol (C6H5OH) with ethanol washout, polymethylmethacrylate (PMMA) and the use of liquid nitrogen (LN2). In an in vitro model, cytotoxic effects were found for concentrations of 1.5% phenol and 42.5% ethanol.29 Furthermore, 96% ethanol is capable of reducing phenol levels for safe washout of the cavity. PMMA is often used in orthopaedic surgery, primarily to fixate endoprostheses. It is also used to fill defects, as it enhances early weight bearing. Another possible advantage is its necrotising effect due to the exothermic chemical reaction during hardening, where temperatures over 80°C are reached. It is estimated that the surgical margins are hereby enlarged by 2 to 5 mm in cancellous bone.30 Cryosurgery using liquid nitrogen is a more potent adjuvant, as 7 to 12 mm of extra bone tissue are necrotised.31 However, it is not widely used as it has drawbacks like temporary nerve damage and increased risk of fracturing.32 Curettage preserves the integrity of the bone and joint dramatically compared to en bloc resection or amputation. As a result, functional outcome is significantly better after curettage than after resection in retrospective comparisons.25-26 Nevertheless, this technique also has its drawbacks, as complications such as fracturing or infection do occur.26-28 In addition, hospital admission is needed and extremities are often protected from weight bearing for several weeks to months. 14 | Advances of treatment in atypical cartilaginous tumours

FIGURE 4. Postoperative FIGURE 5. Working field of an RFA needle35. image of an ACT treated by curettage and PMMA filling of the defect.

RADIOFREQUENCY ABLATION (RFA)

In radiofrequency ablation (RFA) a high-frequency alternating current heats tissue to approximately 80°C.33 An electromagnetic field is created which results in vibration of molecules, leading to heat due to friction in about a 3-cm bony zone34 (Figure 5). As temperatures rise above 46°C coagulation necrosis takes place, with almost instantaneous cell death at 60°C and beyond.36 RFA can be applied percutaneously under computed tomography (CT) guidance under general or spinal anaesthesia (Figure 6). The technique was originally developed successfully for solid organ tumours such as hepatocellular carcinoma.37-38 Over two decades ago it was also introduced in orthopaedics and has become the gold standard for osteoid osteoma, with primary and secondary success rates of 79-96% and 97-100% respectively.39-42 It has proven to be a precise, safe and relatively inexpensive treatment tool for other bony lesions as well, such as chondroblastoma and metastases.43-46 Major advantages are that it allows early weight bearing and can be performed in day care. This technique also has potential complications, mainly burning of the skin or fracturing.24,47 General introduction | 15

FIGURE 6. Per-operative image of CT guided RFA procedure of an ACT in the distal femur

AIM AND OVERVIEW OF THE THESIS

This thesis aims to analyse in two parts the results of current practice of ACT treatment and to investigate new treatment modalities.

PART I

To date, no prospective studies have been published that could help design an adequate treatment algorithm for ACT in the long bones. There are only low-evidence retrospective studies available, with widespread publication dates, surgical indications and applied techniques. Hence in the absence of high-level evidence we first aim to review all available literature and meta-analysis data in a Cochrane Review (Chapter II). Next, we will analyse our own experience of treating ACT by intralesional surgery (Chapter III). As computer-assisted surgery (CAS) has also been introduced in the field of oncologic orthopaedics, we will also evaluate its value compared to fluoroscopy in the treatment of ACT (Chapter IV). CAS offers the surgeon real-time feedback on its whereabouts during surgery, potentially decreasing residual tumour rates and enhancing disease-free survival. Moreover, patients as well as surgeons are protected from X-rays during surgery. 16 | Advances of treatment in atypical cartilaginous tumours

PART II 1 Minimally invasive treatment using RFA is studied in part II of the thesis. In Chapters V and VI we provide insight into the efficacy of RFA in the treatment of ACT, together with evaluation of imaging modalities for follow-up. In Chapter V we also investigate functional outcome by means of musculoskeletal tumour society (MSTS) scores after RFA compared to intralesional surgery. In Chapter VI we analyse the learning curve of applying this new technique. A general discussion and the implications of our studies are provided in Chapter VII, and the thesis is summarised in Chapter VIII. General introduction | 17

REFERENCES 1

1. Borden EC, Baker LH, Bell RS, et al. Soft tissue sarcomas of adults: state of the translational science. Clin. Cancer Res. 9 (6): 1941–56 https://www.oncoline.nl/beentumoren 2. Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH, et al. The clinical approach towards chondrosarcoma. Oncologist 2008 Mar;13(3):320-9. 3. Nota SP, Braun Y, Schwab JH, van Dijk CN, Bramer JA. The Identification of Prognostic Factors and Survival Statistics of Conventional Central Chondrosarcoma. Sarcoma 2015:623746 4. Hogendoorn P. B., Bovee J. M., Nielsen G. P. Chondrosarcoma (grades I-III), including primary and secondary variants and periosteal chondrosarcoma. In: Fletcher C. D. M., Bridge J. A., Hogendoorn P. C. W., Mertens F., editors. World Health Organization Classification of Tumours of Soft Tissue and Bone. Vol. 5. Lyon, France: IARC; 2013. p. p. 264. 5. Hong ED, Carrino JA, Weber KL, Fayad LM. Prevalence of shoulder enchondromas on routine MR imaging. Clin Imaging. 2011 Sep-Oct;35(5):378 6. Kransdorf MJ, Peterson JJ, Bancroft LW. MR imaging of the knee: incidental osseous lesions. Radiol Clin North Am. 2007 Nov;45(6):943-5 7. van Praag VM, Rueten-Budde AJ, Dijkstra PDS, Study group, van de Sande MAJ. Bone and Soft tissue tumours (WeBot) Incidence, outcomes and prognostic factors during 25 years of treatment of chondrosarcomas. Surgical Oncology 27 (2018) 402-8 8. Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical management of conventional grade I chondrosarcoma of long bones. Clin Orthop Relat Res 2007 Oct;463:166- 72 9. Gunay C, Atalar H, Hapa O, Basarir K, Yildiz Y, Saglik Y. Surgical management of grade I chondrosarcoma of the long bones. Acta Orthop Belg. 2013 Jun;79(3):331-7 10. Skeletal Lesions Interobserver Correlation among Expert Diagnosticians (SLICED) Study Group. Reliability of histopathologic and radiologic grading of cartilaginous neoplasms in long bones. J Bone Joint Surg Am. 2007 Oct;89(10):2113-23. 11. Schwab JH, Wenger D, Unni K, Sim FH. Does local recurrence impact survival in low-grade chondrosarcoma of the long bones? Clin Orthop Relat Res. 2007 Sep;462:175-80. 12. Fiorenza F, Abudu A, Grimer RJ, Carter SR, Tillman RM, Ayoub K, Mangham DC, Davies AM. Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg Br. 2002 Jan;84(1):93-9. 18 | Advances of treatment in atypical cartilaginous tumours

13. Hickey M, Farrokhyar F, Deheshi B, Turcotte R, Ghert M. A systematic review and meta- 1 analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Ann Surg Oncol. 2011 Jun;18(6):1705-9. 14. van der Geest IC, de Valk MH, de Rooy JW, Pruszczynski M, Veth RP, Schreuder HW. Oncological and functional results of cryosurgical therapy of enchondromas and chondrosarcomas grade 1. J Surg Oncol 2008 Nov 1;98(6):421-6. 15. Hanna SA, Whittingham-Jones P, Sewell MD, Pollock RC, Skinner JA, Saifuddin A, et al. Outcome of intralesional curettage for low-grade chondrosarcoma of long bones. Eur J Surg Oncol 2009 Dec;35(12):1343-7. 16. Kim W, Han I, Kim EJ, Kang S, Kim H. Outcomes of curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma of long bone. Surgical Oncology 2015;24:89-94. 17. Kim W, Lee JS, Chung HW. Outcomes after extensive manual curettage and limited burring for atypical cartilaginous tumour of long bone. Bone Joint J 2018 Feb;100-B(2):256-261. 18. Meftah M, Schult P, Henshaw RM. Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma. J Bone Joint Surg Am. 2013 Aug 7;95(15):1358-64. 19. Mermerkaya MU, Bekmez S, Karaaslan F, Danisman M, Kosemehmetoglu K, Gedikoglu G, Ayvaz M, Tokgozoglu AM. Intralesional curettage and cementation forlow-grade chondrosarcoma of long bones: retrospective study and literature review. World Journal of Surgical Oncology 2014;12:336-41. 20. Mohler DG, Chiu R, McCall DA, Avedian RS. Curettage and Cryosurgery for Low-grade Cartilage TumorsIs Associated with Low Recurrence and High Function Is Associated with Low Recurrence and High Function. Clin Orthop Relat Res 2010;(468):2765-73. 21. Souna BS, Belot N, Duval H, Langlais F, Thomazeau H. No recurrences in selected patients after curettage with cryotherapy for grade I chondrosarcomas. Clin Orthop Relat Res. 2010 Jul;468(7):1956-62. 22. Verdegaal SH, Brouwers HF, van Zwet EW, Hogendoorn PC, Taminiau AH. Low-grade chondrosarcoma of long bones treated with intralesional curettage followed by application of phenol, ethanol, and bone-grafting. J Bone Joint Surg Am 2012 Jul 3;94(13):1201-1207. 23. Dierselhuis EF, Jutte PC, van der Eerden PJ, Suurmeijer AJ, Bulstra SK. Hip fractureafter radiofrequency ablation therapy for bone tumors: two case reports. Skeletal Radiol 2010;39:1139–1143. General introduction | 19

24. Donati D, Colangeli S, Colangeli M, Di Bella C, Bertoni F. Surgical treatment of grade I central chondrosarcoma. Clin Orthop Relat Res. 2010 Feb;468(2):581-9 1 25. Aarons C, Potter BK, Adams SC, Pitcher JD Jr, Temple HT. Extended intralesional treatment versus resection of low-grade chondrosarcomas. Clin Orthop Relat Res. 2009 Aug;467(8):2105-11. 26. Campanacci DA, Scoccianti G, Franchi A et al. Surgical treatment of central grade 1 chondrosarcomaof the appendicular skeleton. J Orthopaed Traumatol 2013;14:101-107. 27. Etchebehere M, de Camargo OP, Croci AT, et al. Relationship between surgical procedure and outcome for patients with grade I chondrosarcomas. Clinics (Sao Paulo) 2005;60:121-6. 28. Verdegaal SH, Corver WE, Hogendoorn PC, Taminiau AH. The cytotoxic effect of phenol and ethanol on the chondrosarcoma-derived cell line OUMS-27: an in vitro experiment. J Bone Joint Surg Br. 2008 Nov;90(11):1528-32. 29. Malawer MM, Marks MR, McChesney D, et al. The effect of cryosurgery and polymethylmethacrylate in dogs with experimental bone defects comparable to tumor defects. Clin Orthop 1988;226:299-310 30. Marcove RC, Stovell PB, Huvos AG, Bullough PG. The use of cryosurgery in the treatment of low and medium grade chondrosarcoma: a preliminary report. Clin Orthop 1977;122:147- 56 31. Schreuder HWB, Keijser LC, Veth RPH. Beneficial effects of cryosurgical treatment: benign and low-grade malignant bone tumors in 120 patients. Ned Tijdschr Geneeskd 1999;143:2275- 81 32. Patterson EJ, Scudamore CH, Owen DA, Nagy AG, Buczkowski AK. Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size. Ann Surg 1998;227:559–565. 33. Rachbauer F, Mangat J, Bodner G, Eichberger P, Krismer M. Heat distribution and heat transport in bone during radiofrequency catheter ablation. Arch Orthop Trauma Surg 2003 Apr;123(2-3):86-90. 34. Cool-tiptm RF Ablation System E Series; http://www.medtronic.com/covidien/products/ ablation-systems/cool-tip-rf-ablation-system-e-series. Accessed 15.05., 2017. 35. Goldberg SN. Radiofrequency tumor ablation: principles and techniques. European Journal of Ultrasound 2001;13(2):129-147. 20 | Advances of treatment in atypical cartilaginous tumours

36. Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, Xiao JL, et al. A prospective 1 randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Annals of Surgery 2006; 243: 321-8. 37. Livraghi T, Meloni F, Stasi M Di, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 2008; 47: 82-9. 38. Lindner NJ, Ozaki T, Roedl R, Gosheger G, Winkelmann W, Wortler K. Percutaneous radiofrequency ablation in osteoid osteoma. J Bone Joint Surg Br. 2001;83(3):391–6. 39. Akhlaghpoor S, Tomasian A, Arjmand Shabestari A, Ebrahimi M, Alinaghizadeh MR. Percutaneous osteoid osteoma treatment with combination of radiofrequency and alcohol ablation. Clin Radiol. 2007;62(3):268–73. 40. Cioni R, Armillotta N, Bargellini I, Zampa V, Cappelli C, Vagli P et al. CT-guided radiofrequency ablation of osteoid osteoma: longterm results. Eur Radiol. 2004;14(7):1203– 8. 41. Woertler K, Vestring T, Boettner F, Winkelmann W, Heindel W, Lindner N. Osteoid osteoma: CT-guided percutaneous radiofrequency ablation and follow-up in 47 patients. J Vasc Interv Radiol. 2001;12(6):717–22. 42. Rybak LD, Rosenthal DI, Wittig JC. Chondroblastoma: radiofrequency ablation: alternative to surgical resection in selected cases. Radiology 2009;251:599–604. 43. Goetz MP, Callstrom MR, Charboneau JW, Farrell MA, Maus TP, Welch TJ, et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol. 2004;22(2):300–6. 44. Belfiore G, Tedeschi E, Ronza FM, Belfiore MP, Della VT, Zeppetella G, et al. Radiofrequency ablation of bone metastases induces long-lasting palliation in patients with untreatable cancer. Singapore Med J. 2008;49(7):565–70. 45. Kashima M, Yamakado K, Takaki H, Kaminou T, Tanigawa N, Nakatsuka A, et al. Radiofrequency ablation for the treatment of bone metastases from hepatocellular carcinoma. AJR Am J Roentgenol. 2010;194(2):536–41. 46. Finstein JL, Hosalkar HS, Ogilvie CM, Lackman RD. Case reports: an unusual complication of radiofrequency ablation treatment of osteoid osteoma. Clin Orthop Relat Res 2006;448:248–51. General introduction | 21

CHAPTER II

Cochrane Review: Intralesional treatment versus wide resection for central low grade chondrosarcoma of the long bones

Edwin F. Dierselhuis1 Krista A. Goulding2 Martin Stevens3 Paul C. Jutte3

Cochrane Database Syst Rev. 2019 Mar 7;3

1 Department of Orthopaedic Surgery, Radboudumc, Nijmegen, the Netherlands 2 Department of Orthopaedics, Mayo Clinic- Arizona, Phoenix, Arizonia, USA 3 Department of Orthopaedic Surgery, University Medical Center Groningen, the Netherlands 24 | Advances of treatment in atypical cartilaginous tumours

ABSTRACT

Background: Grade I or low-grade chondrosarcoma (LGCS) is a primary bone tumour with low malignant potential. Historically, it was treated by wide resection, since accurate 2 pre-operative exclusion of more aggressive cancers can be challenging and undertreatment of a more aggressive cancer could negatively influence oncological outcomes. Intralesional surgery for LGCS has been advocated more often in the literature over the past few years. The potential advantages of less aggressive treatment are better functional outcome and lower complication rates although these need to be weighed against the potential for compromising survival outcomes.

Objectives: To assess the benefits and harms of intralesional treatment by curettage compared to wide resection for central low-grade chondrosarcoma (LGCS) of the long bones.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 4), MEDLINE and Embase up to April 2018. We extended the search to include trials registries, reference lists of relevant articles and review articles. We also searched ’related articles’ of included studies suggested by PubMed.

Selection criteria: In the absence of prospective randomised controlled trials (RCTs), we included retrospective comparative studies and case series that evaluated outcome of treatment of central LGCS of the long bones. The primary outcome was recurrence-free survival after a minimal follow-up of 24 months. Secondary outcomes were upgrading of tumour; functional outcome, as assessed by the Musculoskeletal Tumor Society (MSTS) score; and occurrence of complications.

Data collection and analysis: We used standard methodological procedures recognised by Cochrane. We conducted a systematic literature search using several databases and contacted corresponding authors, appraised the evidence using the ROBINS-I risk of bias tool and GRADE, and performed a meta-analysis. If data extraction was not possible, we included studies in a narrative summary. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 25

MAIN RESULTS

We included 18 studies, although we were only able to extract participant data from 14 studies that included a total of 511 participants; 419 participants were managed by intralesional treatment and 92 underwent a wide resection. We were not able to extract participant data from four studies, including 270 participants, and so we included them as a narrative summary only. The evidence was at high risk of performance, detection 2 and reporting bias. Meta-analysis of data from 238 participants across seven studies demonstrated little or no difference in recurrence-free survival after intralesional treatment versus wide resection for central LGCS in the long bones (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.92 to 1.04; very low-certainty evidence). MSTS scores were probably better after intralesional surgery (mean score 93%) versus resection (mean score 78%) with a mean difference of 12.69 (95% CI 2.82 to 22.55; P value < 0.001; 3 studies; 72 participants; low-certainty evidence). Major complications across six studies (203 participants) were lower in cases treated by intralesional treatment (5/125 cases) compared to those treated by wide resection (18/78 cases), with RR 0.23 (95% CI 0.10 to 0.55; low-certainty evidence). In four people (0.5% of total participants) a high-grade (grade 2 or dedifferentiated) tumour was found after a local recurrence. Two participants were treated with second surgery with no evidence of disease at their final follow-up and two participants (0.26% of total participants) died due to disease. Kaplan-Meier analysis of data from 115 individual participants across four studies demonstrated 96% recurrence- free survival after a maximum follow-up of 300 months after resection versus 94% recurrence-free survival after a maximum follow-up of 251 months after intralesional treatment (P value = 0.58; very low-certainty evidence). Local recurrence or metastases were not reported after 41 months in either treatment group.

AUTHORS’ CONCLUSIONS

Only evidence of low- and very low-certainty was available for this review according to the GRADE system. Included studies were all retrospective in nature and at high risk of selection and attrition bias. Therefore, we could not determine whether wide resection is superior to intralesional treatment in terms of event-free survival and recurrence rates. However, functional outcome and complication rates are probably better after intralesional surgery compared to wide resection, although this is low-certainty evidence, considering 26 | Advances of treatment in atypical cartilaginous tumours

the large effect size. Nevertheless, recurrence-free survival was excellent in both groups and a prospective RCT comparing intralesional treatment versus wide resection may be challenging for both practical and ethical reasons. Future research could instead focus on less invasive treatment strategies for these tumours by identifying predictors that help 2 to stratify participants for surgical intervention or close observation.

PLAIN LANGUAGE SUMMARY

THE EFFECT OF TYPE OF SURGERY FOR OUTCOME IN LOW-GRADE CHONDROSARCOMA

BACKGROUND AND REVIEW QUESTION

Chondrosarcomas are one of the most common types of bone cancer, with varying degrees of severity. These tumours grow from cartilage forming cells, within the bone, or on the surface of the bone. Low-grade chondrosarcomas (LGCS) are tumours that grow slowly over time and do not generally metastasize and people do not usually die from this disease. In the late 20th century, the condition was treated by cutting out large portions of bone surrounding the tumour (wide resection). However, surgeons today more commonly treat these tumours by scraping the tumour out of the bone (intralesional treatment). In this way, the bone structure is preserved and more extensive surgery can be avoided. Therefore, people are potentially less disabled and complications can be reduced. This is only appropriate if the survival outcome of the cancer treatment is not compromised compared to wide resection. We reviewed the evidence for the harms and benefits of both types of surgery on outcomes in people with LGCS, including tumour recurrence after surgery (local recurrence), level of physical functioning and complications after surgery.

SEARCH DATE

The evidence is current to April 2018. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 27

STUDY CHARACTERISTICS

We identified 14 studies that were suitable for analysis with a total of 511 participants; 92 were treated by wide resection compared to 419 by intralesional treatment. Age of the participants varied from 13 to 82 years with a mean age of 48 years. Women outnumbered men in the studies by just over one and a half times, which reflects that LGCS are more common in women. People were followed-up for between 24 to 300 months after surgery. 2 In addition, there were four studies including 270 participants, from which we could not extract the exact data, but were used to confirm the statistical analysis.

KEY RESULTS

We found that there was little or no difference in rates of local recurrence between treatment types. In 94% to 96% of the cases, the tumour was successfully removed after a single operation. In the few cases where disease recurred, a second operation was needed. People with LGCS probably have better functionality after less aggressive intralesional treatment, and complication rates were probably lower compare to wide surgical resection. Less than 0.3% of all people with LGCS died due to their disease, irrespective of the surgical technique.

CERTAINTY OF EVIDENCE

Overall certainty of the studies was very low, as all studies only described the results of the treatment in hindsight and none of the studies randomly selected patients between treatment groups. 28 | Advances of treatment in atypical cartilaginous tumours

SUMMARY OF FINDINGS FOR THE MAIN COMPARISON (EXPLANATION)

Intralesional treatment versus wide resection for central, low- grade 2 (grade I) chondrosarcoma in the long bones Patient or population: people with central, low-grade (grade I) chondrosarcoma in the long bones Settings: hospital Intervention: intralesional treatment Comparison: wide resection Outcomes Illustrative comparative Relative No of Certainty Comments risks* (95% CI) effect participants of the (95% CI) (studies) evidence (GRADE) Assumed Corresponding risk risk Wide Intralesional resection treatment Recurrence- free 54 per 1000 68 per 1000 RR 0.98 238 ⊕0001 survival (19 to 111) (34 to 116) (0.92 to (7 studies) Very low (24-300 months’ 1.04) follow-up) Functional The mean The MD 12.7 72 ⊕⊕00 outcome based MSTS was mean MSTS was (2.8 to (3 studies) Low2 on MSTS score 78% and 93% and ranged 22.6) (percent) ranged across across intervention Scale 0% to control groups from 89.3% 100%, with groups f rom to 98.6% 100% indicating 72.1% to no functional 94.3% limitations Overall rate 230 per 40 per RR 0.23 203 ⊕⊕00 of major 1000 1000 (0.10 to (six studies) Low2 complications (150 to 337) (13 to 82) 0.55) (24-300 months’ follow-up) Pathological N/A N/A N/A N/A N/A Only 2 cases in upgrading of the overall data tumour had a transition towards grade II chondrosarcoma, based on the narrative reporting of results Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 29

* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and therelative effect of the intervention (and its 95% CI). CI: confidence interval;MD: mean dif ference; MSTS: Musculoskeletal Tumor Society; N/A: not applicable; RR: risk ratio GRADE Working Group grades of evidence High- certainty: further research is very unlikely to change our confidence in the estimate of effect. Moderate- certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low- certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely 2 to change the estimate. Very low- certainty: we are very uncertain about the estimate. 1All included studies were observational studies, which have an initial low level of evidence. We downgraded the evidence level since there were serious risks of bias. 2All included studies were observational studies, which have an initial low level of evidence. We downgraded the evidence since there were serious risks of bias. However, we upgraded them considering the large effect.

BACKGROUND

DESCRIPTION OF THE CONDITION

Chondrosarcoma is the most common primary malignant bone tumour after osteosarcoma (Bauer 1995; Eriksson 1980; Healey 1986; Rosenthal 1984), and is characterised by a heterogeneous group of bone malignancies with a cartilaginous origin (Fletcher 2013). Chondrosarcoma constitute 20% to 27% of all primary bone tumours (Murphey 2003). Reported overall incidence is 1: 200,000 to 1:500,000, with men and women being more or less equally affected (ESMO 2012; Giuffrida 2009). Incidence is highest between the 3rd and 7th decade of life (ESMO 2012; Jundt 2008). Chondrosarcoma vary from low- grade, relatively benign to high-grade or dedifferentiated tumours with very poor survival. Conventional chondrosarcoma can originate outside the bone (periosteal or peripheral chondrosarcoma) or within the bone (central chondrosarcoma); the latter accounts for 75% of all of these tumours. Tumours can either be intra-compartmental (Enneking stage IA) or extra-compartmental (Enneking stage IB (Enneking 1986)). Oncological outcome is predominately determined by histological grading, ranging from I to III, with higher-grade tumours associated with worse prognosis. Central grade I (low-grade (LG)) chondrosarcoma (LGCS) tumours tend to grow slowly and rarely metastasize, resulting in an 83% to 89% 10-year survival rate (Bjornsson 1998; Evans 1977; Fiorenza 2002). Microscopically, they exhibit a matrix rich in hyaline cartilage (Gelderblom 2008). The 30 | Advances of treatment in atypical cartilaginous tumours

most important clinical symptom is persistent (nocturnal) pain, although LGCS can be asymptomatic. Treatment of LGCS is primarily surgical, since these tumours are generally resistant to radiation or systemic therapy (Eriksson 1980; Lee 1999). In clinical practice, the treating physician is presented with a diagnostic dilemma. In a substantial number of cases, it is difficult to differentiate central LGCS from its benign 2 equivalent, enchondroma (Eefting 2009; Geirnaerdt 1997; Mirra 1985; Randall 2005). Intermediate- and high-grade chondrosarcoma display typical signs, such as perilesional oedema and cortical destruction. Enchondroma can be managed conservatively with observation or treated with intralesional curettage. Malignant transformation of a solitary enchondroma is rare. On the other hand, intermediate- and high-grade chondrosarcoma display a much more aggressive course, with 10-year survival rates ranging from 53% to 64% and 29% to 38%, respectively, and a higher incidence of local recurrence and distant metastases (Bjornsson 1998; Fiorenza 2002; Giuffrida 2009). They are treated with ’en bloc’ resection (wide resection) with reconstruction (prosthesis) or amputation, which hampers joint and limb function. Historically, orthopaedic surgeons tended to treat LGCS in a similar fashion. More recently, there has been a tendency to perform intralesional surgery in LGCS by extended intralesional curettage, preferably with local adjuvant therapy, such as phenolisation, the use of polymethyl methacrylate (PMMA) and application of cryotherapy (Donati 2010; Leerapun 2007; Schreuder 1998; Van der Geest 2008; Veth 2005). Some studies suggest that intralesional surgery could lead to higher local recurrence rates, which in itself could lead to upgrading towards high-grade chondrosarcoma (Andreou 2011). LGCS tumours located in the pelvis and axial skeleton tend to be more aggressive and require other treatment strategies, often similar to higher- grade tumours (Gelderblom 2008). Therefore, we have described only treatment of tumours in the long bones in this review.

DESCRIPTION OF THE INTERVENTION

Intralesional surgery in LGCS is carried out by curettage. During this procedure, the tumour is accessed through a cortical window, extensive curettage is carried out and often supplemented with the use of a high-speed burr. After curettage, local adjuvant therapy can be applied, either by phenolisation or cryotherapy (see How the intervention might work). In a large number of cases, bone cement (PMMA) is used as an additional adjuvant and filler. The cavity is filled, where necessary, with bone graft or cement; larger Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 31

cortical windows can then be refashioned to the bone followed by routine wound closure. In some cases, prophylactic hardware (metal pins and plates often used to help repair fractured bones) is used to prevent fracturing. Depending on the site of the tumour, patients are prohibited from weight bearing six to 12 weeks after surgery. Generally, curettage is indicated if the joint surface is unaffected, if the lesion is contained in bone or a sufficient bony architecture remains after surgery. The most serious complications after 2 curettage are fracture of the treated site and infection.

HOW THE INTERVENTION MIGHT WORK

Extended intralesional curettage removes malignant tumour cells, but by definition will likely leave some microscopic cells behind. As a result, local adjuvant therapy is often performed. Phenol has a proven cytotoxic effect on LGCS cells and is used with the inten- tion to kill tumour cells that cannot be reached with the curette (Verdegaal 2012). The strongest evidence exists for cryotherapy, whereby liquid nitrogen is sprayed or poured into the bone cavity (Van der Geest 2008). It is thought that local freezing extends the surgical margin. In some centres, the bone cavity is filled with PMMA, and it is hypothesised that the heat released during the exothermic reaction as it sets has an additional cytotoxic effect on tumour cells. Given the relatively mild nature of LGCS, we hypothesise that these measures are sufficient to treat the disease. The major benefit of curettage compared to wide resection is improved functional outcome as a result of joint preservation and the avoidance of large bony resections or ablative surgery. Although people might be temporarily disabled due to decreased weight bearing after curettage, long-term functionality can often fully be restored.

WHY IT IS IMPORTANT TO DO THIS REVIEW

LGCS has an overall incidence rate that is relatively low compared to other types of cancer. To our knowledge, there are no prospective, randomised controlled trials (RCTs), given the low number of people affected. In literature, only small, retrospective studies have been published comparing intralesional treatment with wide resection (Aarons 2009; Bauer 1995; Donati 2010; Etchebehere 2005; Leerapun 2007; Schreuder 1998; Van der Geest 2008). This type of study is often subject to a high degree of bias and the numbers are often too small for meaningful statistical analysis. A systematic review is necessary to search for and summarise the available evidence. Hickey 2011 performed 32 | Advances of treatment in atypical cartilaginous tumours

a meta-analysis on this specific topic and it showed that intralesional therapy is not necessarily inferior to wide resection. Since then, several studies have been published, which justifies an updated overview. This review will be important, since intralesional treatment may have significant functional benefits compared to resection. Therefore, if the intralesional treatment is equally beneficial from a recurrence and survival point of 2 view, it may be better to perform curettage instead of wide resection.

OBJECTIVES

To assess the benefits and harms of intralesional treatment by curettage compared to wide resection for central low-grade chondrosarcoma (LGCS) of the long bones.

METHODS

CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW

TYPES OF STUDIES

Since no RCTs or other prospective studies were available, we included retrospective cohort studies comparing oncologic outcome of intralesional treatment of LGCS to wide resection in the long bones (i.e. humerus, radius, ulna, femur, tibia and fibula). In addition, we included case series with at least 20 participants. We also included studies examining other types of chondrosarcoma, from which we retrieved data related to central LGCS. If RCTs become available in literature, they still will be eligible for inclusion in future versions of the review.

TYPES OF PARTICIPANTS

We included all participants with central LGCS in the long bones. We did not apply age restrictions. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 33

TYPES OF INTERVENTIONS

We compared intralesional treatment (curettage) with or without adjuvant (phenol and ethanol, cryosurgery, bone cement or combinations) to wide resection, including amputation.

TYPES OF OUTCOME MEASURES 2 We prespecified the following outcomes, which are also included in the ’Summary of findings’ table.

PRIMARY OUTCOMES

Primary outcome was recurrence-free survival (defined as local recurrence and/or metastases), with a minimum follow-up duration of two years after index surgery.

SECONDARY OUTCOMES

We considered the following secondary outcomes: • incidence of pathological upgrading of tumour; • functional outcome based on Musculoskeletal Tumor Society (MSTS) score, if available. The MSTS score is a well-accepted and commonly used score to determine function after surgery for bone tumours (Enneking 1993). It includes six categories (pain, function, emotional acceptance, use of supports, walking ability and gait), with numerical values from 0 to 5 points; in total 30 points can be reached, often also presented as percentage, with 100% equalling 30 points, and 30 points or 100% indicating no functional limitations; • overall rate of major complications based on the following adverse events, if available: fracture, infection, re-operation (due to reasons other than progression of disease) or thromboembolic events. Grading of adverse events is outside the scope of this review. 34 | Advances of treatment in atypical cartilaginous tumours

SEARCH METHODS FOR IDENTIFICATION OF STUDIES

ELECTRONIC SEARCHES

We searched the following databases: • the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, 2 Issue 4), in the Cochrane Library (Appendix 1); • MEDLINE via Ovid (1946 to April 2018) (Appendix 2); • Embase via Ovid (1980 to 2018, week 17) Appendix 3).

We did not apply language restrictions.

SEARCHING OTHER RESOURCES

We extended our search to the reference lists of relevant articles and review articles, as well as contacting study authors to provide missing information. We also scanned related articles suggested by PubMed. In addition, we searched for ongoing trials by scanning online trials registries, such as Current Controlled Trials (http:// www.isrctn.com), and ClinicalTrials.gov, and searched for oral and poster abstracts presented in appropriate meetings (e.g. EMSOS, ISOLS).

DATA COLLECTION AND ANALYSIS

SELECTION OF STUDIES

We downloaded all titles and abstracts retrieved by electronic searching to a reference management database and removed duplicates. Three review authors (EFD, PCJ, KG) examined the remaining references independently. We excluded those studies that clearly did not meet the inclusion criteria. In addition, we obtained copies of the full text of potentially relevant references. Three review authors (EFD, PCJ, KG) independently assessed the eligibility of retrieved publications. We resolved disagreements by discussion between the three review authors and if necessary by involving the fourth review author (MS). We documented our reasons for exclusion. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 35

DATA EXTRACTION AND MANAGEMENT

For included studies, we extracted the following data. • Author, year of publication and journal citation (including language) • Country • Setting • Inclusion and exclusion criteria 2 • Study design and methodology • Study population: · total number enrolled; · patient characteristics; · age • Intervention details: · definition/details • Comparison: · definition/details • Risk of bias in study (see below) • Duration of follow-up • Outcomes: · for each outcome, we extracted the outcome definition and unit of measurement (if relevant). For adjusted estimates, we have recorded variables adjusted for in analyses. • Results: · we extracted the number of participants allocated to each intervention group, the total number analysed for each outcome, and the missing participants (if applicable).

We extracted the following information. • For time-to-event data (survival and disease progression), we extracted the log of the hazard ratio (log (HR)) and its standard error from study reports. If these are not reported, we attempted to estimated the log (HR) and its standard error using the methods of Parmar 1998. • For dichotomous outcomes we extracted the number of participants in each treatment arm who experienced the outcome of interest and the number of 36 | Advances of treatment in atypical cartilaginous tumours

participants assessed at endpoint, in order to estimate an odds ratio (OR). • For continuous outcomes, we extracted the final value and standard deviation of the outcome of interest and the number of participants assessed at endpoint in each treatment arm at the end of follow-up, in order to estimate the mean 2 difference between treatment arms and its standard error. We noted the time points at which outcomes were collected and reported. Three review authors (EFD, PCJ, KG) independently extracted the data onto a data abstraction form specially designed for the review. We resolved differences between review authors by discussion or by appeal to a fourth author (MS) if necessary.

ASSESSMENT OF RISK OF BIAS IN INCLUDED STUDIES

We assessed the risk of bias using ROBINS-I, since all studies were non-randomised, retrospective studies (Sterne 2016). We achieved consensus on seven domains through which bias might be introduced into non-randomised studies for interventions (bias due to confounding, bias in selection of participants into the study, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported result). The first two domains, covering confounding and selection of participants into the study, addressed issues before the start of the interventions that were compared (“baseline”). The third domain addressed classification of the interventions themselves. The other four domains addressed issues arising after the start of interventions: biases due to deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported result (Sterne 2016). Important confounders of interest in this Cochrane Review include the following. • Tumour stage (Enneking 1A or 1B) • Surgical techniques and local adjuvants • Pathological diagnosis • Time period of treatment

Three review authors (EFD, PCJ, KG) applied the ’Risk of bias’ tool independently and resolved differences by discussion or by appeal to a fourth review author (MS). We summarised results in both a ’Risk of bias’ graph and a ’Risk of bias’ summary. We Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 37

interpreted results of meta-analyses in light of the findings with respect to risk of bias. Each of the seven domains of bias contains signalling questions to facilitate judgements of risk of bias. The full signalling question and response framework for each outcome is provided in Sterne 2016. Following completion of the signalling questions, we determined a ’Risk of bias’ judgement for each domain and obtained an overall ’Risk of bias’ judgement for each outcome and result assessed. Overall risk of bias has four categories ranging 2 from low risk of bias (the study is at low risk of bias across all domains) to critical risk of bias (the study is at critical risk of bias in at least one domain). If there was insufficient information to assess the risk of bias in one or more key domains, but there was no indication that there was any critical or serious risk of bias in any of the other domains, then we have designated the overall classification as ’no information’.

MEASURES OF TREATMENT EFFECT

We used the following measures of the effect of treatment. • We had hoped to use hazard ratios (HRs) for time-to-event data but the data only allowed us to compute the risk ratio (RR) and OR. • For dichotomous outcomes, we used the RR. • For continuous outcomes, we used the mean difference (MD) between treatment arms.

UNIT OF ANALYSIS ISSUES

No cluster-RCT or cross-over RCTs were available for inclusion. We could not identify multiple groups within the studies presented.

DEALING WITH MISSING DATA

We did not impute missing outcome data for the primary outcome. If data were missing we contacted study authors to request data only on the outcomes for the participants they had assessed.

ASSESSMENT OF HETEROGENEITY

We assessed heterogeneity between studies by visual inspection of forest plots, by estimation of the percentage heterogeneity between studies that could not be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the 38 | Advances of treatment in atypical cartilaginous tumours

heterogeneity (Deeks 2001). If there had been evidence of substantial heterogeneity, we would have investigated and reported the possible reasons for this.

ASSESSMENT OF REPORTING BIASES 2 Reporting bias was assessed as part of the ’Risk of bias’ tool (Sterne 2016). DATA SYNTHESIS

In case of clinically and statistically homogeneous studies, we pooled their results in meta-analyses using the Cochrane Collaboration’s statistical software, Review Manager 2014. Although there were no signs of significant heterogeneity, due to subtle differences in diagnostics and treatments, we used a random-effects model. If individual time-to- event data were present, we extracted them to compute the Kaplan-Meyer curve of recurrence-free survival. For time-to-event data we were only able to compute RRs and ORs. For dichotomous outcomes, we calculated the RR for each study and pooled them. For continuous outcomes, we pooled the MDs between the treatment arms at the end of follow-up.

SUBGROUP ANALYSIS AND INVESTIGATION OF HETEROGENEITY

We did not conduct subgroup analysis.

SENSITIVITY ANALYSIS

We did not perform sensitivity analyses excluding studies at high risk of bias, since all studies were at high risk of bias.

MAIN OUTCOMES OF ’SUMMARY OF FINDINGS’ TABLE FOR ASSESSING THE CERTAINTY OF THE EVIDENCE

We presented the overall certainty of the evidence for each main outcome according to the GRADE approach, which takes into account issues not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias) but also to external validity, such as directness of results (Langendam 2013). We created Summary of findings for the main comparison based on the methods described the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017), and using GRADEpro GDT (GRADEpro GDT 2015). We used the GRADE checklist and GRADE Working Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 39

Group certainty of evidence definitions (Meader 2014). We downgraded the evidence from ’high’ certainty by one level for serious (or by two for very serious) concerns for each limitation. • High-certainty: we are very confident that the true effect lies close to that of the estimate of the effect. • Moderate-certainty: we are moderately confident in the effect estimate: the true 2 effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. • Low-certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. • Very low-certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

The main outcomes were recurrence-free survival, MSTS scores and rates of major complications.

RESULTS

DESCRIPTION OF STUDIES

RESULTS OF THE SEARCH

No studies were identified through CENTRAL. The MEDLINE and Embase searches identified 331 and 519 records respectively, and handsearching yielded two additional studies. After removal of duplicate studies and title and abstract screening, we included a total of 32 studies for potential eligibility, (see Figure 1 for flow-chart). We fully reviewed the full texts of all 32 selected papers for eligibility and we excluded 14 studies because their sample size was too small, or they had not documented data concerning recurrence- free survival for LGCS in the long bones (see Excluded studies). We included a total of 18 studies in this review. Of these, seven studies were suitable for meta-analysis; details of these studies can be found in the Characteristics of included studies section. In addition, we used participant data from seven case series in the narrative summary or to assess 40 | Advances of treatment in atypical cartilaginous tumours

recurrence-free survival and included four studies for qualitative analysis only, since we could not extract participant data, and are described in the Characteristics of included studies section.

FIGURE 1. Study flow diagram Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 41

INCLUDED STUDIES

DESIGN OF THE STUDIES

There were no RCTs or quasi-RCTs available. Aarons 2009, Bauer 1995, Chen 2017, Campanacci 2013, Donati 2010, Etchebehere 2005 and Gunay 2013 were retrospective studies comparing intralesional treatment versus wide resection. The remaining 11 2 studies were retrospective case series or cohort series available for qualitative analysis on recurrence-free survival (Di Giorgio 2011; Dierselhuis 2016; Funovics 2010; Hanna 2009; Kim 2015; Kim 2018; Leerapun 2007; Mermerkaya 2014; Mohler 2010; Van der Geest 2008; Verdegaal 2012). The case series included only participants that were treated by intralesional surgery and were not controlled by wide resection.

SAMPLE SIZES

In total, the comparative studies included 238 participants (sample sizes from 8 to 85), 146 managed by intralesional management and 92 by wide resection. The case series included in the narrative summary studied 249 participants (sample sizes from 21 to 108), managed by intralesional treatment. The four studies that were only included in the qualitative analysis included 270 participants (sample sizes from 55 to 85).

PARTICIPANTS

AGE, GENDER AND FOLLOW-UP

The mean age of the participants was 45.8 years (range 13 to 80), in participants included in the meta-analysis, and 51.5 (range 18 to 82), in the cases series. A slight female preponderance was present in the cohort included in the meta-analysis, with a male to female ratio of 1:1.3. Mean follow-up was 85.2 months (range 24 to 300), in the studies included in the meta-analysis and 56.8 months (range 26 to 134), in the case series.

DISEASE SEVERITY

Aarons 2009, Chen 2017, Dierselhuis 2016, Hanna 2009, Kim 2015, Kim 2018 and Mermerkaya 2014 included only Enneking stage IA tumours. Bauer 1995, Campanacci 2013, Etchebehere 2005 and Gunay 2013 included both Enneking stage IA and IB. 42 | Advances of treatment in atypical cartilaginous tumours

It is unclear whether Di Giorgio 2011, Donati 2010 and Mohler 2010 included only stage IA or both tumour stages.

EXCLUDED STUDIES

We excluded the following eight studies: Ahlmann 2007, Okada 2009, Ozaki 1996, 2 Puri 2009, Schreuder 1998 and Souna 2010 did not include a sufficient number of participants; and Errani 2017 and Lee 1999 studied a heterogeneous group of LGCS (either primary, secondary, in the axial skeleton or in extremities). These studies did not document the outcome of participants with primary LGCS in the long bones, and we could not, therefore, include them in the meta-analysis or narrative summary, since the majority of study participants did not meet our inclusion criteria. Full exclusion details can be found in Characteristics of excluded studies. Andreou 2011, Angelini 2012, de Camargo 2010, Ma 2009, Meftah 2013 and Streitbuerger 2009 contained valuable data on the outcome of treatment of LGCS, however we could not extract the exact data from the studies due to their heterogeneous nature. In all cases we attempted to contact the study authors for individual participant data, which could not be obtained. We have summarised these studies under Characteristics of studies awaiting classification.

RISK OF BIAS IN INCLUDED STUDIES

Overall, there was a high risk of bias in the included comparative studies (see Figure 2 and Figure 3). This bias was mainly caused by confounding bias, in selection of participants (selection bias) and in classification of interventions. In these studies, identification of confounding variables was absent and thus we did not perform analysis of confounding. Selection bias was apparent in these retrospective studies, as there was no control of the inclusion of participants. In addition, insight into the choice of intervention for a specific participant is very probably related to participant characteristics, such as aggressiveness, or staging of the tumours, or both. About half of the studies suffered from missing data (attrition bias). Measurement of outcomes and selection of reported results (reporting bias) are less likely to be problematic. There were also suspected other biases because groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 43

FIGURE 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study 44 | Advances of treatment in atypical cartilaginous tumours

FIGURE 3. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies

BIAS DUE TO CONFOUNDING

Risk of bias due to confounding was high in all studies

BIAS IN SELECTION OF PARTICIPANTS INTO THE STUDY

Risk of bias in selection of participants into the study was high in all studies, except for Etchebehere 2005, which we regarded as unclear risk.

BIAS IN CLASSIFICATION OF INTERVENTIONS

Risk of bias in classification of interventions was high in all studies, except for Funovics 2010, Van der Geest 2008, Verdegaal 2012, which were regarded as unclear.

BIAS DUE TO DEVIATIONS FROM INTENDED INTERVENTION

Risk of bias due to deviations from intended intervention was unclear in all studies.

BIAS DUE TO MISSING DATA

In Aarons 2009, Campanacci 2013 and Chen 2017 there was a low risk of bias due to missing data. There was a high risk of bias in Bauer 1995, Etchebehere 2005, and Gunay 2013, and an unclear risk in Donati 2010. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 45

BIAS IN MEASUREMENT OF OUTCOMES

Risk of bias in measurement of outcomes was low in all studies, except for Gunay 2013, which we regarded as unclear risk.

BIAS IN SELECTION OF THE REPORTED RESULT

Risk of bias in selection of the reported result was low in Aarons 2009, Campanacci 2013, 2 Chen 2017, Donati 2010 and Etchebehere 2005. High risk of bias was expected in Bauer 1995 and Gunay 2013.

OTHER BIAS

In all studies there was a risk of bias as groups were not controlled for experience of the surgeon, and pre-operative functioning level of the participants. Nevertheless, all studies took place in tertiary referral hospitals, where we would expect to find an experienced operating team.

FROM RISK OF BIAS TO CERTAINTY OF EVIDENCE

As all outcomes were based on solely observational studies, the entry point of the outcomes on a certainty-of-evidence level was low. Further adjustment of the level of certainty of the evidence is indicated under Effects of interventions section.

EFFECTS OF INTERVENTIONS

See: Summary of findings for the main comparison Intralesional treatment versus wide resection for central, low-grade (grade I) chondrosarcoma in the long bones

QUANTITATIVE SYNTHESIS: CONTROLLED STUDIES INCLUDED IN META- ANALYSIS

Data from the comparative studies are represented in the Summary of findings for the main comparison.

RECURRENCE-FREE SURVIVAL

There is very low-certainty evidence (observational studies with a serious risk of bias) from seven studies (n = 238) that the difference in recurrence-free survival after intralesional treatment versus wide resection for central LGCS in the long bones is not 46 | Advances of treatment in atypical cartilaginous tumours

statistically significant (RR 0.98; 95% CI 0.92 to 1.04; Analysis 1.1; Figure 4). There was one participant with upgrading of tumour to grade II, treated with second surgery with no evidence of disease at known follow-up (Campanacci 2013). As is shown in Figure 4, I2 = 0%, which implies that there was no evidence of substantial heterogeneity. 2

FIGURE 4. Forest plot of comparison 1. Comparative studies, outcome 1.1 recurrence- free survival. Event = recurrence-free survival

FIGURE 5. Forest plot of comparison 1. Comparative studies, outcome 1.2 function by MSTS score

FIGURE 6. Forest plot of comparison 1. Comparative studies, outcome 1.3 complications. Event = major complication (e.g. fracture, infection) Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 47

FUNCTIONAL OUTCOME

There is low-certainty evidence (observational studies with a serious risk of bias) from three studies (n = 72) that intralesional surgery is more effective in acquiring higher MSTS scores than wide resection (93% versus 78%, respectively; mean difference 12.7; 95% CI 2.8 to 22.6; P < 0.001; Analysis 1.2; Figure 5). We upgraded the certainty of evidence from very low to low due to the large effect. 2

MAJOR COMPLICATIONS

There is low-certainty evidence (observational studies with a serious risk of bias) from six studies (n = 203) that intralesional surgery is more effective in preventing major complications (5/125) as compared to wide resection (18/78 cases), with RR 0.23 (95% CI 0.10 to 0.55; Analysis 1.3; Figure 6). We upgraded the certainty of evidence from very low to low due to the large effect.

NARRATIVE SUMMARY OF CASE SERIES AND STUDIES NOT INCLUDED IN META-ANALYSIS

Several studies were case series describing one type of treatment, or we were unable to extract data from them, so we have included these studies in the narrative summary only because we could not include them in the meta-analysis.

RECURRENCE-FREE SURVIVAL (CASE SERIES, EXACT PARTICIPANT DATA AVAILABLE)

Recurrence-free survival in the case series in which curettage with adjuvant was applied, was 96% in Di Giorgio 2011 (23 participants), 95% in Dierselhuis 2016 (108 participants), 95% in Hanna 2009 (39 participants), 100% in Kim 2015 (36 participants), 100% in Kim 2018 (24 participants), 100% in Mermerkaya 2014 (21 participants) and 91% in Mohler 2010 (22 participants), all in line with the meta-analysis. In Di Giorgio 2011, there was one participant with upgrading of tumour to grade II, treated with second surgery with no evidence of disease at known follow-up. We were unable to synthesise data from these case series into the meta-analysis due to lack of control group. 48 | Advances of treatment in atypical cartilaginous tumours

RECURRENCE-FREE SURVIVAL (COMPARATIVE STUDIES OR CASE SERIES, EXACT PARTICIPANT DATA NOT AVAILABLE)

Funovics 2010 treated 70 participants with LGCS in the trunk and extremities. Local recurrence occurred in eight participants (11.4%), all in the intralesional (17.9%), or marginal (14.3%), and none in the wide resection group. Recurrence-free survival was 2 significantly better for participants with extremity lesions compared to truncal lesions with 94.0% and 91.5% at 24 and 48 months, in line with the meta-analysis. Leerapun 2007 analysed 70 participants with LGCS in the long bones that were treated either by marginal or wide resection, or by intralesional treatment. Overall five-year recurrence-free survival was 89%, which was not in line with the meta-analysis. There was no difference in survival between intralesional excision (79%) and wide resection (91%) respectively, in line with the meta-analysis. Overall mortality was 2.9%, with one participant after development of a dedifferentiated out of local recurrence and one after local recurrence with upgrading to grade II tumour after resection, which is not in line with the meta- analysis. Verdegaal 2012 analysed 85 participants with LGCS in the long bones, treated by intralesional surgery with local adjuvant. After mean follow-up of 6.8 years there was a 94% recurrence-free survival, in line with the meta-analysis. No metastases, upgrading of tumour or death due to disease was observed, also in line with the meta-analysis. Van der Geest 2008 treated 130 tumours in 123 participants with curettage and cryotherapy. They included active enchondromas (n = 18), aggressive enchondromas (n = 57) and LGCS (n = 55). During follow-up two participants (2%) suffered from a local recurrence, both were participants with an enchondroma. None of the participants with LGCS had a local recurrence, or other oncologic events, in line with the meta-analysis.

FUNCTIONAL OUTCOME (CASE SERIES, EXACT PARTICIPANT DATA AVAILABLE)

The following studies documented MSTS scores: Di Giorgio 2011 (mean 90%); Hanna 2009 (mean 94%); Kim 2018 (mean 92%); Mermerkaya 2014 (mean 95%); and Mohler 2010 (mean 91%). These results were all in line with the meta-analysis. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 49

MAJOR COMPLICATIONS (CASE SERIES, EXACT PARTICIPANT DATA AVAILABLE)

In Di Giorgio 2011, major complications occurred in 13% of participants; in Dierselhuis 2016, 15%; and in Kim 2015, 17%; these results were not in line with the meta-analysis. In Kim 2018, no complications occurred, in Mermerkaya 2014 and Mohler 2010, 5% of participants suffered from complications, in line with the meta-analysis. 2

MAJOR COMPLICATIONS (COMPARATIVE STUDIES OR CASE SERIES, EXACT PARTICIPANT DATA NOT AVAILABLE)

Complications occurred in 13% of participants in Funovics 2010, with 5% in the intralesional group versus 29% in the wide resection group (P value = 0.002), in line with the meta-analysis. In Verdegaal 2012, one participant (1.2%) suffered from a wound infection and two participants (2.4%) from a femoral fracture, in line with the meta-analysis. Verdegaal 2012 re-operated on 11 participants for suspected recurrences, which were confirmed in five cases. Eighteen post-operative fractures occurred (14%) in the series from Van der Geest 2008, which was not in line with meta- analysis.

INDIVIDUAL PARTICIPANT DATA

Kaplan-Meier analysis of the data from 115 individual participants (wide resection n = 51, intralesional surgery n = 64), across four studies (Aarons 2009, Bauer 1995, Donati 2010, Etchebehere 2005), demonstrates 96% recurrence-free survival after a maximum follow- up of 300 months after resection versus 94% recurrence-free survival after a maximum follow-up of 251 months after intralesional treatment (P value = 0.58; Figure 7). Local recurrence or metastases were not reported after 41 months in either treatment group. 50 | Advances of treatment in atypical cartilaginous tumours

FIGURE 7. Kaplan Meyer survival curve of recurrence-free survival of participants with LGCS in the long bones. P = 0.58

DISCUSSION

The objective of this systematic review was to compare the outcome of intralesional surgery versus wide resection for central LGCS of the long bones. The primary endpoint was recurrence- free survival with a minimal follow-up of two years after index surgery. Secondary endpoints were incidence of tumour upgrading, functional outcome (as measured by the MSTS score) and the overall rate of complications.

SUMMARY OF MAIN RESULTS

The review found little or no difference in recurrence-free survival after intralesional surgery as compared to wide resection in LGCS of the long bones (Analysis 1.1). Intralesional surgery probably led to better functional outcome (Analysis 1.2), and Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 51

demonstrated lower major complication rates (Analysis 1.3). Taking into account all limitations from the included studies, we graded the evidence for these outcomes as very low and low certainty. With respect to the qualitative analysis, all but one study (Leerapun 2007), were in line with the meta-analysis concerning recurrence-free survival. In four case series (Di Giorgio 2011; Dierselhuis 2016; Kim 2015; Van der Geest 2008), there were a relatively high number of postoperative fractures, either due to non-aggressive 2 plating or use of cryosurgery.

OVERALL COMPLETENESS AND APPLICABILITY OF EVIDENCE

There is very low-certainty evidence on the treatment of LGCS in the long bones based on the retrospective comparative studies and case series. However, the participants included in the studies and the applied techniques represent the known patient population and are therefore relevant to current practice. All the studies documented the event of a local recurrence or other signs of disease. All local recurrences occurred within 41 months after index surgery; 63% of the participants had a minimal follow-up of five years. Aarons 2009, Chen 2017, Di Giorgio 2011, Donati 2010, Hanna 2009, Mermerkaya 2014 and Mohler 2010 measured functional outcome in 175/487 (36%) of the participants. The studies did not describe the time-point at which they assessed functional outcome, however we hypothesised that the studies had documented it at the final stage of follow-up. The occurrence of major complications was documented in most participants (413/487; 85%), except in Bauer 1995 and Hanna 2009. However, several studies did not document loss to follow-up (Donati 2010; Etchebehere 2005; Gunay 2013; Hanna 2009; Kim 2015; Mermerkaya 2014; Mohler 2010). This might have biased outcomes, since participants that died due to disease or were referred to other centres may not have been included.

QUALITY OF THE EVIDENCE

Certainty (quality) of the evidence was very low according to GRADE (Summary of findings for the main comparison), and ’Risk of bias’ assessment, since only retrospective comparative studies and case series were available for inclusion in this review. Obser- vational studies initially have a low level of evidence certainty, and consequently, we downgraded the included studies considering the high risk of biases. For the secondary outcomes (functional outcome and complications), there was a large effect, which allowed 52 | Advances of treatment in atypical cartilaginous tumours

us to upgrade the level of evidence by one level. To date, there are no prospective studies available in literature nor any RCTs. However, we were able to extract individual data from 115 participants, which enabled as to compute a Kaplan Meyer curve of recurrence- free survival. In this way, progression of disease for LGCS could be reconstructed in detail. It is not to be expected that the level of evidence will increase in studies to come, 2 unless prospective cohort studies evaluating a treatment strategy are designed.

POTENTIAL BIASES IN THE REVIEW PROCESS

The oncological outcomes presented in many of the comparative studies should be interpreted with caution, as these studies are highly susceptible to selection bias, since people treated by intralesional curettage tended to have less aggressive LGCS (Aarons 2009; Bauer 1995; Donati 2010; Gunay 2013). Moreover, case series only reported the outcome of intralesional surgery, while people with more aggressive tumours radiologically were managed with wide resection, and thus excluded. Furthermore, case series concerning intralesional treatment might be subject to publication bias favouring the series in which participants do well. An important distinction should also be highlighted with respect to Enneking stage IA and IB disease. Cortical breakthrough may be a sign of increased local aggressiveness; the implication in terms of treatment modality is unclear and raises the question as to whether these lesions should be treated along the same lines or not. Only Bauer 1995 and Gunay 2013 reported treatment of Enneking stage IB explicitly. Bauer 1995 treated four cases with stage IB, three by intralesional treatment and one by wide resection. None of these tumours developed a local recurrence. Gunay 2013 treated all 11 cases with stage IB LGCS by wide resection. Of these, two (18%) developed a local recurrence. This rate is higher than that reported by other studies in this review, but is nevertheless comparable to their overall rate of local recurrence (6/30 participants (20%)).

AGREEMENTS AND DISAGREEMENTS WITH OTHER STUDIES OR REVIEWS

We are uncertain whether intralesional surgery improves recurrence-free survival, functional outcome and complication rates compared to wide resection, as we assessed the certainty of the evidence as being very low. Nevertheless, this analysis seems in line with the previously published meta-analysis of Hickey 2011. It should be noted that Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 53

one study that we included in the narrative summary observed death due to disease (Leerapun 2007), one case after intralesional treatment and one case after wide resection. This is in conflict with the results from all the other included studies. We are not able to solve the controversy whether local recurrence precedes upgrading of tumour, or that local recurrence is the consequence of a underdiagnosed higher-grade tumour. Although speculative, it is not unthinkable that the absence of (high-certainty) magnetic resonance 2 imaging in the 1970’s and 1980’s could have led to a higher rate of underdiagnosed tumours. This is supported by the fact that death due to disease is no longer seen in studies that are published after 2010, although this could also be subject to publication bias.

AUTHORS’ CONCLUSIONS

IMPLICATIONS FOR PRACTICE

There was very limited and very low-certainty evidence on how to treat central low-grade chondrosarcoma (LGCS) of the long bones. We only found retrospective comparative studies or case series, which are greatly biased by patient selection. Based on these data, there is evidence of very low certainty that recurrence-free survival is equal between intralesional treatment and wide resection. There is evidence of low certainty that intralesional surgery increases functional outcome as reported by Musculoskeletal Tumor Society (MSTS) scores. The included studies described many forms of adjuvants, such as phenolisation, the use of nitrogen, anhydrous alcohol and the application of polymethyl methacrylate (PMMA). Details regarding the use of these adjuvants were lacking in most studies and so we could assess them. Among the papers included in the meta-analysis and Kaplan Meyer calculation, there were no local recurrences after 41 months. Only three cases have been reported in modern literature where local recurrence occurred beyond five years for this tumour subtype. Verdegaal 2012 and Meftah 2013 reported cases of local recurrence at 64 months, 91 months and 67 months respectively. 54 | Advances of treatment in atypical cartilaginous tumours

IMPLICATIONS FOR RESEARCH

Considering the low incidence of this disease and the oncologic sequelae, such as local recurrence, future research is best performed in a multinational setting. The current level of evidence supporting intralesional treatment of LGCS is of very low certainty. Nevertheless, in our opinion a prospective randomised controlled trial comparing 2 intralesional treatment versus wide resection may be unwarranted for both practical and ethical reasons. As this review has demonstrated, local recurrence after intralesional treatment occurs in approximately 5% of people only, with no demonstrable negative effect on patient survival. Future research should, perhaps, instead focus on less invasive treatment strategies for these tumours by identifying predictors that help to stratify people for surgical intervention or close observation. During the development of this review, the World Health Organization (Fletcher 2013), renamed LGCS as an atypical cartilaginous tumour (ACT). By definition, they are now tumours of borderline or low malignant potential. Although outside the scope of this review, considering the very low number of reported local recurrences and the fact the metastasis is so rare, there may even be a case for observation of smaller, less active lesions, especially those without cortical scalloping.

ACKNOWLEDGEMENTS

We thank Jo Platt, Information Manager, for designing the search strategy and for her assistance for the extended search and Clare Jess, Managing Editor, for her contribution to the editorial process. We would also like to thank Roy Stewart, Gerjon Hannink and Wilco Jacobs for their assistance with the statistical strategies and analysis. This project was supported by the National Institute for Health Research, via Cochrane Infrastructure to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 55

REFERENCES

REFERENCES TO STUDIES INCLUDED IN THIS REVIEW

Aarons 2009 {published and unpublished data} 2 Aarons C, Potter BK, Adams SC, Pitcher DJ, Templet TH. Extended intralesional treatment versus resection of low- grade chondrosarcomas. Clinical Orthopaedics and Related Research 2009;467:2105-11.

Bauer 1995 {published data only} Bauer HC, Brosjo O, Kreicbergs A, Lindholm J. Low risk of recurrence of enchondroma and low-grade chondrosarcoma in extremities. 80 patients followed for 2 - 25 years. Acta Orthopaedica Scandinavica 1995;66(3):283–8.

Campanacci 2013 {published data only (unpublished sought but not used)} Campanacci DA, Scoccianti G, Franchi A. Surgical treatment of central grade 1 chondrosarcoma of the appendicular skeleton. Journal of Orthopaedics and Traumatology 2013;14:101–7.

Chen 2017 {published data only (unpublished sought but not used)} Chen YC, Wu PK, Chen CF, Chen WM. Intralesional curettage of central low-grade chondrosarcoma: a midterm follow-up study. Journal of the Chinese Medical Association : JCMA 2017;80(3):178–82.

Dierselhuis 2016 {published data only (unpublished sought but not used)} Dierselhuis EF, Gerbers JG, Ploegmakers JJW, Stevens M, Suurmeijer AJH, Jutte PC. Local treatment with adjuvant therapy for central atypical cartilaginous tumors in the long bones. Journal of Bone and Joint Surgery 2016;98:303–13.

Di Giorgio 2011 {published data only (unpublished sought but not used)} Di Giorgio L, Touloupakis G, Vitullo F, Sodano L, Mastantuono M, Villani C. Intralesional curettage, with phenol and cement as adjuvants, for low-grade intramedullary chondrosarcoma of the long bones. Acta Orthopaedica Belgica 2011;77:666–9. 56 | Advances of treatment in atypical cartilaginous tumours

Donati 2010 {published data only (unpublished sought but not used)} Donati D, Colangeli S, Colangeli M, Di Bella C, Bertoni F. Surgical treatment of grade I central chondrosarcoma. Clinical Orthopaedics and Related Research 2010;468(2): 581–9.

Etchebehere 2005 {published data only (unpublished sought but not used)} 2 Etchebehere M, de Camargo OP, Croci AT, Oliveira CR, Baptista AM. Relationship between surgical procedure and outcome for patients with grade I chondrosarcomas. Clinics (Sao Paulo, Brazil) 2005;60:121–6.

Funovics 2010 {published data only (unpublished sought but not used)} Funovics PT, Panotopoulos J, Sabeti-Aschraf M, Abdolvahab F, Funovics JM, Lang S, et al. Low-grade chondrosarcoma of bone: experiences from the Vienna Bone and Soft Tissue Tumour Registry. International Orthopaedics 2011;35(7): 1049–56.

Gunay 2013 {published data only (unpublished sought but not used)} Gunay C, Atalar H, Hapa O, Basarir K, Yildiz, Saglik Y. Surgical management of Grade I chondrosarcoma of the long bones. Acta Orthopaedica Belgica 2013;79:331–7.

Hanna 2009 {published data only (unpublished sought but not used)} Hanna SA, Whittingham-Jones P, Sewell MD, Pollock RC, Skinner JA, Saifuddin A, et al. Outcome of intralesional curettage for low-grade chondrosarcoma of long bones. Journal of Cancer Surgery 2009;35:1343–47.

Kim 2015 {published data only (unpublished sought but not used)} Kim W, Han I, Kim EJ, Kang S, Kim H. Outcomes of curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma of long bone. Surgical Oncology 2015;24: 89–94.

Kim 2018 {published data only (unpublished sought but not used)} Kim W, Lee JS, Chung HW. Outcomes after extensive manual curettage and limited burring for atypical cartilaginous tumour of long bone. Journal of Bone and Joint Surgery. British Volume 2018;100-B(2):256–61. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 57

Leerapun 2007 {published data only (unpublished sought but not used)} Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical management of conventional grade I chondrosarcoma of long bones. Clinical Orthopaedics and Related Research 2007;463:166–72.

Mermerkaya 2014 {published data only (unpublished sought but not used)} Mermerkaya MU, Bekmez S, Karaaslan F, Danisman M, Kosemehmetoglu K, Gedikoglu G, et al. 2 Intralesional curettage and cementation for low-grade chondrosarcoma of long bones: retrospective study and literature review. World Journal of Surgical Oncology 2014;12:336–41.

Mohler 2010 {published data only (unpublished sought but not used)} Mohler DG, Chiu R, McCall DA, Avedian RS. Curettage and cryosurgery for low-grade cartilage tumors is associated with low recurrence and high function. Clinical Orthopaedics and Related Research 2010;10(468):2765–73.

Van der Geest 2008 {published data only (unpublished sought but not used)} Van der Geest IC, De Valk MH, De Rooy JW, Pruszczynski M, Veth RP, Schreuder HW. Oncological and functional results of cryosurgical therapy of enchondromas and chondrosarcomas grade 1. Journal of Surgical Oncology 2008;98(6):421–6.

Verdegaal 2012 {published data only (unpublished sought but not used)} Verdegaal SH, Brouwers HF, Van Zwet EW, Hogendoorn PC, Taminiau AH. Low-grade chondrosarcoma of long bones treated with intralesional curettage followed by application of phenol, ethanol, and bone-grafting. Journal of Bone and Joint Surgery. American Volume 2012;94(13): 1201–7.

REFERENCES TO STUDIES EXCLUDED FROM THIS REVIEW

Ahlmann 2007 {published data only (unpublished sought but not used)} Ahlmann ER, Menendez LR, Fedenko AN, Learch T. Influence of cryosurgery on treatment outcome of low- grade chondrosarcoma. Clinical Orthopaedics and Related Research 2006;451:201– 7. 58 | Advances of treatment in atypical cartilaginous tumours

Errani 2017 {published data only (unpublished sought but not used)} Errani C, Tsukamoto S, Ciani G, Akahane M, Cevolani L, Tanzi P, et al. Risk factors for local recurrence from atypical cartilaginous tumour and enchondroma of the long bones. European Journal of Orthopaedic Surgery & Traumatology : Orthopedie Traumatologie 2017;27(6):805–11.

2 Lee 1999 {published data only (unpublished sought but not used)} Lee FY, Mankin HJ, Fondren G, Gebhardt MC, Springfield DS, Rosenberg AE, et al. Chondrosarcoma of bone: an assessment of outcome. Journal of Bone and Joint Surgery. American Volume 1999;81(3):326–38.

Okada 2009 {published data only} Okada K, Nagasawa H, Chida S, Nishida J. Curettage with pasteurization in situ for grade 1 chondrosarcoma - long- term follow up study of less invasive surgical procedure. Medical Science Monitor 2009;15(3):CS44–8.

Ozaki 1996 {published data only} Ozaki T, Lindner N, Hillmann A, Rödl R, Blasius S, Winkelmann W. Influence of intralesional surgery on treatment outcome of chondrosarcoma. Cancer 1996;77(7): 1292–7.

Puri 2009 {published data only} Puri A, Shah M, Agarwal MG, Jambhekar NA, Basappa P. Chondrosarcoma of bone: does the size of the tumor, the presence of a pathologic fracture, or prior intervention have an impact on local control and survival?. Journal of Cancer Research and Therapeutics 2009;5(1):14–9.

Schreuder 1998 {published data only} Schreuder HW, Pruszczynski M, Veth RP, Lemmens JA. Treatment of benign and low-grade malignant intramedullary chondroid tumours with curettage and cryosurgery. European Journal of Surgical Oncology 1998;24 (2):120–6.

Souna 2010 {published data only} Souna BS, Belot N, Duval H, Langlais F, Thomazeau H. No recurrences in selected patients after curettage with cryotherapy for grade I chondrosarcomas. Clinical Orthopaedics and Related Research 2010;468(7):1956–62. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 59

REFERENCES TO STUDIES AWAITING ASSESSMENT

Andreou 2011 {published data only (unpublished sought but not used)} Andreou D, Ruppin S, Fehlberg S, Pink D, Werner M, Tunn PU. Survival and prognostic factors in chondrosarcoma results in 115 patients with long-term follow-up. Acta Orthopaedica 2011;82(6):749–55. 2

Angelini 2012 {published data only (unpublished sought but not used)} Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P. Clinical outcome of central conventional chondrosarcoma. Journal of Surgical Oncology 2012;106(8): 929–37. de Camargo 2010 {published data only (unpublished sought but not used)} de Camargo OP, Baptista AM, Atanásio MJ, Waisberg DR. Chondrosarcoma of bone: lessons from 46 operated cases in a single institution. Clinical Orthopaedics and Related Research 2010;468(11):2969–75.

Ma 2009 {published data only} Ma XJ, Dong Y, Zhang CL, Zeng BF. Recurrence analysis in 66 cases with grade I and grade II chondrosarcomas in the extremities. Orthopaedic Surgery 2009;1(2):132–6.

Meftah 2013 {published data only (unpublished sought but not used)} Meftah M, Schult P, Henshaw RM. Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma. Journal of Bone and Joint Surgery. American Volume 2013;95(15):1358–64. Streitbuerger 2009 {published data only (unpublished sought but not used)}

Streitbürger A, Ahrens H, Balke M, Buerger H, Winkelmann W, Gosheger G, et al. Grade I chondrosarcoma of bone: the Münster experience. Journal of Cancer Research and Clinical Oncology 2009;135(4):543–50. 60 | Advances of treatment in atypical cartilaginous tumours

ADDITIONAL REFERENCES

Bjornsson 1998 Bjornsson J, McLeod RA, Unni KK, Ilstrup DM, Pritchard DJ. Primary chondrosarcoma of long 2 bones and limb girdles. Cancer 1998;83(10):2105–19. Deeks 2001 Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. Systematic Reviews in Health Care: Meta- Analysis in Context. 2nd Edition. London: BMJ Publication Group, 2001.

Eefting 2009 Eefting D, Schrage YM, Geirnaerdt MJ, Le Cessie S, Taminiau AH, Bovée JV, et al. Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. American Journal of Surgical Pathology 2009;33(1):50–7.

Enneking 1986 Enneking WF. A system of staging musculoskeletal neoplasms. Clinical Orthopaedics and Related Research 1986; 204:9–24.

Enneking 1993 Enneking WF, Dunham W, Gebhardt MC, Malawar M, Pritchard DJ. A system for the functional evaluation of reconstructive procedures after surgical treatment of tumors of the musculoskeletal system. Clinical Orthopaedics and Related Research 1993;286:241–6.

Eriksson 1980 Eriksson AI, Schiller A, Mankin HJ. The management of chondrosarcoma of bone. Clinical Orthopaedics and Related Research 1980;153:44–66.

ESMO 2012 ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(Suppl 7):vii100– 9. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 61

Evans 1977 Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer 1977;40(2): 818–31.

Fiorenza 2002 Fiorenza F, Abudu A, Grimer RJ, Carter SR, Tillman RM, Ayoub K, et al. Risk factors for survival 2 and local control in chondrosarcoma of bone. Journal of Bone and Joint Surgery. British Volume 2002;84(1):93–9.

Fletcher 2013 Fletcher CD, Bridge JA, Hogendoorn P, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. IARC WHO Classification of Tumours. Fourth. Vol. 5, IARC, 2013.

Geirnaerdt 1997 Geirnaerdt MJ, Hermans J, Bloem JL, Kroon HM, Pope TL, Taminiau AH, et al. Usefulness of radiography in differentiating enchondroma from central grade 1 chondrosarcoma. American Journal of Roentgenology 1997; 169(4):1097–104.

Gelderblom 2008 Gelderblom H, Hogendoorn PC, Dijkstra SD, Van Rijswijk CS, Krol AD, Taminiau AH, et al. The clinical approach towards chondrosarcoma. Oncologist 2008;13(3):320–9.

Giuffrida 2009 Giuffrida AY, Burgueno JE, Koniaris LG, Gutierrez JC, Duncan R, Scully SP. Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database. Journal of Bone and Joint Surgery 2009;91(5): 1063–72.

GRADEpro GDT 2015 [Computer program] McMaster University (developed by Evidence Prime). GRADEpro GDT. Version accessed prior to 30 April 2018. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015. 62 | Advances of treatment in atypical cartilaginous tumours

Healey 1986 Healey JH, Lane JM. Chondrosarcoma. Clinical Orthopaedics and Related Research 1986;204:119–29.

Hickey 2011 Hickey M, Farrokhyar F, Deheshi B, Turcotte R, Ghert M. A systematic review and meta-analysis 2 of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Annals of Surgical Oncology 2011;18(6): 1705–9.

Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557–60.

Jundt 2008 Jundt G, Baumhoer D. Cartilage tumors of the skeleton. Der Pathologe 2008;29(Suppl 2):223–31.

Langendam 2013 Langendam MW, Akl EA, Dahm P, Glasziou P, Guyatt G, Schunemann HJ. Assessing and presenting summaries of evidence in Cochrane Reviews. Systematic Reviews 2013;23 (2):81.

Meader 2014 Meader N, King K, Llewellyn A, Norman G, Brown J, Rodgers M, et al. A checklist designed to aid consistency and reproducibility of GRADE assessments: development and pilot validation. Systematic Reviews 2014;3:82.

Mirra 1985 Mirra JM, Gold R, Downs J, Eckardt JJ. A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases. Clinical Orthopaedics and Related Research 1985; 201:214–37.

Moher 2009 Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA Statement. PLoS Medicine 6;7:e1000097. DOI: 10.1371/ journal.pmed1000097 Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 63

Murphey 2003 Murphey MD, Walker EA, Wilson AJ, Kransdorf MJ, Temple HT, Gannon FH. From the archives of the AFIP: imaging of primary chondrosarcoma: radiologic-pathologic correlation. Radiographics 2003;23(5):1245–78.

Parmar 1998 2 Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in Medicine 1998;17(24): 2815–34.

Randall 2005 Randall RL, Gowski W. Grade 1 chondrosarcoma of bone: a diagnostic and treatment dilemma. Journal of the National Comprehensive Cancer Network 2005;3(2):149–56.

Review Manager 2014 [Computer program] Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Rosenthal 1984 Rosenthal DI, Schiller AL, Mankin HJ. Chondrosarcoma: correlation of radiological and histological grade. Radiology 1984;150(1):21–6.

Schünemann 2017 Schünemann HJ, Oxman AD, Higgins JP, Vist GE, Glasziou P, Akl E, et al. on behalf of the Cochrane GRADEing Methods Group and the Cochrane Statistical Methods Group. Chapter 11: Completing ‘Summary of findings’ tables and grading the confidence in or quality of the evidence. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors), Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017). Cochrane, 2017. Available from www.training.cochrane.org/handbook.

Sterne 2016 Sterne JA, Hernán MA, Reeves BC, Savovi J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non- randomised studies of interventions. BMJ 2016;355:i4919. 64 | Advances of treatment in atypical cartilaginous tumours

Veth 2005 Veth R, Schreuder B, Van Beem H, Pruszczynski M. Cryosurgery in aggressive, benign, and low- grade malignant bone tumours. Lancet Oncology 2005;6(1):25–34. * Indicates the major publication for the study 2 Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 65

CHARACTERISTICS OF STUDIES

CHARACTERISTICS OF INCLUDED STUDIES (ORDERED BY STUDY ID) 2 Aarons 2009

Methods Study design: retrospective cohort study Country: USA Setting: single-centre; hospital; 1989-2005 Participants Total participants: n = 33 (resection n = 16; intralesional n = 17) Loss to follow-up: 3 participants died to unrelated cause Age mean (range): resection 48 (21-80); intralesional 51 (14-76) Sex M:F: 12:21 Inclusion criteria: grade I CS of the long bones of the appendicular skeleton, treated operatively Exclusion criteria: local recurrent disease or metastasis at presentation; extracompart- mental (stage IB) disease Follow-up months (range): 24-203 Interventions Resection: resection with variable reconstructions: intercalary allograft, osteoarticular allograft, endoprosthesis, allograft-endoprosthesis composites Intralesional: 3 cycles of extended curetting; variable adjuvants (phenol, liquid nitrogen, PMMA, hydrogen peroxide, none) Selected prophylactic internal fixation Outcomes Primary outcome: local recurrence Secondary outcome: MSTS scores; complications Notes Individual participant data. Extra data (1 participant) were obtained from the study authors

Risk of bias

Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants

2 Bauer 1995 Methods Study design: retrospective cohort study Country: Sweden Setting: single-centre; hospital; 1967-1991 Participants Total participants: original article n = 40. After exclusion n = 35 (resection n = 13; intralesional n = 22) Loss to follow-up: 2 participants moved abroad; 4 participants died due to unrelated causes Age range: 14-70 Sex M:F: 18:17 Inclusion criteria: histologically proven grade I CS, tumours in the extremities Exclusion criteria: tumours in the hand Follow-up months (range): 24-300 Interventions Resection: resection with or without reconstructions: intercalary allograft, osteoarticular allograft, endoprosthesis Intralesional: intralesional curettage, filled either with bone chips or PMMA Outcomes Local recurrence and metastases

Notes Individual participant data. Five participants were excluded from this analysis since they did not meet the inclusion criteria for this review: 3 participants were treated conservatively, one had a tumour in the foot and 1 in the patella Risk of bias

Bias Authors’ Support for judgement judgement Bias due to confounding High risk Study authors did not use an appropriate analysis method that adjusted for all the important confounding domains and for time-varying confounding Bias in selection of High risk This is a retrospective study comparing 2 surgical techniques, with both Ennek- participants into the study ing grade IA and IB tumours. Intralesional treatment of grade IB tumours could lead to a higher local recurrence rate, although this is not reported. Participants are included over multiple decades (1960s to present), which does raise some concern over the ability to achieve a correct histopathology diagnosis (i.e. distinguishing these lesions from enchondroma and higher-grade CS) given imaging technology limitations Bias in classification of High risk See above interventions Bias due to deviations Unclear risk Post-operative rehabilitation was not documented. from intended interventions Bias due to missing data High risk Although the given individual participant data are complete, local recurrence might be underreported considering the available imaging techniques Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 67

Bias in selection of the High risk Outcome parameters were not well pre-described. reported result Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants

Campanacci 2013 2 Methods Study design: retrospective cohort study Country: Italy Setting: single-centre; hospital; 1994-2010 Participants Total participants: n = 85 (resection n = 21; intralesional n = 64) Loss to follow-up: none Age mean (range): 50 (20-76) Sex M:F: 24:61 Inclusion criteria: participants treated for central grade 1 CS of long bones Exclusion criteria: insufficient follow-up (< 24 months) Follow-up months (range): 24-206 Interventions Resection: resection with variable reconstructions: intercalary allograft, osteoarticular allograft, endoprosthesis, allograft-endoprosthesis composites Intralesional: curettage with phenol/ethanol as local adjuvant in 69% of cases. Filling of the cavity was done with allogenic bone chips in 60 cases, PMMA in 3 cases and bone graft substitute in one case Outcomes Primary outcome: local recurrence, metastases and/or upgrading of tumour Secondary outcome: complications Notes Aggregated data. We tried to contact the study author to obtain individual participant data, but we were unsuccessful Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants 68 | Advances of treatment in atypical cartilaginous tumours

Chen 2017

Methods Study design: retrospective cohort study Country: Taiwan Setting: single-centre; hospital; 1998-2013 Participants Total participants: original article n = 11. After exclusion n = 8 (resection n = 3; intralesional n = 5) Loss to follow-up: not clearly mentioned; 1 participant died due to unrelated cause 2 Age range: 20-71 Sex M:F: unknown Inclusion criteria: stage IA CS Exclusion criteria: locally recurrent or metastatic disease at present; participants diagnosed with so-called borderline, grade I-II CS from preoperative biopsy; secondary CS; extraosseous lesions; stage IB CS Follow-up months (range): 24-300 Interventions Resection: wide excision, reconstruction with arthroplasty or extracorporeal irradiated bone Intralesional: curettage, adjuvant phenolisation or cryotherapy. Allograft Outcomes Local recurrence, progression of disease, complications, MSTS scores

Notes Individual participant data. 3 participants with acetabular lesions were excluded for analyses

Risk of bias

Bias Authors’ Support for judgement judgement Bias due to confounding High risk Study authors did not use an appropriate analysis method that adjusted for all the important confounding domains and for time-varying confounding Bias in selection of High risk Tumours were all stage IA tumours, and tumour size was not significantly participants into the different between groups. However, the latter could be a result of the small study sample size. Mean tumour size was 6.9 ± 5.1 cm and 12.5 ± 3. 1 cm in the intralesional group and resection group respectively, which suggests that the larger tumours were treated more aggressively. Moreover, participants in the resection group were significantly older (34. 0 ± 13.3 years versus 61.0 ± 7.7 years P < 0.001), which might overestimate the risk of complications and underestimate functional outcome Bias in classification of High risk See above interventions Bias due to deviations from Unclear risk Post-operative rehabilitation was not documented intended interventions Bias due to missing data Low risk There were no missing data concerning the pre-described outcomes

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 69

Di Giorgio 2011

Methods Study design: case series Country: Italy Setting: single-centre; hospital; 1997-2008 Participants Total participants: n = 23 Loss to follow-up: not mentioned Age mean (range): 45 (29-71) Sex M:F: 11:12 2 Inclusion criteria: intramedullary grade I CS of a long bone, with diagnosis based on clinical, radiological and histological findings Exclusion criteria: not mentioned Follow-up months (range): 30-132 Interventions Intralesional: curettage, adjuvant phenol/ethanol and filling with either PMMA or bone chips

Outcomes Primary outcome: local recurrence Secondary outcome: MSTS scores; complications Notes

Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias Unclear risk Not applicable 70 | Advances of treatment in atypical cartilaginous tumours

Dierselhuis 2016

Methods Study design: case series Country: the Netherlands Setting: single-centre; hospital; 2006-2012 Participants Total participants: n = 112 Loss to follow-up: 4 Age mean (range): 54 (25-82) 2 Sex M:F: 1:1.8 Inclusion criteria: intramedullary LGCS of a long bone, with diagnosis based on clinical, radiological and histological findings Exclusion criteria: previous treatment in other hospital Follow-up months (range): 24.3-97.5 Interventions Intralesional: curettage, adjuvant phenol/ethanol and filling with either PMMA, bone chips or synthetic bone (Vitoss® or PRO-DENSE®) Outcomes Primary outcome: local recurrence or presence of residual tumour after surgery Secondary outcome: death from disease, metastasis, tumour upgrading or dedifferentiation, and type and rate of complications Notes

Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias Unclear risk Not applicable Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 71

Donati 2010

Methods Study design: retrospective cohort study Country: Italy Setting: single-centre; hospital; 1977-1998 Participants Total participants: n = 31 (resection n = 16; intralesional n = 15) Loss to follow-up: not mentioned Age mean (range): 35 (13-67) Sex M:F: 13:18 2 Inclusion criteria: grade I CS in the long bones Exclusion criteria: presence of Ollier’s disease, inadequate radiographic documentation, < 60 months’ follow-up, tumour in short bones or consultation only Follow-up months (range): 66-296 Interventions Resection: resection with variable reconstructions: intercalary allograft, osteoarticular allograft, or endoprosthesis Intralesional: curettage, some with local adjuvant: phenol/ethanol or liquid nitrogen. Filling with PMMA, allograft or autograft. 3 participants had hardware stabilisation Outcomes Primary outcome: local recurrence Secondary outcome: MSTS scores; complications Notes Individual participant data

Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants 72 | Advances of treatment in atypical cartilaginous tumours

Etchebehere 2005

Methods Study design: retrospective cohort study Country: Brazil Setting: single-centre; hospital; date unknown Participants Total participants: original article n = 23. After exclusion n = 16 (resection n = 5; intralesional n = 11) Loss to follow-up: unknown causes 2 Age mean (range): unknown Sex M:F: unknown Inclusion criteria: grade I CS, confirmed by histology. Enneking stage 1A and 1B were included Exclusion criteria: < 24 months follow-up Follow-up months (range): 24-192 Interventions Resection: wide resection with or without endoprosthesis Intralesional: curettage with or without adjuvant cauterisation and/or PMMA Outcomes Complications, evidence of disease

Notes Individual participant data. We excluded 7 participants from this analysis since they did not meet the inclusion criteria for this review: 2 tumours were localised in a phalanx, one in a metatarsal, one in the scapula, one in the ischium and 2 were peripheral CSs Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Although the given results have not been prespecified in all cases, the most reported result important parameters (oncological results and complications) were well documented Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 73

Funovics 2010

Methods Study design: retrospective cohort study Country: Austria Setting: single-centre; hospital; 1968-2006 Participants Total participants: n = 70 (wide resection n = 24, marginal n = 7, intralesional n = 39; trunk n = 17, extremity n = 53) Loss to follow-up: not mentioned Age mean (range): 40 (10-72) 2 Sex M:F: 39:31 Inclusion criteria: diagnosis of LGCS in any bone based on clinical exploration, radiography and histological evaluation Exclusion criteria: not mentioned Follow-up months (range): 6-317 Interventions Intralesional: curettage, high speed burring and PMMA, with or without plating Resection: resection with or without reconstruction (prosthesis and/or allograft) Outcomes Primary outcome: local recurrence Secondary outcome: complications Notes Tumours involving the hand and foot were included in the series, and cannot be excluded from the whole cohort as it is presented in the article. We tried to contact the study authors for additional data, which could not be obtained Risk of bias

Bias Authors’ Support for judgement judgement Bias due to confounding High risk Study authors did not use an appropriate analysis method that adjusted for all the important confounding domains and for time-varying confounding Bias in selection of Unclear risk In this study, for tumours in extremities, margins were intralesional, marginal or participants into the study wide. It is not clear on which grounds participants were treated by one of the techniques Bias in classification of Unclear risk See above interventions Bias due to deviations Unclear risk Post-operative rehabilitation was not documented. from intended interventions Bias due to missing data High risk Number of participants lost to follow-up, other than unrelated death, was not documented Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants 74 | Advances of treatment in atypical cartilaginous tumours

Gunay 2013

Methods Study design: retrospective cohort study Country: Turkey Setting: single-centre; hospital; 1995-2011 Participants Total participants: n = 30 Loss to follow-up: not mentioned Age mean (range): 41 (16-69) 2 Sex M:F: 12:18 Inclusion criteria: grade I CS, confirmed by histology. Enneking stage 1A and 1B were included Exclusion criteria: < 24 months’ follow-up Follow-up months (range): resection 75 (24-186); intralesional 73 (26-124) Interventions Resection: wide resection with reconstructions, including PMMA, allograft/autograft, endoprosthesis, intramedullary nailing, or Ilizarov external fixator Intralesional: curettage and local adjuvant, PMMA or bone autograft/allograft. 2 participants had hardware stabilisation Outcomes Primary outcome: local recurrence, metastases and/or upgrading of tumour Secondary outcome: complications Notes Aggregated data. We tried to contact the study author to obtain individual participant data but were unsuccessful Risk of bias

Bias in measurement of Unclear risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the High risk Outcome parameters were not well pre-described. reported result Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 75

Hanna 2009

Methods Study design: case series Country: UK Setting: single-centre; hospital; 1999-2005 Participants Total participants: n = 39 Loss to follow-up: not mentioned Age mean (range): 55 (32-82) Sex M:F: 10:29 2 Inclusion criteria: grade 0.5 and I CS, confirmed by histology Exclusion criteria: < 36 months’ follow-up; lesions breaching the bone cortex and/or associated with a soft tissue mass Follow-up months (range): 61 (36-104) Interventions Intralesional: curettage and filling with PMMA

Outcomes Primary outcome: local recurrence Secondary outcome: MSTS scores, metastases and/or upgrading of tumour and complications Notes

Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias Unclear risk Not applicable 76 | Advances of treatment in atypical cartilaginous tumours

Kim 2015

Methods Study design: case series Country: South Korea Setting: single-centre; hospital; 1997-2012 Participants Total participants: n = 36 losses to follow-up: not mentioned Age mean (range): 46 (18-67) 2 Sex M:F: 13:23 Inclusion criteria: grade I CS, confirmed by histology Exclusion criteria: < 24 months’ follow-up; participants who underwent wide excision because of a pathological fracture or extraosseous extension; no use of anhydrous alcohol adjuvant; history of previous surgical treatment; insufficient information from the medical record Follow-up months (range): 62 (24-169) Interventions Intralesional: curettage and additional burring, treatment with anhydrous alcohol, followed by filling of the defect with bone graft or PMMA Outcomes Primary outcome: local recurrence Secondary outcome: metastases and/or upgrading of tumour, complications Notes

Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the High risk Outcome parameters were not well pre-described. reported result Other bias Unclear risk Not applicable Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 77

Kim 2018

Methods Study design: case series Country: South Korea Setting: single-centre; hospital; 2004-2013 Participants Total participants: n = 24 losses to follow-up: not mentioned Age mean (range): 45 (18-62) Sex M:F: 9:15 2 Inclusion criteria: grade I CS, confirmed by histology. Principal indication for surgery was an endosteal erosion and tumour > 6 cm in longitudinal length Exclusion criteria: < 48 months’ follow-up; ACT not in a long bone; escalated histological grade after definitive surgery; separated lesion that was not included within the range of curettage. 1 case was treated conservatively. In the event of extraosseous soft-tissue extension, the tumour was resected Follow-up months (interquartile range): 66 (50-84) Interventions Intralesional: curettage and additional burring, treatment with hydrogen peroxide and saline rinsing, followed by filling of the defect with bone graft or PMMA. In 16 participants, prophylactic hardware was used Outcomes Primary outcome: local recurrence Secondary outcome: metastases and/or upgrading of tumour, complications, MSTS scores Notes The data presented in this paper are from a different institute than Kim 2015.

Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias Unclear risk Not applicable 78 | Advances of treatment in atypical cartilaginous tumours

Leerapun 2007

Methods Study design: retrospective cohort study Country: USA Setting: single-centre; hospital; 1980-2001 Participants Total participants: 70 (intralesional n = 13, wide resection n = 57) Loss to follow-up: not mentioned Age mean (SD): 37 ± 19.3 (intralesional) 43 ± 18.4 (wide resection) 2 Sex M:F: 1:1.6 Inclusion criteria: intramedullary lesion of the appendicular extremity with definite histologic diagnosis of LGCS Exclusion criteria: variants of CS, including secondary peripheral CS, dedifferentiated CS, soft tissue CS, clear cell CS, synovial CS, and mesenchymal CS. Moreover, participants with tumours in the axial skeleton, pelvis, spine, foot, and hand were excluded. Grade 0.5 and borderline CS also excluded Follow-up months (range): 91 (4-274) Interventions Intralesional: curettage with phenolisation and bone graft or PMMA Wide resection: not further specified Outcomes Primary outcome: disease-free survival Secondary outcome: local recurrences, metastases, death due to disease Notes The follow-up interval (see methods section, minimum 2 years) was insufficient, and individual participant data were not available for extraction. We tried to contact the study author to obtain individual participant data but were unsuccessful Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias High risk Groups were not controlled for experience of the surgeon and pre-operative functioning level of the participants Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 79

Mermerkaya 2014

Methods Study design: case series Country: Turkey Setting: single-centre; hospital; 2007-2012 Participants Total participants: n = 21 Loss to follow-up: not mentioned Age mean (range): 49 (18-71) Sex M:F: 7:14 2 Inclusion criteria: Grade I CS, confirmed by histology Exclusion criteria: < 24 months’ follow-up; lesions breaching the bone cortex and/or associated with a soft tissue mass Follow-up months (range): 58.4 (24-85) Interventions Intralesional: curettage followed by application of high-speed burring, thermal cauterisation and PMMA Outcomes Primary outcome: local recurrence Secondary outcome: complications, MSTS scores Notes It was not possible to extract the data needed from the presented data

Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias Unclear risk Not applicable 80 | Advances of treatment in atypical cartilaginous tumours

Mohler 2010

Methods Study design: case series Country: USA Setting: single-centre; hospital; 1997-2008 Participants Total participants: original article n = 46. After exclusion n = 22 Loss to follow-up: not mentioned Age mean (range): 51.1 (37-73) 2 Sex M:F: 7:15 Inclusion criteria: enchondroma, grade 0.5 and I CS, assessed by clinical, radiological and histological results Exclusion criteria: < 18 months’ follow-up Follow-up months (range): 59.8 (28-134) Interventions Intralesional: curettage and 3 cycles of liquid nitrogen application with burr drilling followed by cementation of the defect and internal fixation to prevent pathologic fracture Outcomes Primary outcome: local recurrence Secondary outcome: complications, MSTS scores Notes We excluded 24 participants from this case series since they did not meet the inclusion criteria for this review: enchondroma (n = 16) and/or follow-up too short (n = 6) and/ or axial skeleton tumour (n = 2) Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Inclusion criteria were well described, the pre-specified outcomes were all reported result reported Other bias Unclear risk Not applicable Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 81

Van der Geest 2008

Methods Study design: case series Country: the Netherlands Setting: single-centre; hospital; 1994-2003 Participants Total participants: 123 (130 tumours); active enchondroma n = 18, aggressive enchondroma n = 57, LGCS n = 55 Loss to follow-up: 1 Age mean (range): 49 (13-83) 2 Sex M:F: not mentioned Inclusion criteria: surgical treatment was performed in case of invalidating pain, scalloping of the cortex of the involved bone or suspected low-grade malignancy after biopsy. Lesions with a clinical and radiologic latent appearance were followed periodically and only treated in case of transformation to aggressive behaviour Exclusion criteria: none mentioned Follow-up months (range): 60 (24-144) for LGCS Interventions Intralesional: curettage, cryosurgery, filling of the cavity with homologous or autologous bone chips or PMMA (3 cases). Preventive plating if necessary Outcomes Primary outcome: local recurrence Secondary outcome: secondary operations, complications, functional outcome by means of the MSTS Notes Localisation of tumour not specified, data extraction not possible. Although MSTS scores were obtained, only differences in scores between subgroups were calculated. The scores themselves were not documented. We contacted the study authors, but were not able to obtain individual MSTS scores Risk of bias

Bias in measurement of Low risk Blinding of participants, assessors or personnel was not applied, however we outcomes judged that the occurrence of events was unrelated to blinding Bias in selection of the Low risk Most outcomes were not fully defined in the methods section, however all reported result relevant outcome parameters according to the literature were reported Other bias Unclear risk Not applicable 82 | Advances of treatment in atypical cartilaginous tumours

Verdegaal 2012

Methods Study design: case series Country: the Netherlands Setting: single-centre; hospital; 1994-2005 Participants Total participants: 85 Loss to follow-up: 5 Age mean (range): 47 (15-72) 2 Sex M:F: not mentioned Inclusion criteria: likely presence of LGCS located in 1 of the long bones on the Gd-MRI scan Exclusion criteria: none mentioned Follow-up months (range): 82 (2-169) Interventions Intralesional: curettage, phenolisation and allograft bone chips

Outcomes Primary outcome: local recurrence Secondary outcome: secondary operations, complications Notes Minimal follow-up was insufficient (4 months) and participants with limited follow-up could not be excluded from analysis because data were presented in aggregated form. We attempted to contact the study authors for additional data, which could not be obtained. Only 5 participants had follow-up < 2 years Risk of bias

ACT: atypical cartilaginous tumour; CS: chondrosarcoma; Gd-MRI: gadolinium-magnetic resonance imaging; LGCS: low- grade chondrosarcoma; MSTS: Musculoskeletal Tumor Society; PMMA: polymethyl methacrylate Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 83

CHARACTERISTICS OF EXCLUDED STUDIES (ORDERED BY STUDY ID)

Study Reason for exclusion

Ahlmann 2007 Case series, sample size too small (< 20); n = 10 Errani 2017 35 participants with LGCS were treated by curettage. 33 were in the long bones, 2 were in the 2 calcaneus. After excluding participants with a follow-up < 24 months, with enchondroma and/or with a tumour not in the long bones (e.g. calcaneus), only 12 participants treated by curettage remained, which was too small as a case series Lee 1999 86 participants with LGCS (central and exostotic) were treated by (marginal) resection or intralesional treatment, survival for LGCS localised in the extremities was not fully documented, and could therefore not be included in the meta-analysis or narrative summary. We attempted to contact the study authors for individual participant data with tumours in the long bones, which could not be obtained Okada 2009 Insufficient number of cases (2) to include as a case series

Ozaki 1996 Data extraction shows that were only 3 participants with long bone LGCS included. All other tumours were of higher grade, or localised in the axial skeleton or pelvis Puri 2009 Insufficient number of cases (11 LGCS) to include as a case series

Schreuder 1998 Study analyses a total of 23 cases, however only 9 with a final diagnosis of LGCS. Of those 9 cases, only 3 cases have a minimum follow-up of 24 months Souna 2010 Insufficient number of cases (15) meeting the inclusion criteria to include as a case series

LGCS: low-grade chondrosarcoma; MSTS: Musculoskeletal Tumor Society 84 | Advances of treatment in atypical cartilaginous tumours

CHARACTERISTICS OF STUDIES AWAITING ASSESSMENT (ORDERED BY STUDY ID])

Andreou 2011

Methods Study design: case series Country: Germany 2 Setting: single-centre; hospital; 1982-2004 Participants Total participants: n = 115 (LGCS n = 56) Loss to follow-up: none Age mean (range): 47 (14-79) Sex M:F: 1.56:1 Inclusion criteria: primary central chondrosarcoma (all grades) Exclusion criteria: participants treated with palliative intent or with follow-up of < 5 years after diagnosis Follow-up years (range): mean follow-up period for survivors was 12 (5-24) years Interventions Only margins mentioned (intralesional, marginal, wide and radical)

Outcomes Overall survival (%) at 5 and 10 years

Notes 56 participants were treated for LGCS in the axial skeleton and extremities, with recurrence-free survival of 73% and 68% at 5 and 10 years respectively. Survival for LGCS localised in the extremities was not fully documented since data of extremity LGCS and axial skeleton LGCS was mixed, and could therefore not be included in the meta-analysis or narrative summary. We attempted to contact the study authors for individual participant data with tumours in the long bones, which could not be obtained

Angelini 2012

Methods Study design: case series Country: Italy Setting: single-centre; hospital; 1990-2008 Participants Total participants: n = 296 (LGCS; n = 87) Loss to follow-up: none Age mean (range): 50 (13-88) Sex M:F: not mentioned Inclusion criteria: primary conventional central CS (all grades) Exclusion criteria: incomplete documentation on clinical characteristics, treatment and outcome Follow-up years (range): 7 (1.6-19.8) Interventions For LGCS: intralesional (38%), resection (59%) and amputation (3%)

Outcomes Overall survival (%) at 5, 10, and 15 years

Notes 87 participants with LGCS were treated and showed recurrence-free survival for local recurrence of 90% and 88% at 5 and 10 years respectively and 99% and 5 and 10 years for metastases. They did not find a statistical difference between participants treated by intralesional treatment versus wide resection, or between extremities or trunk site tumours. However, survival for LGCS localised in the extremities was not fully documented, and could therefore not be included in the meta-analysis or narrative summary. We attempted to contact the study authors for individual participant data with tumours in the long bones, which could not be obtained Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 85

de Camargo 2010

Methods Study design: case series Country: Brazil Setting: single-centre; hospital; 1986-2006 Participants Total participants: n = 46 (LGCS n = 23) Loss to follow-up: none Age mean (range): 43.6 (18-79) for LGCS Sex M:F: 1:1.9 2 Inclusion criteria: primary conventional central chondrosarcoma (grade 1 and 2) Exclusion criteria: secondary, mesenchymal, dedifferentiated periosteal and grade 3 CSs. Follow-up of < 30 months for living participants Follow-up months (range): 99 (32-312) Interventions For LGCS: intralesional (n = 19) and wide resection (n = 3)

Outcomes Overall survival rates, local recurrence rates

Notes This study included 23 participants with LGCS, with 22 in the appendicular skeleton. Of those, 19 participants were treated by intralesional treatment, and 3 by wide resection. In total, 6 local recurrences occurred. However, it is not specified which tumours involved the long bones (tumours in hand, feet and shoulder girdle were included as well) and it is not specified in which participants the local recurrences occurred. We attempted to contact the study authors for individual participant data with tumours in the long bones, which could not be obtained

Ma 2009

Methods Study design: case series Country: China Setting: single-centre; hospital; 1996-2007 Participants Total participants: n = 66 (LGCS; n = 22) Loss to follow-up: not mentioned Age mean (range): 45 (10-79) for LGCS Sex M:F: 4.1:1 Inclusion criteria: primary conventional central CS (grades I and II) Exclusion criteria: clear cell, mesenchymal or extraskeletal myxoid CS; CSs diagnosed as borderline grade I/II; and cases with recurrence of CS or a surgical history in another hospital Follow-up months (range): 24.8 (4-131) Interventions For LGCS: intralesional (n = 18), wide resection (n = 3) and radical (n = 1)

Outcomes Local recurrence-free survival rate

Notes The follow-up interval was insufficient in some participants, and individual participant data were not available for extraction because the outcomes were presented as aggregated data. Furthermore, hand tumours were also included in the series. Moreover, there are remarkable differences in local recurrence rates as presented in the table (72%) versus the body text (60%), which raises some concerns over the consistency of the work. We attempted to contact the authors for individual participant data with tumours in the long bones, which could not be obtained 86 | Advances of treatment in atypical cartilaginous tumours

Meftah 2013

Methods Study design: case series Country: USA Setting: single-centre; hospital; 1983-2006 Participants Total participants: n = 42 (43 lesions) Loss to follow-up: 3 Age mean (range): 44.9 (21.8-66.4) 2 Sex M:F: 1:2.2 Inclusion criteria: LGCS treated with intralesional curettage and cryosurgery Exclusion criteria: < 5 years of follow-up Follow-up years (range): 10.2 (5-22.5) Interventions Curettage with adjuvant cryosurgery, of which 2 different types were applied: a modified Marcove direct-pour technique (n = 32) and a technique with closed-circuit cryoprobes (n = 11) Outcomes Local or distant tumour recurrence, complications and functional outcome (MSTS scores)

Notes 43 tumours in 42 participants with LGCS in trunk and extremities were treated by intralesional surgery with adjuvant cryosurgery. After minimal 5 years’ follow-up, there were 4 local recurrences (4 participants, 9.3%), all of which involved lesions that had had soft-tissue involvement at the time of presentation. No secondary recurrences or metastases developed during follow-up. Survival for LGCS localised in the extremities was not fully documented, and could therefore not be included in the meta-analysis or narrative summary. We attempted to contact the study authors for individual participant data with tumours in the long bones, which could not be obtained

Streitbuerger 2009

Methods Study design: case series Country: Germany Setting: single-centre; hospital; 1972-2004 Participants Total participants: n = 80 (primary lesions n = 69) Loss to follow-up: not mentioned Age mean (range): 45.4 (16-80) Sex M:F: 1:1.05 Inclusion criteria: LGCS of the bone in axial skeleton and extremities Exclusion criteria: not mentioned Follow-up months (range): 78.5 (2-365) Interventions Only margins mentioned: intralesional (with or without PMMA), marginal, wide and radical

Outcomes Local recurrence; switch of tumour grading; metastases; second local recurrence; death of disease

Notes 80 participants were treated for LGCS (both primary and secondary tumours in pelvis or extremities) by surgical margins ranging from intralesional to wide resection. During follow-up, 17.5% of participants developed a local recurrence, of whom 3 participants (21%) showed upgrading of tumour. Metastatic disease developed in 4 participants (4.9%), of whom 3 died of disease. This study included a heterogeneous group of participants with LGCS, and data of LGCS localised in the extremities was not fully documented, and could therefore not be included in the meta-analysis or narrative summary. We attempted to contact the study authors for individual participant data with tumours in the long bones, which could not be obtained

CS: chondrosarcoma; LGCS: low grade chondrosarcoma; MSTS: Musculoskeletal Tumor Society; PMMA: polymethyl methacrylate Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 87

DATA AND ANALYSES

Comparison 1. outcome comparative studies Outcome or No. of No. of Statistical method Effect size 2 subgroup title studies participants Recurrence-free survival 7 238 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.92, 1.04]

Function by MSTS score 3 72 Mean Difference (IV, Random, 95% CI) 12.69 [2.82, 22.55]

Complications 6 203 Risk Ratio (M-H, Random, 95% CI) 0.23 [0.10, 0.55]

Analysis 1.1. Comparison 1 outcome comparative studies, Outcome 1 Recurrence-free survival. Review: Intralesional treatment versus wide resection for central low-grade chondrosarcoma of the long bones Comparison: 1 outcome comparative studies Outcome: 1 Recurrence-free survival Study or subgroup intralesional resection Risk Ratio M- Weight Risk Ratio M- n/N n/N H,Random,95% CI H,Random,95% CI Aarons 2009 16/17 14/16 7.8 % 1.08 [ 0.86, 1.34 ]

Bauer 1995 20/21 14/14 17.4 % 0.96 [ 0.83, 1.12 ]

Campanacci 2013 62/64 21/21 58.5 % 0.98 [ 0.91, 1.07 ]

Chen 2017 4/5 3/3 1.1 % 0.86 [ 0.47, 1.55 ]

Donati 2010 13/15 16/16 7.3 % 0.87 [ 0.69, 1.09 ]

Etchebehere 2005 11/11 5/5 5.2 % 1.00 [ 0.76, 1.31 ]

Gunay 2013 10/13 14/17 2.7 % 0.93 [ 0.65, 1.35 ]

Total (95% CI) 146 92 100.0 % 0.98 [ 0.92, 1.04 ]

Total events: 136 (intralesional), 87 (resection) Heterogeneity: Ta u 2 = 0.0; Chi2 = 2.21, df = 6 (P = 0.90); I2 =0.0% Test for overall effect: Z = 0.77 (P = 0.44) Test for subgroup differences: Not applicable 0.5 0.7 1 1.5 2

Favours resection Favours intralesional 88 | Advances of treatment in atypical cartilaginous tumours

Analysis 1.2. Comparison 1 outcome comparative studies, Outcome 2 Function by MSTS score. Review: Intralesional treatment versus wide resection for central low-grade chondrosarcoma of the long bones Comparison: 1 outcome comparative studies Outcome: 2 Function by MSTS score Study or intralesional Mean resection Mean Mean Difference Weight Mean Difference subgroup N (SD) N (SD) IV, Random, IV,Random, 95% CI 95% CI 2 Aarons 2009 17 98.2 (2.8) 16 80 (18.3) 31.4 % 18.20 [9.13, 27.27]

Chen 2017 3 98.6 (3.1) 5 94.3 (5.1) 37.4 % 4.30 [-1.38, 9.98]

Donati 2010 15 89.3 (11.1) 16 72.1 31.2 % 17.20 [8.03, 26.37] (14.8) Total (95% CI) 35 37 100.0 % 12.69 [2.82, 22.55]

Heterogeneity: Tau 2 = 59.33; Chi2 = 9.37, df = 2 (P = 0.01); I2 =79% Test for overall effect: Z = 2.52 (P = 0.012) Test for subgroup differences: Not applicable -100 -50 0 50 100 Favours resection Favours intralesional

Analysis 1.3. Comparison 1 outcome comparative studies, Outcome 3 Complications. Review: Intralesional treatment versus wide resection for central low-grade chondrosarcoma of the long bones Comparison: 1 outcome comparative studies Outcome: 3 Complications Study or intralesional resection Risk Ratio M- Weight Risk Ratio M- subgroup n/N n/N H,Random,95% CI H,Random,95% CI Aarons 2009 1/17 6/16 17.6 % 0.16 [ 0.02, 1.16 ]

Campanacci 2013 1/64 6/21 16.7 % 0.05 [ 0.01, 0.43 ]

Chen 2017 0/5 2/3 9.3 % 0.13 [ 0.01, 2.11 ]

Donati 2010 0/15 0/16 Not estimable

Etchebehere 2005 3/11 3/5 49.1 % 0.45 [ 0.14, 1.51 ]

Gunay 2013 0/13 1/17 7.3 % 0.43 [ 0.02, 9.74 ]

Total (95% CI) 125 78 100.0 % 0.23 [ 0.10, 0.55 ]

Heterogeneity: Tau 2 = 0.0; Chi2 = 3.90, df = 4 (P = 0.42); I2 =0.0% Test for overall effect: Z = 3.37 (P = 0.00074) Test for subgroup differences: Not applicable 0.005 0.1 1 10 200 Favours intralesional Favours resection

Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 89

APPENDICES

APPENDIX 1. CENTRAL SEARCH STRATEGY

#1 MeSH descriptor: [Chondrosarcoma] explode all trees #2 chondrosarcoma* 2 #3 MeSH descriptor: [Chondroma] explode all trees #4 enchondroma* or chondroma* #5 #1 or #2 or #3 or #4 #6 intra-lesion* or intralesion* #7 MeSH descriptor: [Curettage] explode all trees #8 curettage #9 phenol* or ethanol or bone cement #10 MeSH descriptor: [Cryotherapy] explode all trees #11 cryotherapy #12 #6 or #7 or #8 or #9 or #10 or #11 #13 Any MeSH descriptor with qualifier(s): [Surgery - SU] #14 MeSH descriptor: [Amputation] this term only #15 resect* or surgery or amputat* #16 #13 or #14 or #15 #17 #5 and #12 and #16

APPENDIX 2. MEDLINE SEARCH STRATEGY

1. exp Chondrosarcoma/ 2. chondrosarcoma*.mp. 3. exp Chondroma/ 4. (enchondroma* or chondroma*).mp. 5. 1 or 2 or 3 or 4 6. (intra-lesion* or intralesion*).mp. 7. exp Curettage/ 8. curettage.mp. 9. (phenol* or ethanol or bone cement).mp. 90 | Advances of treatment in atypical cartilaginous tumours

10. Cryotherapy/ 11. cryotherapy.mp. 12. 6 or 7 or 8 or 9 or 10 or 11 13. surgery.fs. 14. Amputation/ 2 15. (resect* or surgery or amputat*).mp. 16. 13 or 14 or 15 17. 5 and 12 and 16 key: [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]

APPENDIX 3. EMBASE SEARCH STRATEGY

1. chondrosarcoma/ 2. chondrosarcoma*.mp. 3. chondroma/ 4. (enchondroma* or chondroma*).mp. 5. 1 or 2 or 3 or 4 6. (intra-lesion* or intralesion*).mp. 7. curettage/ 8. curettage.mp. 9. (phenol* or ethanol or bone cement).mp. 10. exp cryotherapy/ 11. cryotherapy.mp. 12. 6 or 7 or 8 or 9 or 10 or 11 13. su.fs. 14. exp amputation/ 15. (resect* or surgery or amputat*).mp. 16. 13 or 14 or 15 17. 5 and 12 and 16 mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword fs=floating subheading Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 91

CONTRIBUTIONS OF AUTHORS

• EFD: designing search protocol, reviewing articles, collecting and analysing data, preparing manuscript 2 • KG: reviewing articles, collecting and analysing data, preparing manuscript. KG collected data from Dierselhuis 2016 independently from the database presented by the study authors. • PCJ: designing search protocol, reviewing articles, collecting and analysing data, preparing manuscript • MS: supervising manuscript, arbiter

DECLARATIONS OF INTEREST

• ED: none known • KG: none known • MS: none known • PJ: none known

ED, MS and PJ are authors of the included study Dierselhuis 2016.

SOURCES OF SUPPORT

INTERNAL SOURCES

• None, Other

EXTERNAL SOURCES

• None, Other 92 | Advances of treatment in atypical cartilaginous tumours

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We did not, as stated in the protocol, perform sensitivity analyses excluding studies at high risk of bias. For time-to-event data we were unable to use hazard ratios as we were 2 only able to compute risk ratios and odds ratios. We judged risk of bias according to ROBINS-I criteria, since all series were retrospective studies. In addition to the meta- analyses, we also performed a narrative summary, either when case series only presented data from one treatment type, or when full outcome data were not available but were still of value for this review. KG was added to the author team during the review process. Intralesional treatment versus wide resection for central low- grade chondrosarcoma of the long bones | 93

CHAPTER III

Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years

Edwin F. Dierselhuis1 Jasper G. Gerbers2 Joris J.W. Ploegmakers2 Martin Stevens2 Albert J.H. Suurmeijer3,4 Paul C. Jutte2,4

J Bone Joint Surg Am. 2016 Feb 17;98(4):303-13

1 Department of Orthopaedic Surgery, Radboudumc, Nijmegen, the Netherlands 2 Department of Orthopaedic Surgery, University Medical Center Groningen, the Netherlands 3 Department of Pathology, University Medical Center Groningen, the Netherlands 4 Dutch National Bone Tumor Committee 96 | Advances of treatment in atypical cartilaginous tumours

ABSTRACT

Background: A central atypical cartilaginous tumour (ACT) – formerly known as chondrosarcoma grade 1 – is a tumour of intermediate-type malignancy, often treated by surgery. The extent of surgery remains controversial, as some advocate resection and other reports favour local treatment by curettage. Due to the low prevalence of ACT/ CS1, availability of data is limited and generally not uniform. Purpose of this study is to 3 present outcome of patients with ACT/CS1 in the long bones, treated by curettage with adjuvant phenolization in a large cohort with minimum two-year follow-up according to national guidelines.

Patients and methods: A retrospective study was designed in which we analysed prospective kept data of 108 patients treated for central ACT/CS1 in the long bones between 2006 and 2012. All patients were treated by curettage with adjuvant phenolization and bone stocking. Mean age at time of surgery was 53.6 years (range 25.7–82.1). Calculated tumour volume averaged 17.5 cm3 (range 1–100). Primary endpoint was local recurrence or residual tumour. Secondary endpoints were type and rate of complications and reoperations.

Results: All patients were free from local recurrence at a mean follow-up of 48.7 months (range 24.3–97.5). Residual tumour was suspected in five patients, leading to a 95.4% disease-free survival rate. Fracture occurred in 11 patients (10.2%). All patients needed open reduction and internal fixation, four needed multiple surgeries. Other complications were fissure during the surgery (two patients), wound infection (one patient), arthrofibrosis (one patient) and skin necrosis (one patient). Tumour volume was related neither to risk of fracture nor to occurrence of residual tumour.

Conclusion: In our hands, curettage of ACT/CS1 in the long bones with adjuvant phenolization is safe, even with large tumours up to 100 cm3. Most worrisome is the risk of fracture, in 10.2% of our patients. Considering the relatively mild nature of ACT/CS1, less aggressive treatment, conservative or by minimal invasive surgery, could be the next step, without compromising oncological results. Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years | 97

INTRODUCTION

Chondrosarcoma (CS) is a cartilage-forming malignancy affecting 1 in 200,0001. Despite its low prevalence, it is the most common primary bone tumours in adults older than 252. Overall survival is predominantly determined by histological grading (I–III) and dedifferentiated CS3. Grade I tumours were recently renamed atypical cartilaginous tumours (ACT) by the World Health Organization (WHO)4. ACT of long bones are cartilaginous tumour with very limited metastatic potential but unpredictable future local 3 aggressive growth. They are frequently incidental findings, and are found more and more often as a result of an increasing use of CT and MRI for common shoulder- and knee complains. This presents a growing challenge for the oncologic orthopaedist, since only few of these patients will ever suffer from a chondrosarcoma5,6. Historically, diagnosis based on imaging has been deemed unreliable7. To prevent tumour upgrading after recurrence or misdiagnosis of a grade-II for an ACT/CS1 tumour, the latter was also treated by en bloc resection or amputation. In general, if treatment is necessary, surgery is the mainstay of treatment for cartilaginous malignancies, since they are relatively insensitive to systemic therapy and irradiation treatment7. Higher-grade tumours show detrimental survival curves and need more aggressive surgery, and ACT/CS1 localized in the axial skeleton may require such an approach too7. More recent data shows that central ACT/CS1 involving the long bones seem to do well with local therapy8. Several case series have demonstrated that curettage with adjuvant phenol and ethanol washout or cryosurgery is not inferior than wide resection in terms of survival9-16. Obviously, functional outcome improves dramatically when limbs and joints are saved. Data is scarce though, and should be anticipated with diligence. Additional data on these patients is therefore valuable, the more so if tumour volume is also taken into account together with mid to long term follow-up. Therefore, the purpose of this study is to analyse the oncologic outcome of all consecutive patients of our hospital with ACT/CS1 in the long bones treated by intralesional treatment with adjuvants. 98 | Advances of treatment in atypical cartilaginous tumours

PATIENTS AND METHOD

A retrospective analysis was done from a prospectively gathered database. All patients with a final diagnosis of ACT/CS1 in the long bones that were treated by curettage, phenol/ ethanol as adjuvant and additional bone grafting were included (Figure 1). Patients were operated between October 2006 and November 2012 at University Medical Center Groningen, with a minimum follow-up of two years. Patients that had been pre-treated 3 by radiofrequency ablation (RFA) were included as well (Figure 2). Exclusion was based on previous treatment for the same lesion elsewhere. All patients were informed that clinical and radiographic data could be used for scientific purposes. This is in accordance to the regulations of the Medical Ethical Review Board of University Medical Center Groningen, which approved our study (8 November 2013 – 2013.398). If patients had objections to the use of their data, these data were not included in the study.

FIGURE 1. T1-weighted MRI scan of a typical image of an ACT in the proximal part of the humerus, showing a large lesion, wall-to-wall filling, but no signs of higher-grade aggressiveness Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years | 99

A B

FIGURE 2. ACT pre-treated by radiofrequency ablation (RFA). The tumour is surrounded by a dense ring – so called Halo – suggesting that the tumour is completely within the ablation zone. After thermal ablation, all these tumours were curetted as well.

TREATMENT PROTOCOL

If a patient was suspected for an ACT/CS1 based on history, physical examination and imaging, agreement about diagnosis and treatment type was achieved during the weekly multidisciplinary meeting in the presence of an orthopaedic oncologist, musculoskeletal pathologist, musculoskeletal radiologist and general oncologist. Based on gadolinium- enhanced magnetic resonance imaging (Gd-MRI), lobular intramedullary lesions were diagnosed as ACT/CS1 in the presence of intermediate T1W signal intensity (SI), increased T2W/S TIR SI and mild endosteal scalloping. Peritumoural oedema, cortical expansion, periostitis, cortical destruction or soft-tissue extension had to be absent, since they are suggestive of a higher-grade malignancy17. After obtaining informed consent, patients were operated on by a dedicated oncologic surgeon. In this operation, the tumour was reached through a cortical window under guidance of fluoroscopy or computer-assisted surgery (CAS) and subsequently removed using a curette. Technical details concerning the CAS procedure have been described previously18. After phenolization (85% concentration) lasting at least two minutes, ethanol washout (96% concentration) and saline rinsing, polymethylmethacrylate 100 | Advances of treatment in atypical cartilaginous tumours

(PMMA) (Palacos®, Heraeus Medical GmbH, Wehrheim, Germany), or other fillings were used to fill the cavity (Figure 3.a). If needed, a prophylactic osteosynthesis was performed. Material retrieved during surgery was sent for histological evaluation by a senior musculoskeletal pathologist. After surgery, patients were admitted to the ward and discharged if pain level and wound leakage were acceptable. During admission a conventional X-ray was taken to check for osseous complications and to serve as a baseline image for follow-up. Patients were instructed regarding mobility and weight-bearing, supervised by physiotherapists. Further follow-up was done according to protocol19. 3 Primary endpoint was local recurrence or presence of residual tumour after surgery. Secondary endpoints were death from disease, metastasis, tumour upgrading or dedifferentiation, and type and rate of complications. Outcome parameters were obtained from clinical charts and our hospital database. Complications were defined as an unintended adverse event leading to re-intervention, increased duration of admission, or re-admission within three months of primary operation. Mean and range of values were noted for all variables. Measurements of tumour size were based on 4-mm slice MRI and 2 1.5-mm slice CT. Tumour volume was estimated as π x radiusmax x height, where radiusmax is the mean of the maximum anterior-posterior and medial-lateral radius17. Analysis of the data was performed with IBM Statistical Package for the Social Sciences (SPSS) version 22. If applicable, differences in means were tested with the Student T-test, while a p-value <0.05 was considered of statistical significance. Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years| 101

A B

C D

FIGURE 3-A THROUGH 3-D. Radiographs of a patient with a tumour in the distal end of the femur. Figure. 3-A Postoperative image of the distal end of the femur after curettage and filling of the defect with PMMA. Figure. 3-B After a low-energy trauma led to a fracture in the cement zone, open reduction and internal fixation was performed. Figures. 3-C and 3-D An atrophic non-union developed (Figure. 3-C) for which a repair was needed, eventually leading to a satisfying result twenty-eight months after the initial trauma (Figure. 3-D). 102 | Advances of treatment in atypical cartilaginous tumours

RESULTS

DEMOGRAPHICS (TABLE 1)

A total of 112 patients were initially included. Mean age was 53.6 years (range 25.7–82.1), with a male-to-female ratio of 1:1.8. The femur was mostly affected (n=63), followed by the humerus (n=33). Mean tumour volume was calculated as 17.5 cm3 (range 1–100), 3 with craniocaudally length of tumour ranging from 10 to 165 mm. Neo-adjuvant RFA was performed in 40 patients, followed by conventional curettage after three to four months20. In 30 patients, curettage was done by conventional means, but with image guidance using computer assistance instead of fluoroscopy. Filling of the cavity was done with PMMA (Palacos®, Heraeus Medical GmbH, Wehrheim, Germany) in 92 cases (82.1%), with (autologous) bone chips in 17 cases, and with synthetic bone (Vitoss® or PRO-DENSE®) in three cases. Prophylactic hardware was used in 15 patients (13.4%) with lesions in the femur.

OUTCOME (TABLE 2)

Four patients were lost to follow-up, leaving 108 patients (96.4%) for analysis. Loss to follow-up was due to the patients’ wish for routine check-up at their nearest hospital in three cases; one patient suffered from rectal carcinoma, which required palliative treatment. All patients were free from local recurrence at a mean follow-up of 48.7 months (range 24.3–97.5). Residual tumour was suspected in five patients, leading to a 95.4% disease-free survival rate at a minimum follow-up of two years. Four out of these five patients had a tumour in the humerus, which was significantly more frequent compared to the disease-free population (p = 0.014) (table 3). A wait-and-see regimen was agreed for four patients in whom residual tumour was suspected. None of these patients showed growth of the tumour over time. One patient needed total knee replacement due to concomitant osteoarthritis and was treated for the residual tumour in the same session. Neither metastatic disease nor upgrading of tumour was seen in any of the patients, hence none of the patients died of the disease. Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years| 103

Table 1. Demographics of all patients included. (n) (%)

Gender

Male 40 35.7

Female 72 64.3

Age at treatment 53.6 (25.7 to 82.1)

Localization Femur 63 56.3 3 Humerus 33 29.5

Tibia 13 10.7

Fibula 2 1.9

Ulna 1 0.9

Calculated tumor volume (cm3) 17.5 (1 to 100)

Surgery type

Curettage and phenolization 112 100

Neoadjuvant radiofrequency ablation (RFA)1 40 35.7

Computer-assisted surgery (CAS)1 30 26.8

Prophylactic hardware1 15 13.4

Bone stocking

PMMA 92 82.1

Bone chips 17 15.2

Synthetic bone 3 2.7 1Regardless of other surgical interventions (RFA, CAS and prophylactic hardware). 104 | Advances of treatment in atypical cartilaginous tumours

Table 2. Overview of patients’ follow-up, primary and secondary outcomes. (n) (%)

Patients included

Total 112 100

Lost to follow-up 4 3.6

Left for analysis 108 96.4

Follow-up (months) mean 48.7 (24.3 to 97.5) 3 Primary outcome Disease free survival 103 95.4

Local recurrence 0 0

Residual tumor 5 4.6

Reoperation for residual tumor 1 0.9

Secondary outcome

Death from disease 0 0

Metastasis 0 0

Upgrading or dedifferentiation 0 0

Complications 16 14.8

Fracture 11 10.2

Non-union 3 2.8

Fissure 2 1.9

Wound infection 1 0.9

Skin necrosis 1 0.9

Arthrofibrosis 1 0.9

Reoperation due to complications 20 (12 patients)

Regarding complications, fracture occurred in 11 patients (10.2%) after a mean of 5 weeks (range 1-13.3 weeks) (Figure 3b). Fractures were seen in the diaphysis of the femur (n=9) and the humerus (n=2). All patients needed open reduction and internal fixation; four patients needed multiple surgeries for non-union or hardware removal (Figure 3c). Other complications were fissure during the surgery as a result of the creation of the bone Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years| 105

window (two patients, both in the femoral diaphysis), wound infection (one patient), arthrofibrosis (one patient, needing manipulation) and skin necrosis of a pretibial wound (one patient). Tumour volume was neither related to risk of fracture nor to occurrence of residual tumour.

Table 3. Characteristics of patients displaying residual tumour Age (sex) Localization Tumour volume Grafting

40 (F) Proximal epiphysis humerus 45 cm3 PMMA 82 (F) Diaphysis humerus 26 cm3 PMMA 3 44 (M) Diaphysis humerus 26 cm3 PMMA

50 (F) Distal metaphysis femur 13 cm3 Bone chips

52 (F) Proximal metaphysis humerus 9 cm3 PMMA

DISCUSSION

Over the last two decades, treatment of low grade cartilaginous lesions has increasingly become a topic of debate6. The need for awareness of potential misdiagnosis of the entity is stressed, to prevent possible over- or undertreatment. A negative impact on survival has been seen in local recurrences in previous studies21. In those days, this was regarded as undesirable from an oncological perspective, since a less harmful lesion can turn into a more aggressive tumour, thus increasing morbidity and even mortality. This is why some authors have questioned whether local treatment of low-grade cartilaginous tumours like ACT would be sufficient22. However, nowadays local recurrence is often to be said a sign of higher grade tumours instead13,16. With overall improvement of diagnostic imaging tools available and an increase in experience of treating these low grade cartilaginous tumours, a trend towards less extensive local surgery can be observed in the literature (see Table 4)9-16. Still, one must be aware that objective histologic criteria for intramedullary cartilaginous tumours of the long bones have not been defined. As a consequence, even pathologists with special interest and expertise in bone tumours cannot accurately discriminate between enchondroma and ACT23. Histologically, host bone entrapment 106 | Advances of treatment in atypical cartilaginous tumours

is currently the best criterion of aggressive invasive growth, by which the tumour may be diagnosed as ACT. However, this feature is seldom present in the initial diagnostic needle biopsy or in tumour tissue obtained by curettage.

Table 4. Recent literature on treatment of ACT/CS1 with a minimal follow-up of two years. Author Patients (n) Treatment (n) LR (%)(1) FU (years) MSTS (%) 3 Aarons et al. 2009 32 Curettage (17) 5.8 4.6 (2 to 16.9) 98 (range not reported) Clin Orthop Relat Res Resection (15) 6.7 84 (range not reported)

Donati et al. 2009 31 Curettage (15) 13.3 13.1 (5.5 to 24.7) 90 (77 to 100)

Clin Orthop Relat Res Resection (16) 0 73 (47 to 90)

Etchebere et al. 2005 23 Curettage (11) 0 (2 to 16) range not reported

Clinics Resection (12) 0

V. Geest et al. 2008(2) 55 Curettage + 0 5 (2 to 12) 94 (range not reported)

Journal Surg Oncol Cryo

Hanna et al. 2009 39 Curettage + 5 unknown 94 (79 to 100)

European Journal Surg Oncol PMMA

Meftah et al. 2013(3) 43 Curettage + 9.3(4) 10.2 (5 to 22.5) 88 (57 to 100)

JBJS Cryo

Souna et al. 2010 15 Curettage + 0 8 (5 to 11) 93 (73 to 100)

Clin Orthop Relat Res Cryo (1) LR = local recurrence; (2) enchondroma excluded from this table; (3) tumors involved long bones, feet and axial skeleton; (4) three out of four LR were found in axial tumors or in the foot with soft tissue extension.

As a consequence of this diagnostic dilemma and because of our lack of understanding of the natural behaviour and progression of these tumours, the term atypical cartilaginous tumour was created in the 2013 WHO classification of bone tumours. In addition, age of the patient, size of the lesion, and erosion of cortical bone cortex can only be considered surrogate markers of potential aggressive growth. Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years | 107

Our current knowledge of the genetic and epigenetic events occurring in cartilaginous tumours of the long bones and their relation to tumour progression is still limited. IDH1/IDH2 mutations, which are considered to be an early event in the genesis of central cartilaginous tumours in the long bones, are found in at least half of the lesions diagnosed as enchondromas, in addition to their presence in most chondrosarcomas24. Both enchondromas and ACT/CS1 are diploid or near diploid tumours, whereas only chondrosarcomas of higher grades 2 and 3 show polyploidization and aneuploidy. Thus, to date, it is impossible to reliably predict the future local aggressive behaviour of a cartilaginous tumour of the long bones by routine histology or genetic analysis. 3 With this in mind, in our patient series we have demonstrated that in a minority of patients (4.6%) tumour mass remains after surgery if treated with curettage and adjuvant phenolization. This had no impact on patient survival. Moreover, neither actual local recurrence, nor upgrading in the local residue did occur. If residual tumour was present, it was significantly more often found in humeral lesions. This might be due to the fact that it is more challenging to have adequate fluoroscopy in the humerus. Moreover, lesions within the humeral head often display tentacle-like features. To our knowledge, the present study is the largest case series so far (see Table 4), with a very satisfying 96.4% completeness of over two years of follow-up. Follow-up was done according to a consensus-based, nationwide follow-up protocol19. There is no evidence in the literature on follow-up frequency and content. In our opinion, peer-based national (and preferably international) agreement on treatment and follow-up for rare tumours like these is very useful and should maybe even be mandatory to improve overall outcome. The study might be flawed by its retrospective nature and the lack of control subjects. One may argue that selection biases our findings, yet large lesions were also treated by curettage. Only one previously published series has assessed tumour volume, although minimal follow-up was relatively short (0.2 years)16. In our series with a minimal follow- up of two years we demonstrated that it is safe to treat lesions up to 100 cm3 with no association seen between tumour volume and occurrence of residual tumour, local recurrence or risk of fracture. None of the patients who were treated locally turned out to have higher-grade tumours. This is in line with a recent publication by Brown et al., which states that it is safe to treat ACT/CS1 without biopsy if imaging seems conclusive25. The exact role of phenol and ethanol as adjuvants is unknown, although Verdegaal et al. have demonstrated in a previous in-vitro study that they both have cytotoxic effects 108 | Advances of treatment in atypical cartilaginous tumours

on chondrosarcoma tumour cells26. Since no adverse events due to phenolization are reported in larger case series, its use can be deemed safe and given the earlier studies it is expected to enhance local tumour control. We did not include functional results by Musculoskeletal Tumour Society (MSTS) scores, as this was not adequately done on a prospective basis. However, from the literature we know that after curettage MSTS scores are consistently good-to-excellent, with mean scores of 88 to 98%9,10, 12–15. Considering the nature of the surgical procedure, we expected our patients to perform equally well. As can be seen in Table 4 patients 3 treated by resection have lower mean MSTS scores, ranging from 73 to 84%9,10. Our main concern was the occurrence of a fracture in up to 10.2% of patients, which is relatively high compared to previous studies. Ever since this observation, we agreed on using prophylactic plate fixation with a low threshold, based on the surgeons’ judgement. Most fractures occurred in the first weeks after surgery in mid-femoral treated lesions. In general, this implies a reoperation for open reduction and internal fixation, often followed by removal of hardware months to years later and prolonged rehabilitation periods. This carries an increased risk of perioperative complications, so the cure might be worse than the disease. Hereby, another challenge for the physician is added and an ongoing debate is present on whether small lesions should be operated at all. There is some agreement among experts that it seems safe to only monitor these tumours. In line with this opinion, we tend to follow the more indolent tumours closely, instead of operating them at once (Figure 4). However, there is a lack of literature available that supports this strategy and we therefor favour a (multinational) prospective cohort study, that could answer this matter. So, in the absence of definitive answers, in our view the physician should discuss the pros and cons of each strategy with his patient. Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years | 109

A B

FIGURE 4-A THROUGH 4-C. Figures. 4-A, 4-B, and 4-C A patient who had a residual tumor. Figures. 4-A and 4-B Gadolinium-enhanced T2-weighted MRI scan (Figure. 4-A) and conventional radiograph (Figure. 4-B), made thirty-five months after curettage, showing the residual tumor.Figure. 4-C Because of osteoarthritis, total knee replacement was performed, curetting the lesion in the same session. 110 | Advances of treatment in atypical cartilaginous tumours

FIGURE 5. T1-weighted MRI scan of a patient with an CS1/ACT in the femur who was managed with four years of conservative treatment. The tumour showed no signs of aggressiveness over time.

In conclusion, not a single patient with an ACT in the long bones, treated with curettage and adjuvant phenolization displayed local recurrence, metastatic disease, or upgrading of tumour. Hereby, this study adds valuable data to the limited existing evidence that it is oncological safe to operate these tumours intralesionally. Although residual tumour was seen in 4.6%, this did not influence patient survival, and intralesional treatment can be considered non-inferior in oncological outcome compared to wide resection. Based on the literature, curettage is superior in terms of functional results, but despite preventive measures fracture rates were relatively high after curettage in our hands. Therefore, with the do no further harm in mind, these specific types of primary bone tumour remain a controversial entity on how to treat. They are increasingly found as incidental findings, so the oncologic orthopaedists should question themselves if and how to handle these tumours. Future research has to focus on improving diagnostic accuracy and less invasive or even conservative strategies to spare patients from unnecessary interventions, without compromising oncological results. Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years | 111

REFERENCES

1. Giuffrida AY, Burgueno JE, Koniaris LG, Gutierrez JC, Duncan R, Scully SP. Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database. The Journal of Bone & Joint Surgery 2009;91(5):1063-1072 2. Rosenthal DI, Schiller AL, Mankin HJ. Chondrosarcoma: correlation of radiological and histological grade. Radiology. 1984; 150:21–26. 3. Lee FY, Mankin HJ, Fondren G, Gebhardt MC, Springfield DS, Rosenberg AE, Jennings 3 LC. Chondrosarcoma of bone: an assessment of outcome. J Bone Joint Surg Am. 1999;81:326- 38 4. Fletcher CDM, Bridge JA, Hogendoorn P, Mertens F. WHO Classification of Tumours of Soft Tissue and Bone. Fourth Edition 5. Hong ED, Carrino JA, Weber KL, Fayad LM. Prevalence of shoulder enchondromas on routine MR imaging. Clin Imaging. 2011 Sep-Oct;35(5):378-84. 6. Stomp W, Reijnierse M, Kloppenburg M, de Mutsert R, Bovée JV, den Heijer M, Bloem JL; NEO study group. Prevalence of cartilaginous tumours as an incidental finding on MRI of the knee. Eur Radiol. 2015 May 21 [Epub ahead of print]. 7. Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH, et al. The clinical approach towards chondrosarcoma. Oncologist 2008 Mar;13(3):320-9. 8. Hickey M, Farrokhyar F, Deheshi B, Turcotte R, Ghert M. A systematic review and meta- analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Ann Surg Oncol. 2011 Jun;18(6):1705-9. 9. Aarons C, Potter BK, Adams SC, Pitcher JD, Jr., Temple HT. Extended intralesional treatment versus resection of low-grade chondrosarcomas. Clin Orthop Relat Res 2009 Aug;467(8):2105-11. 10. Donati D, Colangeli S, Colangeli M, Di BC, Bertoni F. Surgical Treatment of Grade I Central Chondrosarcoma. Clin Orthop Relat Res 2010 Feb;468(2):581-9 11. Etchebehere M, de Camargo OP, Croci AT, Oliveira CR, Baptista AM. Relationship between surgical procedure and outcome for patients with grade I chondrosarcomas. Clinics (Sao Paulo). 2005 Apr;60(2):121-6. 12. van der Geest IC, de Valk MH, de Rooy JW, Pruszczynski M, Veth RP, Schreuder HW. Oncological and functional results of cryosurgical therapy of enchondromas and chondrosarcomas grade 1. J Surg Oncol 2008 Nov 1;98(6):421-6. 112 | Advances of treatment in atypical cartilaginous tumours

13. Hanna SA, Whittingham-Jones P, Sewell MD, Pollock RC, Skinner JA, Saifuddin A, et al. Outcome of intralesional curettage for low-grade chondrosarcoma of long bones. Eur J Surg Oncol 2009 Dec;35(12):1343-7. 14. Meftah M, Schult P, Henshaw RM. Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma. J Bone Joint Surg Am. 2013 Aug 7;95(15):1358-64. 15. Souna BS, Belot N, Duval H, Langlais F, Thomazeau H. No recurrences in selected patients after curettage with cryotherapy for grade I chondrosarcomas. Clin Orthop Relat Res. 2010 3 Jul;468(7):1956-62. 16. Verdegaal SH, Brouwers HF, van Zwet EW, Hogendoorn PC, Taminiau AH. Low-grade chondrosarcoma of long bones treated with intralesional curettage followed by application of phenol, ethanol, and bone-grafting. J Bone Joint Surg Am 2012 Jul 3;94(13):1201-1207. 17. Douis H, Saifuddin A. The imaging of cartilaginous bone tumours. II. Chondrosarcoma. Skeletal Radiol. 2013 May;42(5):611-26. doi: 10.1007/s00256-012-1521-3. Epub 2012 Oct 4. 18. Gerbers JG, Stevens M, Ploegmakers JJ, Bulstra SK, Jutte PC. Computer-assisted surgery in orthopedic oncology. Acta Orthop. 2014 Dec;85(6):663-9. 19. No authors listed. www.oncoline.nl/beentumoren 20. Dierselhuis EF, van den Eerden PJ, Hoekstra HJ, Bulstra SK, Suurmeijer AJ, Jutte PC. Radiofrequency ablation in the treatment of cartilaginous lesions in the long bones: results of a pilot study. Bone Joint J. 2014 Nov;96-B(11):1540-5 21. Schwab JH, Wenger D, Unni K, Sim FH. Does local recurrence impact survival in low-grade chondrosarcoma of the long bones? Clin Orthop Relat Res. 2007 Sep;462:175-80. 22. Fiorenza F, Abudu A, Grimer RJ, Carter SR, Tillman RM, Ayoub K, et al. Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg Br 2002 Jan;84(1):93- 9. 23. Eefting D, Schrage YM, Geirnaerdt MJ, Le Cessie S, Taminiau AH, Bovée JV, Hogendoorn PC. Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol. 2009 Jan;33(1):50-7. Local treatment of atypical cartilaginous tumors in the long bones: results in 108 patients with a minimum follow-up of two years | 113

24. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O’Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011 Jul;224(3):334-43. 25. Brown MT, Gikas PD, Bhamra JS, Skinner JA, Aston WJ, Pollock RC, Saifuddin A, Briggs TW. How safe is curettage of low-grade cartilaginous neoplasms diagnosed by imaging with or without pre-operative needle biopsy? Bone Joint J. 2014 Aug;96-B(8):1098-105 26. Verdegaal SH, Corver WE, Hogendoorn PC, Taminiau AH. The cytotoxic effect of phenol 3 and ethanol on the chondrosarcoma-derived cell line OUMS-27: an in vitro experiment. Bone Joint Surg Br. 2008 Nov;90(11):1528-32

CHAPTER IV

Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones

Jasper G. Gerbers1 Edwin F. Dierselhuis2 Martin Stevens1 Joris J.W. Ploegmakers1 Sjoerd K. Bulstra1 Paul C. Jutte1

PLoS One. 2018 May 17;13(5)

1 Department of Orthopaedic Surgery, University Medical Center Groningen the Netherlands 2 Department of Orthopaedic Surgery, Radboudumc, Nijmegen, the Netherlands 116 | Advances of treatment in atypical cartilaginous tumours

ABSTRACT

Background: Fluoroscopy is currently the standard imaging modality for curettage of atypical cartilaginous tumours/chondrosarcoma grade 1 (ACT/CS1). Computer-assisted surgery (CAS) is a possible alternative, offering higher resolution imaging and continuous three-dimensional feedback without ionizing radiation use. CAS hypothetically makes curettage more accurate, thereby decreasing residue or recurrence rate. This study aims to compare CAS and fluoroscopy in curettage of ACT/CS1.

Patients and methods: A single centre retrospective cohort study was performed. CAS 4 and fluoroscopy were used in parallel. Included were patients who had curettage for ACT/CS1in the long bones, with a minimum follow-up of 24 months. Tumour volume was determined on pre-operative MRI scans. Outcome comprised local recurrence rates, residue rates, complications and procedure time.

Results: Seventy-seven patients were included, 17 in the CAS cohort, 60 in the fluoroscopy cohort. Tumour volume was significantly larger in the CAS cohort (p = 0.04). There were no recurrences in either group. Residual tumour (2/17 vs. 7/60), complications did not differ significantly: fracture rate (3/17 vs. 6/60); nor did surgical time (1.26h vs. 1.34h).

Conclusion: CAS curettage showed good oncologic results. Outcome was comparable to fluoroscopy, while not using ionizing radiation. There was no significant difference in surgical time. Residue rates can likely be decreased with specific software functions and surgical tools. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 117

INTRODUCTION

Atypical cartilaginous tumour/chondrosarcoma grade one (ACT/CS1), recently reclassified from chondrosarcoma grade one (CS1), is one of the most frequently treated lesions in orthopaedic oncology1. The most commonly affected sites are the diametaphysis of the proximal and distal femur, the proximal tibia and humerus. Incidence of chondrosarcoma as a whole was estimated in an analysis of the American Surveillance, Epidemiology and End Results (SEER) database as 1 in 200.000 per year2. A report of the European ESMO/EUROB- ONET registration describes the yearly incidence of chondrosarcoma as ~0.1/ 100.0003. Because of ACT/CS1’s potentially malignant nature, the surgical goal is a complete 4 removal of the tumour to prevent local recurrences and its associated decrease in patient survival4,5. Up until around the 1980’s treatment of all chondrosarcoma consisted of resection with a wide margin. Better clinical and pathological knowledge and improved diagnostic techniques suggested this was not necessary for the less aggressive, low grade lesions. The current standard surgical treatment therefore consists of (extended) intralesional curettage generally supported with fluoroscopy and the use of a local adjuvant such as phenol/ethanol, liquid nitrogen or argon beam coagulation6,7. Reconstruction is done with polymethylmethacrylate (PMMA), synthetic fillers, allografts or autografts. Depending on location and tumour characteristics, such as limited X-ray visibility due to cartilages’ lack of mineralization, it can be difficult to perform a complete curettage. The percentage of residual tumour after curettage is possibly significant, assuming that (early) local recurrence is often in fact local residue8. Fluoroscopy, the current standard, offers two-dimensional imaging and fluorovideo using X-band radiation9. Three-dimensional intra-operative imaging based on MRI may very well be an improvement in this aspect and there is no intra-operative radiation. With the advances of computer technology in the operating room, a new potential alternative has been developed. Computer-assisted surgery (CAS) is a relatively new modality, originally developed for neurosurgery in the early 1990’s. The main advantage of CAS over fluoroscopy is that it gives real-time, continuous, high resolution 3D feedback, all that and without the use of intra-operative ionizing radiation. It uses pre- operative computed tomography (CT) and/or magnetic resonance imaging (MRI) scans 118 | Advances of treatment in atypical cartilaginous tumours

as visual datasets. Fusion of both modalities improves image clarity, especially for cartilage containing tumours. Tracked instruments are visible in the imaging environment. This means the surgeon is continuously aware of the 3D tumour and instruments location, with feedback on movement in three dimensions. In theory, better orientation through CAS could make the surgery less demanding and improve outcome in recurrence and residue rates. Cited disadvantages for CAS use are lack of intra-operative assessment of the actual surgical result (i.e. the system shows a virtual result) and the system takes valuable surgical time to setup and configure10,11. This study aims to compare fluoroscopy and CAS in terms of safety and efficacy in treatment of ACT/CS1 in the long bones.

4 PATIENTS AND METHODS

DESIGN

A single centre retrospective cohort study was performed using the prospectively kept local bone tumour database. All patients with the procedure code for curettages of bone tumours were analysed. In accordance to regulations of the local Medical Ethical Review Board, all patients were informed about the fact that their data could be used for scientific research. If patients had objections to the use of their data, these data were not included in the study.

PATIENTS

Inclusion criteria were: a curettage type procedure for histologically proven ACT/CS1 in the long bones with the use of the adjuvants phenol and ethanol with a minimum follow-up of two years. Exclusion criteria were: the use of other means of treatment for the same lesion (e.g. radiofrequency ablation or cryotherapy), a non-complete follow- up and procedures that treated a recurrence. As this was a retrospective study patients were not randomized. This retrospective cohort study does not require an approval of the institutional review board (METc UMCG), following our research code. Patient approval is registered in the prospectively kept research database. Both techniques were used in parallel, with CAS use depending on system availability, planning and dataset quality. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 119

Tumour volume approximation was done for each case on pre-operative MRI scans. The method used was as described by Verdegaal et al: calculation of the volume of an 2 imaginary cylinder (π * rmax * hmax). For rmax the sum of maximum measured radii anterior- posterior and medial-lateral was divided by two to produce the maximum radius. We 8 defined maxh as the largest measurement of proximal-distal size .

OUTCOME MEASURES

The primary outcome measure was local residue or local recurrence. Local residue was defined as a suspect lesion (i.e. showing tumour like characteristics) reported on standard post-operative baseline imaging (MRI three to six months post-operatively), with consensus between the radiologist and orthopaedic surgeon. When there was no consensus an independent radiologist or orthopaedic surgeon was consulted. Recurrence 4 was defined as a positive pathological sample for ACT/CS1 after a (radiologically) tumour-free period. Secondary outcome measures were: complications like fractures, defined as a fracture at the surgical site regardless of adequate or inadequate trauma, other complications (eg. infection) and intra-operative and surgical time. Technique related time requirements were compared using the surgical time and patient-in-OR time. The surgical time was defined as the hours and minutes between first incision and wound closure as registered in the operative procedures registration database. Duration of the patient-in-OR time was defined as the period between the registered times of the patient entered the operating room and patient leaving the operating room.

PATIENT WORK-UP

Pre-operative workup included a CT scan (for the CAS navigation group), a gadolinium enhanced MRI with or without Short inversion-Time Inversion Recovery (STIR) fat suppression sequences. Core needle biopsies were performed to rule out grade 2 chondrosarcoma; they were done under CT-guidance and classified by one specialized musculoskeletal pathologist (AS) In case of earlier biopsy and referral, the material was revised by the pathologist. Pathology classification is standardized in the Netherlands by the Dutch Bone Tumour Committee, following the WHO classifications12. Surgical indication were clear diagnosis of ACT on MRI (e.g. septonodular Gadolinium enhancement, scalloping, wall-to-wall filling, perilesional oedema), growth of the tumour 120 | Advances of treatment in atypical cartilaginous tumours

over time, and/or persistent pain on the tumour site. The procedures were performed by two orthopaedic consultant surgeons ( JP, PJ).

CAS WORKFLOW

The curettages were done without pre-operative planning. Image fusion, generally CT with MRI, was done in the operating room while the patient was being prepared for surgery. The time consumption of tracker placement and software matching was measured using a stopwatch. After bone exposure, the procedure differentiates from a standard (fluoroscopic) procedure13. During a navigated procedure, a CAS patient tracker was rigidly attached to the affected bone using two 3 mm pins. Care was taken not to place the tracker in the expected path of the curette. Trackers were usually placed 4 percutaneously near joint lines, for example near the medial condyle of the femur, the anteromedial tibia plateau or the trochanteric complex. The pointer tool was then used for position checking, system calibration and remote control of the software. Image- based navigation was set-up by entering reference points both in the software and on the patient. The point based match was refined by surface matching where data points are entered with the pointer tool directly on the navigated bone. The system then presents an approximation of accuracy based on the difference between the entered points and the bone surface. The aim was an approximation of accuracy of lower than 1.0 mm. A Stryker Navigation System II with OrthoMap 3D software (Stryker Mahwah, NJ) was used in all cases. Surface matching on MRI is not supported on the used system. After the setup of the CAS the place for the bone window is determined using the pointer tool and the window is made in a regular fashion. The curettage technique, from a surgical point of view, is not different from a normal procedure; curettes are used to scrape out the lesion. The CAS system was used as a continuous-on imaging modality during the curettage process. A standard curette was attached to a tracker using a universal clamp and calibrated in the calibration device (Figure 1). During the procedure, the situation on screen did not update as it was still based on pre-operative imaging data (Figure 2). A final check at the end of the procedure is performed by using the navigated curette to check the whole cavity: in all directions, the pointer should access beyond the borders of the tumour (Figure 3). Screenshots were taken to register the extent of the curettage, comparable to a workflow with fluoroscopy. All CAS procedures were done without intra-operative fluoroscopy control. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 121

FIGURE 1. CAS tracker. Instrument tracker attached using a universal clamp to a large curette. Note the maximized three-dimensional spacing of the infrared LED lights. The backside and battery compartment of another instrument tracker is visible in the background. 122 | Advances of treatment in atypical cartilaginous tumours

4 FIGURE 2. CAS procedure. Photograph during a typical CAS supported curettage procedure. Imagebased visualization mode is set to standard view. The system shows the relevant MRI slices, fused to the CT dataset, based on position of the tool. The ACT/ CS1lesion is coloured yellow by manual segmentation. The curette is visible as the blue line and the blue dotted line shows its vector in each direction. The lower right screen shows a volume render of the dataset, with the curette as the blue tool.

FIGURE 3. Screenshot of the CAS interface during a final check of the curettage. An MRI dataset is used for navigation in this image. The pointer tool is inserted in the cavity and can extend beyond the tumour boundary. Annotation point marked by numbers are visible on the most extreme edges of the lesion as a further check. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 123

FLUOROSCOPY WORKFLOW

During a fluoroscopy supported curettage procedure imaging data was loaded onto digital displays in the OR for use during surgery. After dissection, the lesion was localized with the fluoroscope to guide the place for the bone window. A window was made in a regular fashion in the cortex of the bone with an osteotome and hammer or electrical saw. The cavity was then curetted in a systematic clockwise way. Fluoroscopy was used for orientation during the procedure and to check if the curette reaches beyond all the visible edges of the tumour. Regardless of the navigation modality, the second part of the surgery is the same: when the curettage result was satisfying, the cavity was then partially filled with the first adjuvant: phenol. Small swabs were used to clean the edges of the whole cavity. The phenol was then washed out with 95% ethanol. The bone window was also cleaned using 4 this protocol. The cavity was filled with PMMA or allograft bone chips. When indicated protective osteosynthesis material was applied to prevent a postoperative fracture (large window size, cortical resorption, diaphyseal localization). Plating was performed with a tibial LCP plate in diaphyseal lesions with at least two bicortical screws proximal and distal of the bone window. Weight bearing and return to activities depended on lesion size and location, usually it was six weeks of partial weight bearing with crutches.

FOLLOW-UP

After surgery, a standard X-ray was obtained as a routine post-operative check. Then a standard radiograph at the six-week follow-up and at three to six months a baseline Gadolinium enhanced MRI. Further controls were yearly done with radiographs till year 3. Then a radiograph at year 5. When a residue was suspected or if the lesion appeared active, a more frequent MRI follow-up pattern was chosen. If the osteosynthesis material caused a too large interference for radiological analysis, even with MRI metal suppression protocols, CT scans were used.

STATISTICAL ANALYSES

Descriptive statistics were used to describe the main characteristics of the patient groups. General patient data as age and sex were compared, depending on data type, using independent sample t-tests or Pearson chi-square tests. Specific categorical or dichotome variables, as recurrence and fracture rates, were compared with Fisher’s exact test due to 124 | Advances of treatment in atypical cartilaginous tumours

small sample sizes. Distribution of the different categories of reconstruction methods and the ASA classification were compared with the Freeman-Halton extension of Fisher’s exact test, using the exact method. Numerical surgical characteristics data were tested for normality using the Shapiro- Wilk test and were tested with a Student’s t-test. Non-continuous variables were compared with a Mann–Whitney U test. To assess potential causes for fractures binary logistic regression tests were performed with the dichotomous fractures as a dependent variable and calculated lesion size variable as continuous predictor and for the fracture rate as dependent variable and cement use as dichotomous predictor. All tests were done two-sided when applicable. A significance level of 0.05 was chosen. Analysis of the data was performed with IBM Statistical Pack- age for the Social Sciences (SPSS) version 22. 4

RESULTS

PATIENT CHARACTERISTICS

Seventy-seven patients were included from 2006 to 2014; 17 patients in the CAS cohort and 60 patients in the fluoroscopy cohort. Mean age at surgery was 53 years (range 24–82 years). Females were slightly more affected than males with a ratio of 1.1:1. Median follow-up was 79 months (29–134 months, 50–134 for alive patients). Of the 77 patients included for analysis, 75 patients are currently alive; two patients have died of unrelated disease. Further demographic information is displayed in Table 1 and Figure 4.

TABLE 1. Demographic characteristics between the two cohorts. CAS Fluoroscopy p value Number of patients (n) 17 60 Patient age x years) 56,1 53,8 0.50 Sex >0.99

Male (n, %) 8 (47%) 29 (48%)

Female (n, %) 9 (53%) 31 (52%) Follow-up x, months) 41 45 0,43 N is number of patients, x is cohort mean, x is cohort median. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 125

FIGURE 4. General distribution of location of the ACT/CS1 lesions 126 | Advances of treatment in atypical cartilaginous tumours

SURGICAL CHARACTERISTICS

Analysis of the pre-operative data showed a significant difference between the lesion width (medial-lateral), with larger dimensions in the CAS cohort (p = 0.01). Median tumour volume was 18 cm3. Tumour volume was significantly larger (p = 0.04) in the CAS cohort; 23 cm3 (9 cm3–100 cm3) versus 16 cm3 (1 cm3–61 cm3) (see Table 2). Patient time in the operating room (patient-in-OR time) (2.15h versus 2.27h) and surgical time (1.26h versus 1.34h) was lower in the CAS cohort than in the fluoroscopy cohort, however both differences were not significant. CAS setup was measured in the last ten procedures from where the procedures deviates from the normal procedure (tracker placement) to the system fully set-up and running. This took on average 4 minutes and 25 seconds (range 2:03 min to 5:40 min). 4 TABLE 2. Surgical characteristics between the two cohorts. CAS Fluoroscopy p value

ASA classification 0.92*

ASA I (n, %) 6 (35%) 18 (30%)

ASA II (n, %) 9 (53%) 35 (58%)

ASA III (n, %) 2 (12%) 7 (12%)

Lesion length (x cm) 6.5 5.2 0.33**

Lesion width (x cm) 2.5 2.0 0.01*

Lesion depth (x cm) 2.1 1.9 0.15*

Calculated volume (x cm3) 23 16 0.04**

Surgical time (x h:mm) 1:26 1:34 0.29**

OR time (x h:mm) 2:15 2:27 0.24**

Reconstruction 0.91*

PMMA (n, %) 13 (76%) 45 (75%)

Bonegraft (n, %) 4 (24%) 11 (18%)

Synthetic graft (n, %) 0 3 (5%)

None (n, %) 0 1 (2%) x is cohort mean, x is cohort median. Percentage displayed is percentage of cohort for that specific category. * Tested using Freeman-Halton extension of Fisher’s exact test. ** Tested using Mann-Whitney U test, uniformly for length category. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 127

CLINICAL OUTCOME

Nine patients, two in the CAS cohort (2/17, 12%) and seven in the fluoroscopy cohort (7/60, 12%) had a potential residue (p = NS). A more frequent follow-up strategy was initiated for these cases to check the potential residue for progression. Two of the potential residues have been biopsied, both in the CAS cohort. Both biopsies showed viable ACT/ CS1 and the residues were treated using radiofrequency ablation (RFA). There were no recurrences of the treated tumours in both cohorts (see Table 3).

TABLE 3. Clinical outcome between the groups in events and percentage of that category. CAS Fluoroscopy p value N = 17 N = 60 Recurrence (n, %) 0 0 - 4 Potential residue (n, %) 2 (12%) 6 (10%) >0.99

Fractures (n, %) 3 (18%) 6 (10%) 0.41

Other complications (n, %) 0 5 0.58 Complications were split in fractures and other complications. Other complications are split out in the text.

There were nine fractures, related to the bone window, in the treated patients (9/77, 12%), all were within five months after the initial surgery and five were within one month. There were three fractures in the CAS group (3/17, 18%), all three in the diaphysis of respectively the femur (two) and humerus (one). There were six fractures in the fluoroscopy group (6/60, 10%). Five of these were in the diaphysis of the femur and one in the proximal metaphysic of the humerus. All fractures were treated with osteosynthesis and are currently healed. The difference in fracture rate between the CAS and fluoroscopy cohort was not significant. There was no significant difference in the calculated tumour volume between the groups that had a fracture and those that did not (median of 19 cm3 versus 14 cm3). Prophylactic plating was done in 14 patients, although this could not prevent a fracture in two cases (12%). There were eight fractures in the PMMA reconstruction group (8/58, 13.3%), none in the bone graft group (0/15 patients, 0%), none in the synthetic bone grafts group (0/3, 0%) and one in the no reconstruction group (1/1, 100%). Comparison of the tumour volume between PMMA and the non-PMMA groups showed no significant difference. The distribution of fractures over the groups 128 | Advances of treatment in atypical cartilaginous tumours

was not significant (p = 0.1). In this dataset neither tumour volume, nor reconstruction method proved to be a predictive value for fractures in binary logistic regression. No complications were associated with either imaging modality.

DISCUSSION

Computer-assisted surgery has become an accepted treatment modality for difficult tumour resections11,14. While it offers potentially superior imaging feedback there have been no reports on use of CAS for the curettage of bone tumours, other than a few 4 reported cases for bone tumours located in the spine15. The higher resolution imaging, three-dimensional feedback and no limitations in feedback time make CAS a potential alternative to fluoroscopy. Clinical results of the CAS and fluoroscopy cohorts were comparable, with a significantly larger tumour volume in the CAS cohort. There were no tumour recurrences according to the definition; however nine residues were identified (13%). Although these outcome figures seem satisfying, they are difficult to compare to literature, were recurrence rates are reported between 3.5% and 13.3%, in studies with similar adjuvants16,17. Important is that this depends on the interval and modality of follow-up imaging (i.e. MRI versus radiographs). As Verdegaal et al. have demonstrated, some local recurrences might actually be residues8. ACT/CS1 is a low-grade tumour and generally grows slowly. Thus, suspect lesions on the three-month baseline scans should be considered tumour residue. Furthermore, studies reporting recurrence rates using radiographs will likely miss smaller tumour residues. An example of a potentially missed residue can be seen in an image collage in Figure 5. While the post-operative radiographs of the knee show no apparent tumour residue the baseline MRI shows a suspect lesion. Taking this into account, recurrence will likely be over-reported and residue under-reported in studies using radiographs during follow-up. As residue is primarily a problem of intra-operative orientation, this is something the three-dimensional and high-resolution feedback aspect of CAS can possibly improve. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 129

FIGURE 5. Residue. Series of images of a female patient after a CAS procedure for CS1 in the right distal femur. A: the post-operative 4 radiograph (Follow-up: 0 days). The defect is reconstructed with a bonechips (bonegraft). No residue visible. B: shows the baseline MRI scan of the same patient (follow-up 3 months). The depicted TIRM sequence shows a reactive response to the graft, with local oedema. However, below the reconstruction is another lobular, fluid rich structure: retrospectively suggestive for local residue but the radiologist describes it as most likely a postoperative reaction of the bone. Further radiographic follow-up shows no recurrence. C: TIRM sequence of the same patient (follow-up: 25 months) shows a nearly died down reaction to the graft but a comparable reaction in the suspected zone. Biopsy before RFA treatment confirmed CS1 tissue.

Potential residues were found in two out of 17 CAS patients and in seven out of 60 fluoroscopy patients. Both potential residue cases in the CAS cohorts and one out of the fluoroscopy cohort showed tumour tissue at biopsy. Actual residue rate for the fluoroscopy cohort may be lower than six as GD-MRI has positive prediction rate of 45% for actual residue on suspect follow-up scans8. Analysis of the CAS residue cases did not show a clear cause. Our hypothesis is that the feedback mode is currently not yet good enough for CAS to be better than fluoroscopy, especially the lack of progress tracking (i.e. there is no change in the image dataset on screen during the procedure). It also shows that it is not an infallible guide. While no navigational inaccuracies were experienced, regular accuracy checks, on a known landmark, are advised during the procedure to prevent drift. Fracture rates in this study (12%) are high compared to literature. Recent studies, with the same adjuvants, show a fracture rate ranging from 5.0 to 6.6 percent. A possible cause for this can be difference in preventive osteosynthesis strategies.7, 17-21. 58 of the 77 patients treated in this study had a reconstruction with PMMA. While it is suspected that the exothermic PMMA hardening process can have a beneficial effect as an 130 | Advances of treatment in atypical cartilaginous tumours

adjuvant, it may have a negative effect on the host bone. Literature shows no significant difference in recurrence and fracture rates between using PMMA or other reconstruction methods17,22. As there were no recurrences, we cannot draw conclusions on PMMA and recurrence rate. Fracture rate in PMMA seems higher with 8 fractures out of 58 patients treated (14%) compared with a 6% fracture rate in the other reconstruction methods, although this did not reach significance. As the fracture rate was considered too high, a more aggressive plating strategy (longer plates and more cortices for smaller lesions) was adopted for procedures in the diaphysis of the femur. There was also a possible bias in fracture risk as a concurrent radiofrequency ablation (RFA) trial meant the exclusion of patients with mainly smaller ACT/CS1 lesions in the femoral metaphysis23. The often-cited downside of CAS use, the long set-up time, was not experienced10. 4 Set- up time, measured in the later cases, was on average just 4 minutes and 25 seconds. This was with an experienced team with over 50 procedures into the learning curve. The median surgical and patient in OR time was less than for fluoroscopy. While not significantly better, it shows that the set-up time is recouped during the procedure. Use of CAS has been described by both surgeons as useful, due to the continuous three-dimensional feedback, compared with the intermitted two-dimensional feedback in fluoroscopy. It was helpful in checking for complete removal in difficult zones for example directly around the cortical window. Application of CAS in the humerus was considered more difficult due to issues with tracker placement in the working field. Smaller trackers could solve this issue. There were no direct complications nor any morbidity related to use of the CAS system. Possible complications as pin tract fractures or pin tract infections did not occur. Inter-observer variability is a high and ongoing issue in the grading of cartilaginous bone tumours. The SLICED study group reported that grading reliability, even by experienced pathologists and radiologist, is low and that this may partially explain difference in outcomes between centres24. The difference is even the highest between discerning enchondroma and low grade chondrosarcoma (kappa 0.54)25. In this study one specialized pathologist with extensive expertise in sarcoma and two specialized radiologists either reviewed the samples or supervised a resident for nearly all the cases. All external work was reviewed. Guidelines on classification for ACT/CS1 were rigidly followed. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 131

This study has some limitations. It was set-up as a retrospective cohort study, the study population was not equally divided and the techniques were not actively randomized. Both the techniques were however used in parallel, with CAS use only depending on system availability, planning and dataset quality. The only adjuvant treatment in this study was phenol/ethanol, results may be different using argon beam coagulation or cryotherapy as adjuvant. CAS curettage was tested only for ACT/CS1, the effect on lesions with higher recurrence rates as giant cell tumour may be different. As far as we know, this is the first study on the usage of CAS for curettage of ACT/CS1 in the long bones. This study can be seen as a pilot study on CAS efficacy. Some improvements to workflow and instruments will probably have a positive effect on outcome measurements. Currently it is not possible to see the extent of the already treated area. A ‘paintbrush’ mode, where the position of the tip is painted into the three- 4 dimensional view would provide feedback on surgical progress. This together with the addition of a planning mode to the software could provide an intra-operative residue check (i.e. colouring in the planned 3d structure). Furthermore, it is likely that a more accurate curettage with less healthy bone removed can decrease fracture rates. Also, there should be support for non-straight tools like bended, hockey stick, shaped curettes and pointers, for easier access to tumour tissue in corners of the lesion.

CONCLUSION

CAS curettage with phenol/ethanol adjuvants has shown good oncological results at medium length follow-up, at least comparable to the fluoroscopy cohort and literature. CAS curettage in this study was safe and effective. There were no recurrences, and no difference in the occurrence of residues between the cohorts, this despite significantly larger lesions in the CAS cohort. Fracture rates in both groups were higher than expected. In this study this was not linked to CAS technique, PMMA use or size of the lesions. Especially a suspected high residue rate after curettage supports the development of better intra-operative orientation. Clinical outcome of the present study supports CAS use as an alternative to fluoroscopy. With CAS, no ionizing radiation was used during these surgeries and there was no increase in surgical time. Residue rates can likely be improved with specific, curettage targeted, software modules and tools. 132 | Advances of treatment in atypical cartilaginous tumours

REFERENCES

1. Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma, and Ewing’s sarcoma: national cancer data base report. Clin Orthop. 2007; 459: 40-47. 2. Giuffrida AY, Burgueno JE, Koniaris LG, Gutierrez JC, Duncan R, Scully SP. Chondrosarcoma in the United States (1973 to 2003): an analysis of 2890 cases from the SEER database. The Journal of Bone & Joint Surgery. 2009; 91: 1063-1072. 3. Hogendoorn P, Athanasou N, Bielack S, De Alava E, Dei Tos A, Ferrari S, et al. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology. 2010; 21: v204-v213. 4 4. Gelderblom H, Hogendoorn PCW, Dijkstra S, van Rijswijk C, Krol A, Taminiau AHM, et al. The clinical approach towards chondrosarcoma. Oncologist. 2008; 13: 320-329. 5. Andreou D, Ruppin S, Fehlberg S, Pink D, Werner M, Tunn P. Survival and prognostic factors in chondrosarcoma: Results in 115 patients with long-term follow-up. Acta orthopaedica. 2011; 82: 749-755. 6. Hickey M. A systematic review and meta-analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Annals of Surgical Oncology. 2011; 18: 1705-1709. 7. Van Der Geest I, De Valk M, De Rooy J, Pruszczynski M, Veth R, Schreuder H. Oncological and functional results of cryosurgical therapy of enchondromas and chondrosarcomas grade 1. J Surg Oncol. 2008; 98: 421-426. 8. Verdegaal SH, Brouwers HF, van Zwet EW, Hogendoorn PC, Taminiau AH. Low-grade chondrosarcoma of long bones treated with intralesional curettage followed by application of phenol, ethanol, and bone-grafting. J Bone Joint Surg Am. 2012; 94: 12011207. 9. Kahler D. Image guidance: fluoroscopic navigation. Clin Orthop. 2004: 70-76. 10. Saidi K. Potential use of computer navigation in the treatment of primary benign and malignant tumors in children. Current reviews in musculoskeletal medicine. 2012: 1-8. 11. Wong KC, Kumta SM. Computer-assisted Tumor Surgery in Malignant Bone Tumors. Clinical Orthopaedics and Related Research. 2012: 1-12. 12. Rosenberg AE. WHO Classification of Soft Tissue and Bone, fourth edition: summary and commentary. Curr Opin Oncol. 2013; 25: 571-573. Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 133

13. Gerbers JG, Stevens M, Ploegmakers JJ, Bulstra SK, Jutte PC. Computer-assisted surgery in orthopedic oncology: Technique, indications, and a descriptive study of 130 cases. Acta orthopaedica. 2014; 85: 1-7. 14. Jeys L, Matharu GS, Nandra RS, Grimer RJ. Can computer navigation-assisted surgery reduce the risk of an intralesional margin and reduce the rate of local recurrence in patients with a tumour of the pelvis or sacrum? Bone Joint J. 2013; 95-B: 1417-1424. 15. Rajasekaran S, Kamath V, Shetty AP. Intraoperative Iso-C three-dimensional navigation in excision of spinal osteoid osteomas. Spine (Phila Pa 1976). 2008; 33: E25-9. 16. Donati D, Colangeli S, Colangeli M, Claudia Di Bella M, Bertoni F. Surgical treatment of grade I central chondrosarcoma. Clinical Orthopaedics and Related Research. 2010; 468: 581- 589. 17. Campanacci DA, Scoccianti G, Franchi A, Roselli G, Beltrami G, Ippolito M, et al. Surgical 4 treatment of central grade 1 chondrosarcoma of the appendicular skeleton. Journal of Orthopaedics and Traumatology. 2013: 1-7. 18. Aarons C, Potter BK, Adams SC, Pitcher JD Jr. Extended intralesional treatment versus resection of low-grade chondrosarcomas. Clinical Orthopaedics and Related Research. 2009; 467: 2105-2111. 19. Souna BS, Belot N, Duval H, Langlais F, Thomazeau H. No recurrences in selected patients after curettage with cryotherapy for grade I chondrosarcomas. Clinical Orthopaedics and Related Research. 2010; 468: 1956-1962. 20. The International Agency for Research on Cancer (IARC). Who Classification of Tumours of Soft Tissue and Bone: World Health Organization; 2013. 21. Verdegaal SH, Brouwers HF, van Zwet EW, Hogendoorn PC, Taminiau AH. Low- Grade Chondrosarcoma of Long Bones Treated with Intralesional Curettage Followed by Application of Phenol, Ethanol, and Bone-Grafting. The Journal of Bone & Joint Surgery. 2012; 94: 1201-1207. 22. Streitbuerger A, Ahrens H, Balke M, Buerger H, Winkelmann W, Gosheger G, et al. Grade I chondrosarcoma of bone: the MuÈnster experience. J Cancer Res Clin Oncol. 2009; 135: 543-550. 23. Dierselhuis EF, van den Eerden PJ, Hoekstra HJ, Bulstra SK, Suurmeijer AJ, Jutte PC. Radiofrequency ablation in the treatment of cartilaginous lesions in the long bones: results of a pilot study. Bone Joint J. 2014; 96-B: 1540-1545. 134 | Advances of treatment in atypical cartilaginous tumours

24. Skeletal Lesions Interobserver Correlation among Expert Diagnosticians (SLICED) Study Group. Reliability of histopathologic and radiologic grading of cartilaginous neoplasms in long bones. J Bone Joint Surg Am. 2007; 89: 2113-2123. 25. Eefting D, Schrage YM, Geirnaerdt MJ, Le Cessie S, Taminiau AH, Bovee JV, et al. Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol. 2009; 33: 50-57

4 Computer-assisted surgery compared to fluoroscopy in curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones | 135

CHAPTER V

Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study

Edwin F. Dierselhuis1 Pepijn J.M. van den Eerden2 Harald J. Hoekstra HJ3 Sjoerd K. Bulstra1 Albert J.H. Suurmeijer4 Paul C. Jutte1

Bone Joint J. 2014 Nov;96-B(11):1540-5

1 Department of Orthopaedic Surgery, University Medical Center Groningen, the Netherlands 2 Department of Radiology, University Medical Center Groningen, the Netherlands 3 Department of Surgical Oncology, University Medical Center Groningen, the Netherlands 4 Department of Pathology, University Medical Center Groningen, the Netherlands 138 | Advances of treatment in atypical cartilaginous tumours

ABSTRACT

Background: Atypical cartilaginous tumours are usually treated by curettage. The purpose of this study was to show that radiofrequency ablation was an effective alternative treatment.

Patients and methods: We enrolled 20 patients (two male, 18 female, mean age 56 years (36 to 72) in a proof-of-principle study. After inclusion, biopsy and radiofrequency ablation were performed, followed three months later by curettage and adjuvant phenolisation. The primary endpoint was the proportional necrosis in the retrieved material. Secondary endpoints were correlation with the findings on gadolinium enhanced MRI, functional outcome and complications.

5 Results: Our results show that 95% to 100% necrosis was obtained in 14 of the 20 patients. MRI had a 91% sensitivity and 67% specificity for detecting residual tumour after curettage. The mean functional outcome (MSTS) score six weeks after radiofrequency ablation was 27.1 (23 to 30) compared with 18.1 (12 to 25) after curettage (p < 0.001). No complications occurred after ablation, while two patients developed a pathological fracture after curettage.

Conclusion: We have shown that radiofrequency ablation is capable of completely eradicating cartilaginous tumour cells in selective cases. MRI has a 91% sensitivity for detecting any residual tumour. Radiofrequency ablation can be performed on an outpatient basis allowing a rapid return to normal activities. If it can be made more effective, it has the potential to provide better local control, while improving functional outcome. Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study | 139

INTRODUCTION

The mainstay of treatment for primary bone tumours is surgery. Central atypical cartilaginous tumours (ACT - formerly known as chondrosarcoma grade I) are generally treated by curettage: previously, treatment consisted of wide resection or amputation1. In general, the treatment of chondroid tumours can be problematic, since they are relatively resistant to irradiation and chemotherapy. It can also be difficult to differentiate ACT from its benign counterpart (enchondroma) and grade II tumours2,3. In contrast to higher grade chondrosarcoma, ACTs grow slowly and do not metastasise, unless upgrading or dedifferentiation occurs4,5. Although curettage causes less morbidity than more extensive surgery, it still has a negative impact on functional outcome1. Local recurrence (LR) occurs in up to 7.7 % of patients after curettage6. In the event of LR, a repeat operation is often needed, exposing the patient to the additional risks of common peri-operative complications such as infection or fracture. In addition, 5 prophylactic hardware is sometimes needed7. All these measures have a negative effect on a patient’s quality of life. Although the adage ‘life before limb’ remains true for ACT, the relatively mild nature of these tumours in the long bones might justify less aggressive treatment. Therefore, a new treatment strategy is needed that improves local control and functional outcome, while lowering the rate of complications. Moreover, follow-up must be sufficient to evaluate the effect of such treatment. A minimally-invasive approach using radiofrequency ablation (RFA), monitored by gadolinium-enhanced magnetic resonance imaging (G-MRI), might be capable of meeting these requirements. For nearly two decades, RFA has been used as a minimally-invasive surgical technique in orthopaedics. With RFA, a high-frequency alternating current heats tissue to approximately 80°C, causing it to necrose8. Initially, RFA was used to treat osteoid osteoma9,10. With increasing clinical experience, bone metastases and chondroblastomas have also been successfully treated11,12. Complications are rare, although local adverse events such as cellulitis or burns of the surrounding skin have been reported9,10. When more challenging sites, such as the femoral neck, are treated, fracture is possible13. Nonetheless RFA is a safe, precise and inexpensive technique which can be performed in the outpatient department. 140 | Advances of treatment in atypical cartilaginous tumours

The purpose of the study was twofold: to demonstrate the effective ablation of cartilaginous tumour cells in the long bones and to evaluate the ability of G-MRI to detect residual tumour after thermal ablation.

TABLE 1. Demographic data and primary outcome. Case no. Age (sex) Location Diameter Histology Histological biopsy1 response2

1 57 (M) Femur diaphysis 34 mm ACT R0

2 52 (F) Tibia metaphysis 28 mm ACT R0

3 50 (F) Femur metaphysis 31 mm ACT R0

4 64 (F) Femur metaphysis 23 mm ACT R0

5 70 (F) Tibia metaphysis 31 mm ACT R2

6 49 (F) Tibia diaphysis 31 mm ACT R0 5 7 63 (F) Femur metaphysis 35 mm ACT R2 8 36 (F) Humerus metaphysis 26 mm ACT R1

9 61 (F) Humerus metaphysis 35 mm ACT R2

10 60 (M) Femur metaphysis 26 mm ACT R1

11 59 (F) Femur diaphysis 24 mm ACT R0

12 52 (F) Femur diaphysis 22 mm ACT R1

13 64 (F) Femur metaphysis 29 mm ACT R0

14 72 (F) Femur metaphysis 31 mm ACT R2

15 50 (F) Humerus metaphysis 37 mm ACT R2

16 49 (F) Femur metaphysis 15 mm ACT R1

17 54 (F) Humerus metaphysis 36 mm ACT R1

18 49 (F) Femur diaphysis 25 mm ACT R0

19 70 (F) Femur metaphysis 37 mm ACT R2

20 44 (M) Femur diaphysis 35 mm ACT R0

1ACT = Atypical cartilaginous tumour. 2Necrotic response based on curetted material three months after radiofrequency ablation (RFA). R0 = complete necrosis, R1 = 95-99% necrosis, R2 = <95% necrosis. Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study | 141

PATIENTS AND METHODS

A prospective, proof-of-principle study was designed to evaluate the amount of tumour necrosis after RFA for ACT. Patients were included if there was clinical suspicion of ACT, which did not exceed 35 mm in its largest diameter on diagnostic MRI, in a long bone. Patients had to be aged 18 years or older and able to give informed consent after being told about the purpose of the study. Patients were excluded if the tumour was in the hand, foot, pelvis or axial skeleton. Other exclusion criteria were the presence of cognitive impairment; clear breakthrough of the cortex and infiltration of the surrounding soft- tissue by the tumour; previous treatment of the same lesion and a histological diagnosis of enchondroma. Between 2009 and 2011, we identified 20 patients, (two male, 18 female) in whom ACT was suspected for inclusion in the study. The mean age of the patients was 56 years (36 to 72) at the time of RFA. Their demographic details are presented in Table I. The study was approved by our institutional medical ethics committee (18th September 5 2009 – M09.07334). Patients first underwent CT-guided needle biopsy. After obtaining representative material, RFA under CT guidance was performed in the same session, using a Soloist Single Needle Electrode (Boston Scientific, Natick, Massachusetts). The ablation session was performed or supervised by a musculoskeletal interventional radiologist (PJME). The RFA needle was inserted through the access hole of the biopsy needle and ablation was performed starting with 2 watts, and increasing by 1 watt per minute until automatic switch-off. Patients were discharged the same day and instructed about weight-bearing, which depended on the size and localisation of the tumour, and post-operative pain management. After 14 days, the patients visited the outpatient department to have the wound checked and for their histological results. The bone biopsy was examined by a senior histopathologist with experience in bone and soft-tissue tumour pathology (AJHS) to confirm the diagnosis. Three months after thermal ablation, each patient underwent G-MRI to check for residual tumour and to assess the effect of ablation. Within four weeks of the MRI, patients underwent curettage at the site of the previously identified lesion with adjuvant phenol and ethanol, thereby receiving the conventional treatment for the condition. The tumour was approached through a cortical window under radiological guidance and removed with a curette. After phenolisation of at least 142 | Advances of treatment in atypical cartilaginous tumours

two minutes, ethanol washout and saline rinsing, polymethylmethacrylate (PMMA) was used to fill the cavity. The material retrieved during surgery was sent for histological evaluation. Each specimen was checked by the same pathologist to confirm the diagnosis of ACT and to assess the extent of any necrosis. In this way, patients served as their own control for the RFA procedure. All operations were carried out by the orthopaedic oncologist in our hospital (PCJ). Three months after curettage, G-MRI was undertaken as a baseline study for follow-up. The primary endpoint was the proportional necrosis of the material retrieved during curettage. This was classified as complete necrosis (R0); focal viable tissue (R1) with 95% to 99% necrosis; and substantial viable tissue (R2), with > 5% viable tumour tissue. Histological analysis was performed according to World Health Organization standards.3 Secondary endpoints were signs of residual tumour on post-RFA G-MRI; correlation of G-MRI with histological findings; local recurrence after curettage; complications; functional outcome and duration of admission. 5 Radiological results based on MRI were also divided into R0 (no sign of residual tumour or contrast enhancement and the tumour clearly within the ablation halo), R1 (little or doubtful gadolinium uptake and the tumour on the border of the halo with no clear tumour outside the halo) and R2 (clear residual tumour with contrast enhancement and localisation outside the halo) (Figure 1). Complications were defined as an unintended adverse event leading to re-intervention, increased duration of admission or re-admission within three months of primary operation. Judgement of local recurrence was based on follow-up with G-MRI according to our national protocol14. Functional outcome was assessed using the Musculoskeletal Tumour Society (MSTS) scores with a maximum score of 30/30 points15. These scores were documented by the treating physician (PCJ) after RFA and after curettage. Functional scores were measured six and 12 weeks after both types of treatment (T1 = six weeks after RFA, T2 = 12 weeks after RFA, T3 = six weeks after curettage, T4 = 12 weeks after curettage). We assessed the MSTS scores in ten random patients after one year (T5). Weight-bearing regimes were also noted. Duration of admission was calculated from the clinical charts. Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study | 143

FIGURE 1. Images corresponding with radiological grading of tumour response after radiofrequency ablation (RFA); A) no sign of residual tumour (R0) in the right distal femur (arrowed); B) little or doubtful uptake of gadolinium (R1) in the right proximal humerus (arrowed); C) obvious residual tumour lying outside the zone of ablation (R2) in the left distal femur (arrowed). 144 | Advances of treatment in atypical cartilaginous tumours

STATISTICAL ANALYSIS

For all variables, the mean and range of values were noted. Measurements of tumour size were based on 4 mm slice MR images and 1.5 mm slice CTs. SPSS version 22.0 software (IBM-SPSS, Armonk, New York) was used for all statistical testing. A univariate analysis was undertaken, while a p-value < 0.05 was considered to be statistically significant.

RESULTS

ACT was confirmed histologically in all 20 patients. None were diagnosed by CT-guided biopsy as an enchondroma or tumour higher than grade 1. Tumours were located in the femur13, humerus (4) or tibia (3). There were 14 tumours in the metaphysis and six in the diaphysis. The mean tumour size was 29.7 mm (15 to 37) in its largest diameter. RFA 5 was performed using 1 to 3 cycles of 1 to 14 minutes in duration. Typically, two or three procedures were performed within one session, with a mean cumulative roll-off time of 16 minutes (11 to 27). Complete necrosis (R0) was found histologically in nine patients, focal areas of viable ACT (R1) in five, and more than focal areas of viable ACT (R2) in six patients (Figure 2). Complete necrosis was present in five of the six tumours located in the diaphysis and four of the 14 tumours in the metaphysis (p = 0.02). There was no sign of enchondroma or a higher-grade tumour in any of the viable tissue. All patients with a tumour in the lower extremity (n = 16) were kept half-weight- bearing for the first six weeks after curettage: this was increased to full weight-bearing after three months. The mean MSTS score six weeks after RFA (T1) was 27.1 (23 to 30) compared with a mean score of 18.1 (12 to 25) six weeks after curettage (T3) (p < 0.001). The mean MSTS score 12 weeks after RFA (T2) was 27.2 (23 to 30) compared with a mean score of 22.9 (15 to 30) 12 weeks after curettage (T4) (p < 0.001). One year after curettage (T5) the mean MSTS score, measured in ten patients, was 27.4 (24 to 30) (Figure 3). Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study | 145

FIGURE 2. Histology showing an example of the focal area (R1) of viable atypical cartilaginous tumour after radiofrequency ablation treatment (Haematoxylin and Eosin 400x). 5

FIGURE 3. Functional outcome reflected by Musculoskeletal Tumor Society (MSTS) scores. MSTS scores are a doctor-dependent score with a maximum of 30 points. Scores six and 12 weeks after radiofrequency ablation (RFA) were significantly higher than scores after curettage (*p < 0.001 compared with MSTS 6 weeks after RFA, §p< 0.001 compared with MSTS 12 weeks after RFA). 146 | Advances of treatment in atypical cartilaginous tumours

After a mean follow-up of 35.8 months (18 to 50) from curettage there were no signs of residual tumour or local recurrence. No adverse events were seen after RFA. A pathological fracture occurred in two patients after curettage, which required open reduction and internal fixation. All patients were discharged from the hospital the same day after the RFA procedure. Patients remained in hospital for three to five days after curettage. As shown in Table II, ten patients with positive histology (focal or more than focal remnants of viable ACT) after curettage also had positive MRI results. One positive case was missed on MRI. Six of nine patients were truly negative, leaving three false- positive cases. A calculation based on these outcomes shows that G- MRI has a 91% sensitivity for detecting residual tumour after curettage, and a specificity of 67%. The positive predictive value (PPV) is 77% and negative predictive value (NPV) 86%. The one case missed on MRI showed a R1 tumour response histologically. The three false- positive cases on MRI were all considered R1 (little or doubtful gadolinium uptake). 5 Finally, one R2 case histologically was adjudged to be R1 on MRI.

TABLE 2. Results and correspondence between histological response and G-MRI findings. MRI1

R0 R1 R2 Total

R0 6 3 0 9 Histological R1 1 4 0 5 response R2 0 1 5 6 Total 7 8 5 20 1Tumours fully surrounded by a halo and no Gadolinium uptake were R0, tumours within the halo but with some Gadolinium uptake were R1, and tumours that lied partially or totally outside the ablation zone and had substantial uptake were R2. Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study | 147

DISCUSSION

Surgery is the mainstay of treatment for chondroid tumours as they are mostly unresponsive to radiotherapy or adjuvant chemotherapy. Currently, most patients with a central ACT are treated by local curettage. This does not in itself reduce overall survival, but does improve functional outcome1. However, surgery has some disadvantages such as prolonged hospital admission, risk of complications and restricted weight-bearing afterwards. Moreover, recurrence occurs in up to 7.7% of patients requiring further intervention, with the risk of additional complications6. We hypothesised that minimally-invasive treatment using RFA can eradicate the chondroid tumour cells thereby lowering the rate of complications and improving functional outcome. This pilot study shows that only nine of 20 tumours were completely necrosed by RFA. Although this confirms that RFA has the capacity to eradicate ACT, the remaining 5 patients were undertreated. Consequently, on the one hand its effectiveness has to be improved, and on the other, follow-up must be sensitive to the detection of residual tumour. These conditions have to be met before one could safely state that RFA is a reliable alternative to curettage with adjuvant phenolisation. To increase the precision of the RFA procedure, the factors that determine the efficiency of ablation need to be considered. First, the proportional necrosis is directly related to the volume of the tumour, as the area heated is limited. Our primary inclusion criteria stated that the diameter of the tumour should not exceed 35 mm. However, in three patients the actual diameter was a little over 35 mm on CT with a maximum of 37 mm. These cases were included on the basis of the baseline MRI studies, but appeared larger on CT during RFA. Since this study is about initial experiences, we decided that these cases should also be included. Of all tumours > 30 mm ablated, only five of 11 were R0 or R1, compared with nine out of nine in tumours < 30 mm (p = 0.006). There were no significant differences between localisation and total ablation time in these two groups but the groups are small. RFA might cover a diameter > 30 mm, but asymmetrical placement of the needle carries a greater risk of insufficient heating at the borders of the tumour. If larger tumours are to be ablated, we would recommend using more needle positions. 148 | Advances of treatment in atypical cartilaginous tumours

Second, the number and duration of the sessions varied substantially. A session automatically ended when there was an increase in tissue impedance due to necrotic tissue, the so-called ‘roll-off ’. Although we could not find any significant difference, we feel that at least three ablation cycles are needed to provide a more constant result and to improve reliability of the procedure. Third, the tissue response may not only be dependent on tumour size and exposure to heat: the surrounding tissue may also have an influence. Adjacent blood vessels may extract heat from the zone of ablation by their blood flow – the so-called heat sink effect – a phenomenon that occurs when a vessel > 3 mm lies within the ablation zone16. In order to study the capability of G-MRI to detect residual tumour after ablation, we undertook this three months after the RFA session, just prior to curettage. By comparing the results of G-MRI and histopathology it was possible to determine sensitivity and specificity of G-MRI for showing signs of residual tumour three months after RFA. Of all the tumours that were not completely destroyed (R1 and R2), ten of 11 were 5 also identified on MRI. Hence G-MRI is 91% sensitive to detecting residual tumour. As six of nine patients with an R0 histological response were correctly predicted on MRI, specificity is 67%. All false-negative and false-positive cases were R1, so neither R2 tumours were missed nor were R0 pathological responses presumed to be R2 on MRI. Given these facts, we feel that G-MRI is sufficiently accurate to detect residual tumour and therefore to safely monitor and guide further treatment. On this basis, we propose that patients with R0 radiological results be monitored in the same way as patients after curettage in current clinical practice, since there is an 86% NPV of MRI. Patients who show clear signs of residual malignancy on MRI (R2) should undergo a second session of RFA or curettage. We think that patients for whom the radiologist describes the MR image as R1 should be followed more closely than R0 patients. In such cases there is an 87.5% chance of there being no residual tumour, or only a little tumour tissue left. The latter might be hazardous, since it can lead to local recurrence, upgrading or dedifferentiation. The expected benefits of using RFA have all been confirmed by the current study. All patients were treated on an outpatient basis, unlike when treated by curettage, those of whom needed three to five days in hospital. After RFA, patients were allowed to bear full weight and rapidly returned to normal daily activities (Figure 3). In the ten patients reviewed one year after curettage, levels of Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study | 149

function and comfort were equal to those achieved by ablation. In two cases, fracture occurred after curettage and internal fixation was needed. No adverse events were seen after RFA. One could argue that ACT could be mistaken for an enchondroma or even a higher grade of tumour, since it is known that this diagnosis has high inter-observer variability17. We are aware that biopsy alone is not a reliable method of differentiating ACT from a grade II chondrosarcoma. However, in our experience, G-MRI is a reliable method of detecting signs of higher grade tumour18. Moreover, in this study the final histology always included all material harvested during curettage, and grade II chondrosarcoma was found in none of the viable tissue, nor did extensive follow-up with G-MRI, ranging from 18 to 50 months, show signs of recurrent tumour. We therefore think that the advantages of minimally-invasive therapy outweigh the disadvantages given the relatively benign nature of ACT. Nevertheless, we underscore the fact that if there is any doubt about the original diagnosis, curettage is still the safer option. The purpose of this study was to demonstrate the ablative effect of RFA on cartilage 5 cells. The histological differences between enchondroma and ACT are subtle and it seems reasonable that this small difference does not influence the efficiency of RFA. While our investigation was intended to study lesions measuring < 35mm in diameter on MRI, future developments might include monitoring lesions of this size and only treating them if they enlarge or show other aggressive features. Larger tumours (> 50 mm), on which we would currently operate, might be treatable with RFA using multiple tip positions. In conclusion, in this proof-of-principle study we have shown that RFA has the potential to eradicate cartilaginous tumour cells. If residual tumour after ablation is present, G-MRI has a 91% sensitivity for detecting residual tumour. RFA can safely be performed on an outpatient basis, with a rapid return to normal daily activities. We believe that the concept of minimally-invasive therapy using RFA is an attractive alternative to surgery, although its effectiveness in achieving local control has to improve. Currently, the size and location of the tumour in the bone are the main predictors of success. More consistency is needed and further research is being conducted to improve the accuracy of the ablation procedure. 150 | Advances of treatment in atypical cartilaginous tumours

REFERENCES

1. Hickey M, Farrokhyar F, Deheshi B, Turcotte R, Ghert M. A systematic review and meta- analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Ann Surg Oncol 2011;18:1705– 1709. 2. Gelderblom H, Hogendoorn PC, Dijkstra SD, et al. The clinical approach towards chondrosarcoma. Oncologist 2008;13:320–329. 3. Fletcher C, Unni K, Mertens F. World health organization classification of tumours. Cartilage tumours. Pathology and genetics of tumours of soft tissue and bone. 2002:233. http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb5/ BB5.pdf (date last accessed 18 July 2014). 4. Lee FY, Mankin HJ, Fondren G, et al. Chondrosarcoma of bone: an assessment of outcome. 5 J Bone Joint Surg [Am] 1999;81-A:326–338. 5. Fiorenza F, Abudu A, Grimer RJ, et al. Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg [Br] 2002;84-B:93–99. 6. Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical management of conventional grade I chondrosarcoma of long bones. Clin Orthop Relat Res 2007;463:166– 172. 7. Donati D, Colangeli S, Colangeli M, Di Bella C, Bertoni F. Surgical Treatment of Grade I Central Chondrosarcoma . Clin Orthop Relat Res 2010;468:581–589. 8. Patterson EJ, Scudamore CH, Owen DA, Nagy AG, Buczkowski AK. Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size. Ann Surg 1998;227:559–565. 9. Rosenthal DI, Hornicek FJ, Torriani M, Gebhardt MC, Mankin HJ. Osteoid osteoma: percutaneous treatment with radiofrequency energy. Radiology 2003;229:171–175. 10. Akhlaghpoor S, Tomasian A, Arjmand Shabestari A, Ebrahimi M, Alinaghiza- deh MR. Percutaneous osteoid osteoma treatment with combination of radiofrequency and alcohol ablation. Clin Radiol 2007;62:268–273. 11. Goetz MP, Callstrom MR, Charboneau JW, et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol 2004;22:300– 306. Radiofrequency ablation as a new treatment modality in cartilaginous lesions in the long bones; results of a pilot study | 151

12. Rybak LD, Rosenthal DI, Wittig JC. Chondroblastoma: radiofrequency ablation: alternative to surgical resection in selected cases. Radiology 2009;251:599–604. 13. Dierselhuis EF, Jutte PC, van der Eerden PJ, Suurmeijer AJ, Bulstra SK. Hip fracture after radiofrequency ablation therapy for bone tumors: two case reports. Skeletal Radiol 2010;39:1139–1143. 14. No authors listed. Oncoline. www.oncoline.nl/beentumoren (date last accessed 19 September 2014). 15. Enneking WF, Dunham W, Gebhardt MC, Malawar M, Pritchard DJ. A system for the functional evaluation of reconstructive procedures after surgical treatment of tumors of the musculoskeletal system. Clin Orthop Relat Res 1993;286:241–246. 16. Hong K, Georgiades C. Radiofrequency ablation: mechanism of action and devices. J Vasc Interv Radiol 2010;21(Suppl):S179–S186. 17. Skeletal Lesions Interobserver Correlation among Expert Diagnosticians (SLICED) Study Group. Reliability of histopathologic and radiologic grading of cartilaginous neoplasms in long bones. J Bone Joint Surg [Am] 2007;89-A:2113–2123. 5 18. Brown MT, Gikas PD, Bhamra JS, et al. How safe is curettage of low-grade cartilaginous neoplasms diagnosed by imaging with or without pre-operative needle biopsy? Bone Joint J 2014;96-B:1098–1105.

CHAPTER VI

Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience

Edwin F. Dierselhuis1 Jelle Overbosch2 Thomas C. Kwee2 Albert J.H. Suurmeijer3 Joris J.W. Ploegmakers4 Martin Stevens4 Paul C. Jutte4

Skeletal Radiol. 2018 Sep 29

1 Department of Orthopaedic Surgery, Radboudumc, Nijmegen, the Netherlands 2 Department of Radiology, University Medical Center Groningen, the Netherlands 3 Department of Pathology, University Medical Center Groningen, the Netherlands 4 Department of Orthopaedic Surgery, University Medical Center Groningen, the Netherlands 154 | Advances of treatment in atypical cartilaginous tumours

ABSTRACT

Background: Surgery is the cornerstone of treatment of symptomatic cartilaginous neoplasms. We previously studied the application of radiofrequency ablation of atypical cartilaginous tumours in the long bones. The purpose of the present study was to investigate the additional effect of placing multiple needles and longer procedure duration on the proportion of completely ablated tumours. Post-ablation MRI findings and occurrence of complications were also assessed.

Methods: We prospectively included 24 patients with atypical cartilaginous tumours in the long bones. Patients underwent CT-guided radiofrequency ablation followed by curettage with adjuvant phenolisation three months later, retrieving material assessed for viable tumour. Prior to curettage, gadolinium-enhanced MRI was performed to check for residual tumour. Occurrence of complications was noted.

Results: Complete tumour ablation was achieved in 17/24 (71%) of patients. Complete ablation was achieved in five of the six cases (83%) when multiple needles were used 6 in tumours ≥ 30 mm. There was incomplete ablation in 8% of patients. Post-ablation Gadolinium-enhanced MRI findings agreed with histological results in 17/23 cases and negative predictive value of 83%. One patient suffered a fracture after radiofrequency ablation.

Conclusion: Radiofrequency ablation might be an alternative to curettage when treating atypical cartilaginous tumours in the long bones. It was shown that multiple needle placement in addition to longer duration of the ablation procedure is an effective measure to achieve complete tumour ablation in tumours ≥ 30 mm. Gadolinium-enhanced MRI has a negative predictive value of 83% and could guide post-ablation follow-up. Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 155

INTRODUCTION

Atypical cartilaginous tumours (ACTs), also known as chondrosarcoma grade I, are bone tumours of borderline or low malignant potential1. These lesions increasingly present as a coincidental finding, when patients are evaluated for other bone- or joint-related conditions2-4. ACTs are a type of cartilage-forming neoplasm, but unlike higher-grade tumours they generally not metastasise (< 2%) and show excellent survival rates, with <3% local recurrences5. Correct diagnosis in the past has been deemed rather difficult, as histological or radiological features alone are not always conclusive6. Consequently, tumour upgrading was seen in some cases of local recurrence. For this reason, wide resection of bone and surrounding tissue used to be recommended sometimes even as primary treatment to avoid this risk7. However, recent literature shows that atypical cartilaginous tumours in the appendicular skeleton can be safely treated by curettage with adjuvant phenolisation or cryotherapy, provided that local recurrence rates are low (0-7.7%) and have no negative effect on patient survival5, 6, 8-16. Application of this surgical technique has led to an improvement in functional results, although complications such as fracturing may still occur in up to 13% of cases6, 8-13. In this context, the tumour biology should be weighed against the morbidity of intralesional surgery. For this reason, some 6 favour a conservative approach, but data is scarce and only retrospective17. Minimally invasive treatment might be an alternative, with the advantage of local control, but largely without the burdens of conventional surgery. In orthopaedic oncology, there is increasing interest in thermal ablation of bone tumours. Radiofrequency ablation (RFA) is a minimally invasive and highly accurate treatment tool. Thermal ablation by RFA has become the gold standard for treatment of certain benign bone tumours (i.e. osteoid osteomas) and can be advantageous in the treatment of skeletal metastases or solid organ tumours (i.e. renal cell carcinoma and hepatocellular carcinoma)18-21. In a previous proof-of-principle study by our group, ablation efficacy of RFA in ACTs was assessed by MRI and subsequent histological examination of ablated tumour tissue. Occurrence of complications and short-term functional outcome were also assessed22. Complete necrosis was achieved in 45% of patients, whereby size and localisation of the tumour were the main predictors of failure. This result was promising but not satisfactory. 156 | Advances of treatment in atypical cartilaginous tumours

Tumours over 30 mm in diameter were prone to incomplete ablation. Significance of the ‘heat sink’ effect could not be demonstrated. We therefore altered the protocol so that tumours ≥ 30 mm were to be ablated using multiple needle placement. We also increased the amount of energy delivered with more ablation cycles. The purpose of the current study is to report on the effect of these measures on the proportion of completely ablated tumours, the correlation with post-ablation MRI findings and the occurrence of complications.

MATERIALS AND METHODS

DESIGN

A prospective cohort study was conducted among patients with ACT in the long bones. Inclusion criteria were: patients aged ≥18 with a diagnosis of ACT in the long bones on MRI (e.g. septonodular gadolinium enhancement, no or limited endosteal scalloping, no perilesional oedema) who opted for surgical intervention (Figure 1). Other indications for surgery were growth of the tumour over time and/or persistent pain at the tumour 6 site. Tumour size was limited to 50 mm maximum diameter in any plane. Tumours were not included if localised in the hand, foot, pelvis or axial skeleton. Other exclusion criteria were presence of cognitive impairments, cortical breakthrough and previous treatment of the same lesion. Written informed consent was obtained from all participants. The study was approved by the medical ethical review committee of our hospital (METc no. M09.077334). All procedures performed in studies involving human participants complied with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its subsequent amendments or comparable ethical standards.

METHODS: ABLATION AND SURGICAL TECHNIQUE

A CT-guided biopsy under general or spinal anaesthesia, followed by RFA in the same session, was conducted as previously reported [22]. Three months later, gadolinium-enhanced magnetic resonance imaging (Gd-MRI) was performed to assess for completeness of tumour ablation, followed within four weeks by curettage and adjuvant phenolisation. The Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 157

ablation session was performed by one of our consultant musculoskeletal interventional radiologists using a SoloistTM Single Needle Electrode (Boston Scientific, Natick, MA, USA) (Figure 1). The session started with 2 watts, adding 1 watt every minute, and ended automatically when the needle reached its point of roll-off due to highly elevated impedance of the ablated tissue. Multiple needle placement was applied when incomplete ablation was anticipated in tumours ≥ 30 mm (Figure 2). Material obtained during biopsy was examined by a pathologist with special expertise in bone- and soft-tissue tumours (A.S.). Patients were discharged from the hospital on the same day. Curettage was done according to our usual care: a cortical window was created and the lesion was curetted (Figure 3). After removal of the tumour, phenolisation of the cavity was done for two minutes, followed by ethanol washout and saline rinsing. Polymethylmethacrylate (PMMA) was used to fill the defect in all cases. The retrieved material was sent to pathology for histological confirmation of ACT and assessment of the proportion of necrotic tumour tissue. All surgical procedures were performed by one of two orthopaedic oncologists (P.J. and J.P.).

FIGURE 1. Representative MRI of atypical cartilaginous tumour (ACT) in the proximal femur Transverse (b) and coronal (c) images of CT-guided radiofrequency ablation (RFA) of the same tumour 158 | Advances of treatment in atypical cartilaginous tumours

FIGURE 2. RFA procedure of ACT in the proximal humerus with two- needle placement

FIGURE 3. Exposure of the bone to reach the tumour through a cortical window that has to be created Note the scar of the previous insertion of a radiofrequency ablation (RFA) needle. Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 159

PATHOLOGY

Endpoint was success rate expressed as percentage of patients who had a complete tumour ablation on histology. Reaching 100% cell necrosis was regarded as a pR0 response. Subtotal (95-99%) or incomplete (<95%) tumour eradication were considered pR1 and pR2 respectively. Correlation with post-ablation Gd-MRI findings was noted, as well as occurrence of complications.

RADIOLOGY

Measurements of tumour size (largest diameter in any plane) were based on 4-mm slice MR images and 1.5-mm slice CTs. Analysis of the imaging was also done using a grading system that included three categories: (rR0) no signs of residual tumour, (rR1) little or doubtful gadolinium uptake at the tumour border, and (rR2) clear residual tumour outside the ablation zone. Needle positioning was assessed retrospectively. All post-RFA Gd-MR images were graded by a musculoskeletal radiologist ( J.O.), blinded for histological results.

STATISTICAL ANALYSIS

Mean and range of values were noted for all variables. SPSS version 22.0 software (IBM-SPSS, Armonk, NY) was used for all statistical testing. If applicable, a univariate 6 analysis was undertaken using the Student T-test for normally distributed values and the Mann-Whitney U-test for non-parametric data; a p-value < 0.05 was considered to be statistically significant.

RESULTS

DEMOGRAPHICS

In total 24 patients were included, with a mean age of 51.1 years (range 31-75). The femur was affected most (n = 16), followed by the humerus (n = 5) and tibia (n = 3). Mean tumour size was 28.3 mm (range 15-43). Six patients received multiple needle placement, all in tumours ≥ 29 mm. The RFA procedure took on average 23.6 min (range 12-37) (Table 1). In one patient, a Gd-MRI after RFA was not made, as a fracture occurred 160 | Advances of treatment in atypical cartilaginous tumours

prior to the planned date of the scan. It was a low-energy fracture, seven weeks after the index ablation procedure. Curettage was performed, followed by mini-open plate fixation without reduction. A non-union developed which needed second surgery with reduction, bone graft and plate fixation. The fracture healed well. This patient was still included for histological analysis purposes.

PROPORTION OF COMPLETELY ABLATED TUMOURS

On a histological level, total ablation (pR0) was reached in 17/24 (71%) cases. Incomplete ablation (pR2) was present in 2/24 (8%) and subtotal ablation (pR1) in 5/24 (21%) cases. In diaphyseal tumours, pR0 response was achieved in 13/15 (87%) cases compared to 4/9 for metaphyseal tumours (P = 0.027). Duration of the ablation procedure was 24.4 min (range 14-37) in pR0, 23.6 min (range 14-34) in pR1 and 16.5 min (range 12-21) in pR2 cases (p = NS).

CORRESPONDENCE WITH GD-MRI

Complete ablation was correctly diagnosed as rR0 in 15/16 cases, with the other case judged as rR1; pR1 corresponded with rR1 in 2/5 and rR0 in 3/5 cases respectively. The 6 cases with a pR2 response were considered rR1 (1/2) and rR2 (1/2) (Table 2). Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 161

TABLE 1. Patient characteristics and outcome Case Age Sex Location Diameter Ablation Needles Histological Radiological Com- number (years) (mm) duration response response plications (min)

1 56 Female Femur (M) 24 22 Single Focal residue Focal uptake None

2 63 Female Femur (M) 21 19 Single Complete necrosis No uptake None

3 51 Female Femur (M) 30 25 Single Complete necrosis No uptake None

4 67 Female Femur (M) 27 29 Single Complete necrosis No uptake None

5 49 Female Femur (D) 35 23 Multiple Complete necrosis No uptake None

6 43 Female Humerus (D) 15 19 Single Complete necrosis No uptake None

7 31 Male Femur (M) 28 34 Single Focal residue No uptake None

8 52 Female Humerus (D) 29 14 Multiple Complete necrosis No uptake None

9 46 Female Femur (M) 31 21 Single Substantial residue Substantial uptake None

10 49 Female Humerus (D) 29 29 Single Complete necrosis Focal uptake None

11 53 Female Tibia (D) 24 26 Single Complete necrosis No uptake None

12 48 Female Femur (D) 22 17 Single Complete necrosis No uptake None

13 63 Female Femur (D) 29 37 Single Complete necrosis – Fracture

14 48 Male Femur (D) 21 15 Single Complete necrosis No uptake None

15 58 Female Femur (M) 24 12 Single Substantial residue Focal uptake None 6

16 63 Male Humerus (D) 34 21 Multiple Complete necrosis No uptake None

17 40 Female Humerus (D) 36 19 Multiple Complete necrosis No uptake None

18 59 Female Femur (D) 36 14 Multiple Focal residue No uptake None

19 33 Female Femur (D) 31 31 Single Complete necrosis No uptake None

20 31 Male Femur (D) 30 21 Single Focal residue Focal uptake None

21 50 Female Tibia (D) 43 31 Multiple Complete necrosis No uptake None

22 75 Female Femur (M) 36 35 Single Complete necrosis No uptake None

23 49 Female Femur (M) 26 27 Single Focal residue No uptake None

24 47 Female Tibia (D) 19 25 Single Complete necrosis No uptake None M metaphysis, D diaphysis 162 | Advances of treatment in atypical cartilaginous tumours

TABLE 2. Correlation of Gd-MRI with histological findings. Gd-MRI

No uptake Focal uptake Substantial Total uptake

pathology Complete necrosis 15 1 0 16

Focal residue 3 2 0 5

Substantial residue 0 1 1 2

Total 18 4 1 23

FIGURE 4. RFA procedure of ACT in the proximal humerus, with eccentric placement of the needle

NEEDLE POSITIONING

For tumours ≤ 30 mm needle positioning was centric in 11/14 cases, eccentric in two cases, and in one case multiple needles were applied in a 29-mm diameter tumour. For tumours > 30 mm needle placement was centric in 4/10 cases, multiple needles were applied in 5/10 cases, and in one case of a 31-mm tumour the needle was placed Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 163

eccentrically (Figure 4). In one out of two pR2 cases the needle was placed eccentrically (non-significant compared to pR0 and/or pR1 cases). In tumours > 30 mm, centric or multiple needle positioning led to pR0 in 7/10 patients and pR1 in 2/10. This group had one pR2 in which the needle was placed eccentrically. When multiple needed were used, complete ablation was achieved in all but one case.

DISCUSSION

We demonstrated in 71% of patients that complete tumour necrosis is achievable using RFA for ACT in the long bones. Implementation of multiple needle placement in larger tumours and longer procedure duration improved ablation effectiveness. After our previous proof-of-principle study, we presented three possible causes for a failed ablation procedure: (1) number and total ablation time of cycles, (2) tumour size (> 30 mm) and (3) heat sink effect. We slightly adjusted our study ablation technique by delivering more local energy, either by multiple needles or longer ablation duration22. We found that in all but one case complete ablation was achieved when multiple needles were used. Time is an issue since temperature rise is a result of conductivity – hence the longer the procedure 6 takes, the more tissue is heated. Whether the heat sink effect plays a major role in the difference between success rates in metaphyseal and diaphyseal tumours is questionable, but more heat loss to surrounding tissue is plausible in metaphyseal bone if one considers the lesser thickness of the cortex and the higher vascularity of the metaphysis23. Although a quantitative comparison with our previous study was not performed, the achieved level of complete necrosis in 71% of the participants was higher than in the proof-of-principle study (45%), with a decrease of evident failures from 30% to 8% in the current study. Based on univariate analysis, diaphyseal tumours are most amenable for RFA treatment, with an 87% success rate. There were two cases with substantial viable tissue after ablation. In one case, total ablation time was relatively short (12 min). In the other case the needle was placed eccentrically and, considering the size (31 mm), there should have been multiple needle placement. Both cases can thus be regarded as technical failures and were not conducted in accordance with our treatment protocol. 164 | Advances of treatment in atypical cartilaginous tumours

Post-ablation Gd-MRI findings corresponded with histological results in 17/23 cases, with five cases under-staged (radiological response better than histology) and one case over-staged (radiological response less than histology). 15 out of 18 cases were correctly diagnosed as R0 on Gd-MRI (NPV = 83%). We want to stress that both failures (pR2) were seen on Gd-MRI, with one regarded as rR1. There is a chance of a small amount of residual tumour (pR1) being overlooked, but development of local recurrence (out of residue) is very gradual and has no negative effects on patient survival according to the current literature5. A recent paper has proposed a classification of MRI response after curettage with a consequent follow-up regime, which in our opinion can be extrapolated to MRI after ablation24. Despite the increased efficacy rates compared to our initial proof-of-principle study, there is still room for improvement. We are currently studying needle placement planning, in which ideally an algorithm can be developed using computer modelling and planning with computer-assisted surgery (CAS) to determine and execute optimal needle positioning, especially when multiple probe positions are used. Moreover, a needle that is regulated by temperature sensors instead of impedance could generate a more predictable ablation zone. Real-time imaging of the lesion during ablation would be of great value to monitor the ablation effect, albeit technically demanding. Needles used 6 for thermal ablation are not MRI-compatible, and currently CT-scans cannot detect temperature changes during RFA. Finally, an alternative might be the use of microwave ablation (MWA), as it is less dependent on tissue conductivity than RFA25. Our study also has some limitations. Only relatively small lesions were ablated and long-term follow-up after RFA is lacking. Some lesions might arguably have been enchondroma, yet imaging and biopsy results convinced us of ACT in all cases. In addition, this study was designed as proof-of-principle for whether thermal ablation can treat chondroid tumours and to investigate the reliability of Gd-MRI to check for viable tumour post-ablation. For that reason, curettage served as a control for the effects of RFA on a histological level and assess correspondence of post-RFA histology with Gd-MRI. In the future, RFA will be investigated as a treatment tool instead of curettage, in order to draw definitive conclusions after adequate follow-up. To summarise, we have demonstrated that RFA is capable of ablating ACT in the long bones in 71% of the cases, especially diaphyseal tumours. However, long term follow-up is lacking and future studies should de designed to assess long-term outcome after RFA Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 165

without subsequent curettage. It should be noted that for many years there has been a dearth of surgical innovations in the treatment of bone tumours, and we believe that the use of local tumour ablation can be a very valuable adjunct to current treatment options. We stress that not all ACT are candidates for surgery, and yet there is neither a clear consensus on a conservative approach nor clear definitions of indications for surgery17. With this study, we have shown that multiple needle placement in addition to longer duration of the ablation procedure is an effective measure to achieve complete tumour ablation in tumours ≥ 30 mm. Gadolinium-enhanced MRI has a negative predictive value of 83% and could safely guide follow-up after RFA. Future studies should focus on planning, monitoring and further improving ablation efficacy by RFA technique, with adequate follow-up after the ablation procedure.

6 166 | Advances of treatment in atypical cartilaginous tumours

REFERENCES

1. Hogendoorn P. B., Bovee J. M., Nielsen G. P. Chondrosarcoma (grades I-III), including primary and secondary variants and periosteal chondrosarcoma. In: Fletcher C. D. M., Bridge J. A., Hogendoorn P. C. W., Mertens F., editors. World Health Organization Classification of Tumours of Soft Tissue and Bone. Vol. 5. Lyon, France: IARC; 2013. p. p. 264. 2. Hong ED, Carrino JA, Weber KL, Fayad LM. Prevalence of shoulder enchondromas on routine MR imaging. Clin Imaging. 2011 Sep-Oct;35(5):378-84. 3. Stomp W, Reijnierse M, Kloppenburg M et al. NEO study group. Prevalence of cartilaginous tumours as an incidental finding on MRI of the knee. Eur Radiol. 2015 May 21 4. Kransdorf MJ, Peterson JJ, Bancroft LW. MR imaging of the knee: incidental osseous lesions. Radiol Clin North Am. 2007 Nov;45(6):943-5 5. Hickey M, Farrokhyar F, Deheshi B, Turcotte R, Ghert M. A systematic review and meta- analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Ann Surg Oncol. 2011 Jun;18(6):1705-9. 6. Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical management of conventional grade I chondrosarcoma of long bones. Clin Orthop Relat Res 2007 Oct;463:166- 6 72 7. Eriksson AI, Schiller A, Mankin HJ. The management of chondrosarcoma of bone. Clin Orthop Relat Res. 1980;153:44–66. 8. Aarons C, Potter BK, Adams SC, Pitcher JD Jr, Temple HT. Extended intralesional treatment versus resection of low-grade chondrosarcomas. Clin Orthop Relat Res. 2009 Aug;467(8):2105-11. 9. Di Giorgio L, Touloupakis G, Vitullo F, Sodano L, Mastantuono M, Villani C Intralesional curettage, with phenol and cement as adjuvants, for low-grade intramedullary chondrosarcoma of the long bones. Acta Orthop Belg. 2011 Oct;77(5):666-9. 10. Dierselhuis EF, Gerbers JG, Ploegmakers JJ, Stevens M, Suurmeijer AJ, Jutte PC. Local Treatment with Adjuvant Therapy for Central Atypical Cartilaginous Tumors in the Long Bones: Analysis of Outcome and Complications in One Hundred and Eight Patients with a Minimum Follow-up of Two Years. J Bone Joint Surg Am. 2016 Feb 17;98(4):303-13 11. Donati D, Colangeli S, Colangeli M, Di Bella C, Bertoni F. Surgical treatment of grade I central chondrosarcoma. Clin Orthop Relat Res. 2010 Feb;468(2):581-9 Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 167

12. Hanna SA, Whittingham-Jones P, Sewell MD et al. Outcome of intralesional curettage for low-grade chondrosarcoma of long bones. Eur J Surg Oncol. 2009 Dec;35(12):1343-7 13. Kim W, Han I, Kim EJ, Kang S, Kim HS. Outcomes of curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma of long bone. Surg Oncol. 2015 Jun;24(2):89-9 14. Meftah M, Schult P, Henshaw RM. Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma. J Bone Joint Surg Am. 2013 Aug 7;95(15):1358 15. van der Geest IC, de Valk MH, de Rooy JW, Pruszczynski M, Veth RP, Schreuder HW. Oncological and functional results of cryosurgical therapy of enchondromas and chondrosarcomas grade 1. J Surg Oncol 2008 Nov 1;98(6):421-6. 16. Verdegaal SH, Brouwers HF, van Zwet EW, Hogendoorn PC, Taminiau AH. Low-grade chondrosarcoma of long bones treated with intralesional curettage followed by application of phenol, ethanol, and bone-grafting. J Bone Joint Surg Am. 2012 Jul 3;94(13):1201-7 17. Deckers C, Schreuder BH, Hannink G, de Rooy JW, van der Geest IC. Radiologic follow-up of untreated enchondroma and atypical cartilaginous tumors in the long bones See comment in PubMed Commons belowJ Surg Oncol. 2016 Dec;114(8):987-991 18. Rosenthal DI, Hornicek FJ, Torriani M, Gebhardt MC, Mankin HJ. Osteoid osteoma: percutaneous treatment with radiofrequency energy. Radiology 2003 Oct;229(1):171-5. 19. Weis S, Franke A, Mössner J, Jakobsen JC, Schoppmeyer K. Radiofrequency (thermal) 6 ablation versus no intervention or other interventions for hepatocellular carcinoma. Cochrane Database Syst Rev. 2013 Dec 19;12:. 20. Katsanos K, Mailli L, Krokidis M, McGrath A, Sabharwal T, Adam A. Systematic review and meta-analysis of thermal ablation versus surgical nephrectomy for small renal tumours. Cardiovasc Intervent Radiol. 2014 Apr;37(2):427-37. 21. Goetz MP, Callstrom MR, Charboneau JW et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol 2004 Jan 15;22(2):300-6. 22. Dierselhuis EF, van den Eerden PJ, Hoekstra HJ, Bulstra SK, Suurmeijer AJ, Jutte PC. Radiofrequency ablation in the treatment of cartilaginous lesions in the long bones: results of a pilot study. Bone Joint J. 2014 Nov;96-B(11):1540-5 23. Hong K, Georgiades C. Radiofrequency ablation: mechanism of action and devices. J Vasc Interv Radiol. 2010 Aug;21(8 Suppl):S179-86. 168 | Advances of treatment in atypical cartilaginous tumours

24. Verdegaal SH, van Rijswijk CS, Brouwers HF et al. MRI appearances of atypical cartilaginous tumour/grade I chondrosarcoma after treatment by curettage, phenolisation and allografting: recommendations for follow-up. Bone Joint J. 2016 Dec;98-B(12):1674-1681. 25. Hinshaw JL, Lubner MG, Ziemlewicz TJ, Lee FT Jr, Brace CL. Percutaneous tumor ablation tools: microwave, radiofrequency, or cryoablation--what should you use and why? Radiographics. 2014 Sep-Oct;34(5):1344-62.

6 Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: Lessons learned from our experience | 169

CHAPTER VII

General discussion, implications and future perspectives 172 | Advances of treatment in atypical cartilaginous tumours

OVERVIEW

This thesis provided an overview of the current treatment strategies for ACT and investigated new treatment options. For that reason, it was divided in two sections. Objectives of Part I were to evaluate the current literature and our own results of intralesional surgery for ACT in long bone. A systematic review of the literature was conducted in Chapter II. In Chapter III we investigated the oncological results and complications of intralesional surgery for ACT that we performed. The influence of preoperative guidance by computer-assisted surgery (CAS) versus fluoroscopy in treatment of these tumours was assessed in Chapter IV. In Part II we focussed on a new treatment modality for ACT, radiofrequency ablation (RFA), with a prospective analysis in Chapters V and VI of clinical outcome and safety of RFA for ACT in the long bones. Follow-up by G-MRI, risk of complications and the learning curve for the application of this tool were all investigated in these chapters too. The current chapter will discuss the main findings of both sections of this thesis and their implications for clinical practice and future research.

PART I 7 SURGICAL TECHNIQUES AND PATIENT SURVIVAL

Wide resection was often performed for ACT until two decades ago. It used to be notoriously difficult to differentiate between low-grade and high-grade cartilaginous tumours.1 Nowadays, MRI is better at distinguishing high-grade tumours from enchondroma and ACT.25 Local recurrence was thought to precede upgrading of tumour, negatively influencing patient survival.6 For that reason, local control was best provided by extensive surgery since systemic and radiation therapy have only marginal effects.7 In the last 20 years a trend towards intralesional surgery has been observed in literature, as reviewed in 2011 by Hickey et al.,8 who concluded it could not be demonstrated that curettage greatly increased the risk of local recurrence or metastases. Several studies and case series on this matter have since been published, urging us to redo a systematic review General discussion, implications and future perspectives | 173

and meta-analysis, this time according to Cochrane standards. The results of this study in Chapter II show that, based on data from 781 patients across 18 studies, there is very uncertain evidence of intralesional surgery being as effective as wide resection. Despite the methodological limitations of the conducted studies, we were able to reconstruct a recurrence-free survival (RFS) curve for 115 individual patients. RFS was comparable between groups, with 94% in the intralesional (curettage) group versus 96% in the wide resection group (p = NS). Thus on the one hand evidence is of very low certainty, but best available evidence suggests that oncological outcome after curettage for ACT in the long bones is excellent. This raises some concerns on the grounds to take clinical decisions on. Considering the low incidence rate of ACT and the very low incidence rate of events of local recurrence, it is not feasible to design a randomised controlled trial to solve this matter (Chapter II). The feared upgrade of tumour was seen in only 0.5% of all study participants. They were treated with second surgery, and only two patients (0.26%) died due to disease. Leerapun et al. describes two cases of death from pulmonary metastases after a local recurrence.9 One should realise that upgrading of local recurrences could also be a misinterpretation of events. As mosaicism exists within chondroid tumour, grade-II tumours could have been falsely diagnosed as lower-grade tumours.10 As a consequence, upgrading of tumour is not a result of local recurrence, but local recurrence takes place since it was a higher-grade tumour from the beginning. This could be exactly the case in the previously mentioned paper: one patient developed a local recurrence showing dedifferentiated chondrosarcoma just four months after curettage of an ACT and died within nine months. Considering 7 the rather benign tumour biology and slow-growing nature of nearly all other ACTs we found in literature, it is quite imaginable for the tumour to have been understaged in first place. The same is true for the other patient, who was treated by wide resection since it was a lytic lesion with soft-tissue extension. These signs are more suggestive of a higher- grade tumour rather than reassuring features of an ACT.3 The fact that local recurrences developed only in the years shortly after the index procedure (which was also seen in our own centre, as reported in Chapter III) suggests that those were in fact residual tumours. Given that MRI was not as widely available back then, the tumours could have been easily missed and only brought to light once they became visible on conventional X-rays. Considering the time frame of local recurrences in our review, one could propose limiting follow-up to five years after surgery if G-MRI remains negative for tumour activity. This 174 | Advances of treatment in atypical cartilaginous tumours

is supported by a recent paper by Verdegaal et al. that was able to classify postoperative G-MRI studies and stratify patients for re-intervention, intense follow-up or moderate follow-up.11 It should be noted that they also advise routinely scanning all patients 10 years after index surgery, which might be defensive and open for discussion. Hence although all the evidence has very low certainty, it is defendable to say that ACT runs quite a benign course. The complication rates of more extensive surgery – as described below – are therefore not acceptable in terms of ‘life over limb’.

SURGICAL TECHNIQUES AND ITS BURDENS

Wide resection has high morbidity, as 23% of patients experienced major complications like nerve injury, infection, fracturing and implant loosening (Chapter II). This is reflected in the Musculosketal Tumour Society (MSTS) scores, which were significantly and remarkably lower in those patients treated with more extensive surgery. Although these scores could be at risk for performance bias to some extent (as they are ‘doctor’s scores’), one would think that a patient who underwent joint- and bone-preserving surgery performs better than one who did not. As most data from papers that published on wide resection are somewhat archaic, and in the light of the sound oncological outcome of patients with ACT in the long bones, this technique can be deemed obsolete in the absence of radiological signs of higher-grade malignancy. Even less invasive surgery like curettage has its own morbidity rates, and postoperative fracturing does occur. In our own centre 10% of patients had fractures, leading to at least one additional operation. 7 Prophylactic hardware stabilisation might lower this chance and is widely applied, but has disadvantages such as increased infection risk, limited visibility of local recurrence or residue, and hardware complaints (Chapter III). These problems were not only encountered by our group but were also seen in other studies.12-14

PERIOPERATIVE GUIDANCE

If one opts for intralesional surgery, perioperative navigation should ideally be precise, able to give 3D feedback, and harmless to the patient and operating theatre employees. Fluoroscopy is traditionally used as preoperative guidance, but has the drawbacks that only 2D imaging is possible and uses ionising radiation. Computer-assisted surgery (CAS) does not have these disadvantages but is supposed to be time-consuming.15-16 However, in our retrospective study (Chapter IV) we were able to demonstrate that operating times General discussion, implications and future perspectives | 175

were equal regardless of the imaging technique used. We did not experience setup-related problems like pin-tract infections or fractures. This did not have a significant impact on patient outcome, but it should be noted that only lesions that are easy to access were treated since we were gaining experience with the CAS system. Moreover, the study was underpowered, considering the low incidence of local recurrences. Our findings support the use of computer navigation on a more structural basis in oncologic orthopaedics. Farfalli et al. studied the use of computer guidance in locally aggressive tumours. They found that CAS-guided en bloc resection showed no recurrences except for two patients in the curettage group (one ABC and one GCT), while baseline characteristics, functional outcome and complication rates were alike.17

PART II

Considering the relatively mild nature of ACT in the long bones and the drawbacks of surgery, less invasive treatment might add an option for the treating physician. We reckoned radiofrequency ablation (RFA) as most suitable, since there is considerable experience with this tool in bony lesions such as osteoid osteoma. Complications are rare, it is relatively cheap, and it can be performed in day care. The use of RFA for ACT in the long bones was prospectively evaluated in Chapters V and VI. Complete eradication of tumour cells was achievable according to our first results. However, the 7 initial efficacy rate was only 45%, which was worrisome in our opinion. After careful evaluation we hypothesised that there were three main predictors of failures: (1) number and total ablation time of cycles, (2) size of the tumour (> 30 mm) and (3) the heat sink effect. For that reason, we slightly adjusted our ablating protocol by delivering more local energy. We prolonged the duration of the ablation procedure and/or placed multiple needles in tumours > 30 mm. Although the main element of success could not be identified, we saw primary efficacy rates rising to 71%, and complete failures dropping from 30% to 8% (Chapter VI). It is not feasible to relate our results to others, as only one published study used RFA to treat small (<10 mm) residues of ACT after curettage.18 In terms of functional outcome, there was a rapid return to normal activities after RFA, as opposed to lower MSTS scores after curettages in the first 12 weeks. Additionally, all 176 | Advances of treatment in atypical cartilaginous tumours

RFA procedures could be done in day care, while curettage involved a 3-5-day hospital admission. Fractures occurred twice after curettage and once after RFA. It cannot be said that thermal ablation preceded the fractures after curettage, but the fracture rate was in correspondence with the literature.19 The effects of RFA on the mechanical properties of bone nonetheless remain a concern for future research.

IMPLICATIONS AND FUTURE PERSPECTIVES

As shown in Chapter II, intralesional treatment of ACT in the long bones could be considered the gold standard, with wide resection reserved for doubtful cases only. Only four cases out of 781 patients (0.5%) demonstrated evolution towards a higher-grade tumour, hardly hampering patient survival: we found that only 0.26% of patients died due to disease, and those might have been higher-grade tumours from the beginning – therefore with careful patient selection, curettage is a safe treatment option. ACT has been notorious for correct diagnosis, with the risk of overstaging or understaging. As previously pointed out, understaging seems less of a concern nowadays. However, overstaging could still be a factor to reckon with, since harmless enchondromas might have also been operated on.20 In our own case series of intralesional treatment (Chapter III) there was still a considerable number of serious complications. Hence the adage better 7 safe than sorry might not be exactly true for ACT, as occasionally the cure might be worse than the disease. With this in mind, we deemed that development of other treatment strategies is needed. Although we could not demonstrate advantages of the use of CAS in terms of local control (Chapter IV), 3D planning and executing techniques might still be of relevance if more challenging sites are treated. In line with our conviction that further polishing of the treatment regime is needed, some argue that active surveillance could be the treatment of choice. Deckers et al. retrospectively analysed 49 cases of enchondroma and ACT that were treated conservatively.21 Only 6% of patients eventually needed surgery, underscoring that overtreatment is possible if one operates in all cases. Although these are appealing figures, this was also a retrospective study, presumably blurred by selection bias to some extent. General discussion, implications and future perspectives | 177

Considering the current absence of clear criteria, or when a patient opts for surgery at his own request, less invasive procedures might be a valuable adjunct to current practices. RFA is not a new technique, and indications of its usage have increased over time, also in the field of orthopaedic oncology. It is considered to be a safe technique, with only fracturing and burning wounds reported anecdotally. Local tumour ablation by RFA has the advantage that it can be performed in day care, improves short-term function, and can be safely monitored by MRI (Chapters V and VI). Since we have only analysed the effect on short notice, future research should focus on prospective long-term outcome and improving ablating techniques with real-time monitoring and 3D positioning techniques. All in all, treatment of ACT remains controversial, but this thesis has added valuable data to the debate: curettage seems safe for chondroid tumours that lack signs of higher-grade malignancy on MRI. Local recurrence after surgery might be actual residue and can be detected by MRI, so follow-up can be limited if signs of residue are absent. Undertreatment does not seem to be a concern nowadays, but there is the risk of overtreatment, which unnecessarily exposes patients to the burdens of surgery. For that reason, when opting for intervention minimally invasive treatment by RFA might add a valuable adjunct to current practice. With the right execution it is an effective treatment tool that can be performed in day care with no negative effect on functional outcome and low complication rates. A conservative approach towards ACT was outside the scope of this thesis, but is an interesting strategy that needs further prospective investigation. To find definitive answers, it is a must for clear criteria to be developed: if we want to get 7 directions, we want to know where we are starting.22,23 It is of the utmost importance that any research in this field be conducted in a multicentre, multinational setting. In this way, patients and doctors are provided with the best evidence available to balance their considerations and choose the best possible treatment strategy. 178 | Advances of treatment in atypical cartilaginous tumours

REFERENCES

1. Skeletal Lesions Interobserver Correlation among Expert Diagnosticians (SLICED) Study Group. Reliability of histopathologic and radiologic grading of cartilaginous neoplasms in long bones. J Bone Joint Surg Am. 2007 Oct;89(10):2113-23. 2. Brown MT, Gikas PD, Bhamra JS, Skinner JA, Aston WJ, Pollock RC, Saifuddin A, Briggs TW. How safe is curettage of low-grade cartilaginous neoplasms diagnosed by imaging with or without pre-operative needle biopsy? Bone Joint J. 2014 Aug;96-B(8):1098-105 3. Douis H, Singh L, Saifuddin A. MRI differentiation of low-grade from high grade appendicular chondrosarcoma. Eur Radiol. 2014 Jan;24(1):232-40. 4. Chung BM, Hong SH, Yoo HJ, Choi JY, Chae HD, Kim DH. Magnetic resonance imaging follow-up of chondroid tumors: regression vs. progression. Skeletal Radiol. 2018 Jun;47(6):755-761. 5. Mulligan ME. How to Diagnose Enchondroma, Bone Infarct, and Chondrosarcoma. Curr Probl Diagn Radiol. 2018 Apr 6 6. Schwab JH, Wenger D, Unni K, Sim FH. Does local recurrence impact survival in low-grade chondrosarcoma of the long bones? Clin Orthop Relat Res. 2007 Sep;462:175-80. 7. Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH, et al. The clinical approach towards chondrosarcoma. Oncologist 2008 Mar;13(3):320-9. 8. Hickey M, Farrokhyar F, Deheshi B, Turcotte R, Ghert M. A systematic review and meta- 7 analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. Ann Surg Oncol. 2011 Jun;18(6):1705-9. 9. Leerapun T, Hugate RR, Inwards CY, Scully SP, Sim FH. Surgical management of conventional grade I chondrosarcoma of long bones. Clin Orthop Relat Res 2007 Oct;463:166- 7 10. Laitinen MK, Stevenson JD, Parry MC, Sumathi V, Grimer RJ, Jeys LM. The role of grade in local recurrence and the disease-specific survival in chondrosarcomas. Bone Joint J. 2018 May 1;100-B(5):662-666. 11. Verdegaal SH, van Rijswijk CS, Brouwers HF et al. MRI appearances of atypical cartilaginous tumour/grade I chondrosarcoma after treatment by curettage, phenolisation and allografting: recommendations for follow-up. Bone Joint J. 2016 Dec;98-B(12):1674-1681. General discussion, implications and future perspectives | 179

12. Aarons C, Potter BK, Adams SC, Pitcher JD Jr, Temple HT. Extended intralesional treatment versus resection of low-grade chondrosarcomas. Clin Orthop Relat Res. 2009 Aug;467(8):2105-11. 13. Campanacci DA, Scoccianti G, Franchi A et al. Surgical treatment of central grade 1 chondrosarcomaof the appendicular skeleton. J Orthopaed Traumatol 2013;14:101-107. 14. Etchebehere M, de Camargo OP, Croci AT, et al. Relationship between surgical procedure and outcome for patients with grade I chondrosarcomas. Clinics (Sao Paulo) 2005;60:121-6. 15. Kahler D. Image guidance: fluoroscopic navigation. Clin Orthop. 2004: 70-76. 16. Saidi K. Potential use of computer navigation in the treatment of primary benign and malignant tumors in children. Current reviews in musculoskeletal medicine. 2012: 1-8. 17. Farfalli GL, Albergo JI, Piuzzi NS, Ayerza MA, Muscolo DL, Ritacco LE, Aponte- Tinao LA. Is Navigation-guided En Bloc Resection Advantageous Compared With Intralesional Curettage for Locally Aggressive Bone Tumors? Clin Orthop Relat Res. 2018 Mar;476(3):511-517 18. Verdegaal SH, Brouwers HF, van Zwet EW, Hogendoorn PC, Taminiau AH. Low-grade chondrosarcoma of long bones treated with intralesional curettage followed by application of phenol, ethanol, and bone-grafting. J Bone Joint Surg Am 2012 Jul 3;94(13):1201-1207. 19. Dierselhuis EF, Goulding KA, Stevens M, Jutte PC. Cochrane Review: Intralesional treatment versus wide resection for central low grade chondrosarcoma of the long bones (sumitted) 20. Douis H, Parry M, Vaiyapuri S, Davies AM. What are the differentiating clinical and MRI-features of enchondromas from low-grade chondrosarcomas? Eur Radiol. 2018 7 Jan;28(1):398-409 21. Deckers C, Schreuder BH, Hannink G, de Rooy JW, van der Geest IC. Radiologic follow- up of untreated enchondroma and atypical cartilaginous tumors in the long bones. J Surg Oncol. 2016 Dec;114(8):987-991 22. Aboulafia A. If you don’t know where you’re starting from, you can’t get directions: Commentary on an article by Morteza Meftah, MD, et al.: “Long-term results of intralesional curettage and cryosurgery for treatment of low-grade chondrosarcoma”. J Bone Joint Surg Am. 2013 Aug 7;95(15):e112 23. Anderson ME, Wu JS, Vargas SO. CORR (®) Tumor Board: Do Orthopaedic Oncologists Agree on the Diagnosis and Treatment of Cartilage Tumors of the Appendicular Skeleton? Clin Orthop Relat Res. 2017 Sep;475(9):2172-2175.

CHAPTER VIII

Summary 182 | Advances of treatment in atypical cartilaginous tumours

SUMMARY

Primary bone tumours are rare entities in oncology, with a widespread range of aggressiveness, localisation, age of onset and treatment regimes. Chondrosarcoma (CS) is the third most common primary bone malignancy, whose atypical cartilaginous tumours (ACT) are the most benign in terms of local aggressiveness, metastatic potential and patient survival. Chondrosarcoma was historically regarded as a true malignancy when it was named low-grade or grade I CS. In 2013, the World Health Organization renamed it ACT and from then on was deemed as a tumour of borderline malignant potential. Chapter I describes tumour characteristics, clinical considerations and treatment options, postulates subsequent research questions, and presents the outline of this thesis.

Chapter II reviews literature on the outcome of intralesional treatment versus wide resection of chondrosarcoma grade I in the long bones. In a Cochrane study we included 781 participants from 18 studies and were able to extract patient data from 511 participants in 14 studies. In a Cochrane review across seven studies with 238 patients and a minimal follow-up of two years we demonstrated that there was no significant difference in recurrent free survival (RFS) between intralesional treatment and wide resection. A Kaplan-Meyer curve based on individual patient data from 115 participants showed a 94% (intralesional) to 96% (wide resection) RFS after a follow-up of maximum 300 months, with no significant differences between the treatment groups. In only 0.5% of all cases was a higher-grade tumour found in a later stage, and only two patients (0.26%) died from the disease in the analysed studies. Based on three studies, 8 functional outcome as measured by the musculoskeletal tumour society (MSTS) score was significantly better after intralesional treatment (mean score 93%) versus resection (mean score 78%). Occurrence of major complications (e.g. fracture or wound infection) was significantly lower after curettage.

Our own results for intralesional treatment of ACT in the long bones are analysed in Chapter III. In a retrospective cases series including 108 patients we found a 95.4% disease-free survival after a mean follow-up period of 48.7 months. Tumours up to 100 cm3 were treated by curettage and adjuvant phenolisation, and in only five patients was Summary | 183

residual tumour suspected. One patient persisted on second surgery; all others could be monitored closely with no evidence of tumour growth over time. Complications occurred in 14.8% of patients, predominantly fractures needing additional surgery. A total of 20 reoperations due to complications had to be performed in 12 patients (11%). We found no correlation between tumour size and risk of local recurrence or of complications.

To see whether computer-assisted surgery (CAS) is of value in the treatment of ACT, patients that had been treated using either CAS or fluoroscopy guidance were studied in a retrospective comparison (Chapter IV). In a study with 77 patients (fluoroscopy n = 60 vs CAS n = 17) we did not find significant differences in terms of residual tumour (2/17 vs 6/60), fracture rate (3/17 vs 6/60) or surgical time (1.26h vs 1.34h). Hence, although the value of CAS in terms of oncological outcome remains uncertain, we did not encounter longer operation durations or procedure-related complications like pin tract infections. CAS can be a safe alternative imaging modality for curettage of ACT.

We prospectively reviewed 20 patients in a proof-of-principle study using radiofrequency ablation (RFA) for treatment of ACT (Chapter V). We developed a sequence that enabled us to directly study the effect of RFA on the tumour tissue in patients without withholding standard care from them: after inclusion, patients underwent CT-guided biopsy of the tumour, directly followed by an RFA procedure. Three months later, a gadolinium-enhanced MRI (G-MRI) was made to assess the post-ablation effect. Material retrieved from the subsequent operation could thereby be directly related to the G-MRI images, and its sensitivity and specificity calculated. We graded the tumour response both on imaging and on histology as complete (R0), near-complete (R1) or incomplete (R2). Histological analysis demonstrated that >95% of tumour necrosis 8 was achieved in 70% of cases, with 9/20 cases showing complete tumour eradication. G-MRI had a 91% sensitivity to detect residual tumour and a negative predictive value (NPV) of 86%. Besides the ablation efficacy, we also inquired about functional outcome by assessing MSTS scores after RFA and curettage and checking for complications. On a 0-to-30-point scale, MSTS scores were 27.1 (23 to 30) versus 18.1 (12 to 25) six weeks after RFA and curettage respectively. Twelve weeks after the procedures the differences between the groups narrowed, yet were still significant (27.2 vs 22.9). No adverse events were seen after RFA. A pathological fracture occurred in two patients after curettage, 184 | Advances of treatment in atypical cartilaginous tumours

requiring additional surgery. This study proved the safety and efficacy of RFA in ACT treatment, making the next step possible.

After evaluating the results of our pilot study we slightly adjusted our treatment protocol and prospectively studied it in 24 patients in Chapter VI. Inclusion criteria were similar, but we added an extra run to the ablation procedure and used multiple needle positions when the tumour was >30 mm. We found an increase to 71% of complete necrosis after ablation, and only 8% obvious failures. One fracture occurred after RFA, but no other complications were seen. Five out of six tumours exceeding 30 mm in diameter showed full response when treated with multiple needles.

In short, based on the best available literature, in this thesis we found that intralesional treatment is oncologically safe and superior to wide resection in terms of functional outcome and complication rates for ACT in the long bones. The results of curettage in our own hands were comparable to literature, with the role of computer-assisted surgery for this type of surgery still unknown. Radiofrequency ablation was studied as an alternative to curettage, with promising results in terms of tumour eradication, preservation of function and quick return to daily activities. Optimisation of the RFA procedure, especially intraoperative monitoring of position, temperature and ablation zone, and definitive outcome after adequate follow-up remain subjects of future research.

8 Summary | 185

CHAPTER IX

Nederlandse samenvatting 188 | Advances of treatment in atypical cartilaginous tumours

SAMENVATTING

Sarcomen zijn een zeldzame vorm van kanker die jaarlijks bij 1% van de nieuwe patiënten met kanker wordt gediagnosticeerd. In Nederland wordt er per jaar bij circa 150 patiënten een primaire kwaadaardige bottumor geconstateerd. Van deze bottumoren is het chondrosarcoom (CS) het op twee na meest voorkomend, en wordt vooral gevonden bij personen tussen hun 40e en 70e levensjaar. Chondrosarcomen bestaan uit kraakbeenmatrix producerende cellen en komen in verschillende varianten voor. De atypische cartilagineuze tumor (ACT) is hiervan een veel voorkomende tumor en wordt steeds vaker als toevalsbevinding gezien door het stijgende aantal MRI-scans en CT-scans dat verricht wordt. Voorheen werd deze afwijking als kwaadaardigheid beschouwd (CS graad I) maar sinds de naamswijziging in 2013 naar ACT door de Wereldgezondheidsorganisatie wordt deze nu gedefinieerd als een tumor met borderline kwaadaardige eigenschappen. Uitzaaiing van ziekte en overlijden van ziekte zijn zeer zelden beschreven, maar de tumor kan wel lokaal agressief zijn. In het verleden vond men deze tumor lastig te onderscheiden van meer kwaadaardige kraakbeentumoren. Bovendien zijn er ook casus bekend waarbij na een operatie de tumor terugkwam in een hogere gradering, met uitzaaiingen en overlijden tot gevolg. Om die redenen was men eerder vrij agressief wat betreft de behandeling van het ACT en werden grote operaties uitgevoerd tot amputaties aan toe. De laatste twee decennia is er echter steeds meer een tendens om deze tumoren alleen te behandelen met curettage. Hierbij wordt via een klein luikje in het bot het tumorweefsel uit het gezonde weefsel geschraapt, om zo verdere groei van de tumor te voorkomen. Na de curettage wordt er ook nog regelmatig gebruik gemaakt van aanvullende technieken (zoals bevriezen of etsen met fenol) om zo zeker mogelijk alle tumorcellen te bestrijden. Alhoewel dit tot minder functieverlies leidt dan grotere operaties en er ook minder complicaties voorkomen, hebben ook deze ingrepen 9 aanmerkelijke morbiditeit die mogelijk niet tegen de ziektelast van ACT opwegen. Een minder invasieve behandeling is dus misschien aangewezen, zoals die ook wordt gebruikt bij de behandeling van goedaardige botafwijkingen (osteoïd osteoom). Radiofrequente ablatie (RFA) is een techniek waarbij een naald door de huid in het bot wordt geprikt en de tumor door hitte wordt behandeld. Dit is een techniek die ook regelmatig bij andere kankersoorten (zoals leverkanker of niercelkanker) wordt toegepast en staat Nederlandse samenvatting | 189

bekend als een goedkope, precieze en veilige behandelmethode. Een voordeel is dat het in dagbehandeling verricht kan worden en het bot sneller belastbaar is. Doelen van dit proefschrift waren om de resultaten van de operatieve technieken die tot nu toe gebruikt worden te analyseren, en om de nieuwe techniek met RFA te onderzoeken. Om die reden was dit proefschrift uitgesplitst in twee delen.

DEEL I

In Hoofdstuk II hebben we een Cochrane systematische review uitgevoerd van de literatuur betreffende intralesionale behandeling (curettage) versus wijde resectie van ACT/CS-I in de lange pijpbeenderen. In totaal konden we 18 studies includeren met 781 patiënten. Hiervan konden we bij 419 patiënten uit 14 studies de patiëntdata verkrijgen. Uit de meta-analyse van 238 patiënten uit zeven studies bleek dat er geen verschil was in recurrence free survival (RFS) tussen wijde resectie en curettage (risk ratio (RR) 0.98; 95% betrouwbaarheidsinterval (CI) 0.92 – 1.04). Complicaties beschreven in zes studies met 203 patiënten kwamen significant minder voor bij curettage (5/125) dan bij wijde resectie (18/78) (RR 0.23; 95% CI 0.10 – 0.55). Uit drie studies met totaal 72 patiënten bleek dat de functionele uitkomst uitgedrukt in de MSTS-score significant beter was na curettage (gemiddeld 93%) dan na wijde resectie (gemiddeld 78%), p<0.001). Van 115 patiënten waren we in staat om de exacte RFS te berekenen en uit te drukken in een Kaplan Meyer curve, waarbij we ook geen significant verschil vonden tussen de twee operatieve technieken na een maximale follow-up van 300 maanden (curettage = 94% en wijde resectie = 96%). Bij vier patiënten (0.5% van alle inclusies) werd een hooggradige tumor gevonden na lokaal recidief, waarvan uiteindelijk twee patiënten (0.26% van alle inclusies) zijn overleden. Kortom, curettage bij ACT leek oncologisch veilig en zorgde voor minder complicaties en betere functionele uitkomst in vergelijking met wijde resectie. De bewijslast van alle bevindingen was echter van (zeer) hoge onzekerheid, door het retrospectieve karakter van de meegenomen studies, waarbij er een grote kans was op performance, detection en reporting bias. 9

In Hoofdstuk III analyseerden we onze eigen resultaten van intralesionale behandeling van ACT in de lange pijpbeenderen. In een retrospectieve case serie met 108 patiënten vonden we een 95.4% ziektevrije overleving (geen lokaal recidief, metastase en/of overlijden) na een gemiddelde follow-up duur van 48.7 maanden. Tumoren tot 100 cm3 190 | Advances of treatment in atypical cartilaginous tumours

werden middels curettage en adjuvant fenol behandeld, waarbij bij vijf patiënten residu tumor werd vermoed. Eén patiënt wilde persé een tweede ingreep, de overige patiënten werden nauwlettend gevolgd, zonder aanwijzing voor tumorgroei in het verloop van de tijd. In 14.8% van de patiënten ontstond een complicatie, in het overgrote deel fracturen die extra operaties tot gevolg hadden. Uiteindelijk waren er 20 re-operaties als gevolg van de complicaties nodig bij 12 patiënten (11%). We konden geen verband vinden tussen de grootte van de tumor en het risico op lokaal recidief of kans op complicaties.

Om te oordelen of computer geassisteerde chirurgie (CAS) van waarde is bij de behandeling van ACT hebben we retrospectief patiënten vergeleken waarbij CAS of fluoroscopie was gebruikt bij de peroperatieve navigatie (Hoofdstuk IV). In onze studie van 77 patiënten (CAS n = 17 versus fluoroscopie n = 60) konden we geen significant verschil vinden betreffende residu tumor (2/17 versus 6/60), fractuurrisico (3/17 versus 6/60) en duur van de ingreep (1 u 26 min versus 1 u 34 min). Het gebruik van CAS zorgde dus niet voor langere operatieduur, en ook werden er geen problemen gezien zoals pin-tract infectie.

In een prospectieve studie onderzochten we bij 20 patiënten het gebruik van radiofrequente ablatie (RFA) als behandeling voor ACT (Hoofdstuk V). We ontwikkelden een studie- opzet waarbij we in staat waren direct het effect van RFA op tumorweefsel te onderzoeken, zonder de patiënten standaardbehandeling te onthouden. Na inclusie ondergingen patiënten een CT-geleid biopt gevolgd door RFA. Na drie maanden werd een MRI met Gadolinium (G-MRI) gemaakt om het ablatie effect te beoordelen. Vervolgens vond er curettage plaats van de laesie, teneinde de patiënt definitief te behandelen en het PA- materiaal te correleren aan de post-ablatie MRI-beelden. Tumor respons werd zowel histologisch als radiologisch gecategoriseerd als volledig (R0), bijna volledig (R1) of incompleet (R2). Histologisch onderzoek wees uit dat bij 70% van de patiënten er 95% of 9 meer tumor necrose was bereikt, waarvan bij 9/20 er volledige necrose te zien was. G-MRI was 91% sensitief voor residu tumor, met een negatief voorspellende waarde (NPW) van 86%. Naast de werkzaamheid van de ablatie, werd ook de functionele uitkomst na RFA en curettage middels MSTS-scores onderzocht en vóórkomen van complicaties. Op een schaal van 0 tot 30, was de score 27.1 (23 tot 30) zes weken na RFA, ten opzichte van 18.1 (12 tot 25) zes weken na curettage (p < 0.001). Twaalf weken na de procedures was Nederlandse samenvatting | 191

het verschil minder groot, maar nog steeds significant (27.2 versus 22.9; p < 0.001). Er traden geen complicaties op bij of na de RFA-procedures. Na curettage trad bij twee patiënten een fractuur op, waarvoor operatief ingrijpen nodig was.

Na evaluatie van deze eerste pilotstudie, maakten we enkele aanpassingen aan het studieprotocol, welke in 24 patiënten prospectief werd onderzocht (Hoofdstuk VI). De inclusiecriteria bleven onveranderd, echter pasten we een extra cyclus tijdens de RFA- procedure toe en werden bij tumoren groter dan 30 mm meerdere naaldposities gebruikt. We zagen een duidelijke toename naar 71% van de patiënten met een volledige respons op de RFA-behandeling, en slechts 8% incomplete behandeling. Er trad één fractuur op na RFA, verder zagen we geen andere complicaties. Vijf van de zes tumoren die groter dan 30 mm waren en met meerdere naaldposities waren behandeld lieten een volledige respons zien.

Samenvattend hebben we in dit proefschrift op basis van de best beschikbare literatuur laten zien dat intralesionale behandeling oncologisch veilig is en superieur ten opzichte van wijde resectie wat betreft functionele uitkomst en kans op complicaties bij behandeling van ACT in de lange pijpbeenderen. De uitkomst van curettage in ons eigen handen is vergelijkbaar met de huidige literatuur, waarbij de rol van computer geassisteerde chirurgie bij dit type operaties nog niet duidelijk is. Radiofrequente ablatie werd onderzocht als alternatief voor curettage, met veelbelovende resultaten wat betreft lokale tumor controle en behoud van functie en snelle terugkeer naar dagelijkse activiteiten. Het optimaliseren van de RFA-procedure, met name intra-operatieve monitoring, en de lange termijn uitkomsten van thermoablatie op ACT blijven onderwerpen van toekomstig onderzoek.

Dankwoord

List of publications

Research Institute SHARE

Curriculum Vitae 194 | Advances of treatment in atypical cartilaginous tumours

DANKWOORD

Tien jaar geleden zette ik mijn eerste onderzoekstappen binnen de orthopedie, en eindelijk is het resultaat daar! Er zijn veel mensen die me direct of indirect door de jaren heen ondersteund hebben, die ik hier graag persoonlijk wil bedanken.

Geachte prof. Bulstra, beste Sjoerd. Als mijn promotor én oud-opleider heb je de basis gelegd voor mijn academische orthopedische carrière. Je scherpe, maar vooral ook nuchtere blik heeft vaak als katalysator gewerkt van dit project. De persoonlijk benadering van de mensen om je heen, en de tomeloze inzet voor het vak straalt af op de afdeling en de opleiding, waaraan ik dan ook veel plezier heb beleefd. Ik ben blij dat je nog voor je emeritaat kan optreden als mijn promotor!

Geachte dr. Jutte, beste Paul. Na mijn junior co-schap was ik overtuigd van de orthopedie en de oncologische orthopedie in het bijzonder! Een kort mailtje was het begin van een avontuur dat met dit proefschrift een mijlpaal heeft bereikt. Ik heb ontzettend veel plezier beleefd aan onze samenwerking door de jaren heen, zowel in het onderzoek als in de kliniek, laten we deze band in de toekomst onderhouden. Een persoonlijk hoogtepunt was onze trip naar Beijing, waarbij ik vooral nog steeds heel blij ben dat je de uitbundige hoestbui in een obscure Chinees hebt overleefd!

Geachte prof. Suurmeijer, beste Albert. Dank dat je hebt aan willen sluiten als promotor en ons ondersteunt met je pathologische kijk op de zaken. De sarcoom wereld is er één van uitdagingen voor de patholoog, waarbij je vaak de vinger op de zere plek legde waar het om ging bij de laaggradige kraakbeen tumoren. Je correcties van mijn Engels waren niet mis en hebben dit proefschrift duidelijk naar een hoger niveau gestuwd!

Geachte dr. Stevens, beste Martin. De onderzoeksduizendpoot van de afdeling en daarom van grote waarde voor mijn PhD. Waar nodig stuurde je ons bij en ik heb vaak kunnen terugvallen op je routine voor het schrijven van manuscripten en dus ook uiteindelijk deze thesis. Dankwoord | 195

Ook een woord van mijn dank aan mijn andere oud-opleiders. Michiel, Paul en Kees, jullie hebben de voorwaarden gecreëerd voor mijn opleiding, waarbij ik mij kon ontwikkelen tot de professional die ik nu ben. Ik heb veel goede herinneringen aan mijn jaren in Emmen, Leeuwarden en Zwolle, en fijn dat ik de kans kreeg om qua research me vooral op mijn eigen onderzoek te richten. Dankzij de goede samenwerking tussen de heelkunde en de orthopedie in Zwolle heb ik me ook verder in de traumatologie kunnen onderdompelen, dit had niet zonder de inzet van Sven en Rutger gekund.

Al mijn oud-collegae AIOS, de opleiding maak je zelf en dankzij jullie was dit een fantastische periode. Ieder heeft zijn eigen aardigheden en alle unieke persoonlijkheden maken dit ook zo’n boeiend vak! Ik heb heel veel lol beleefd aan alle borrels en congressen, laten we dit vooral blijven doen.

Jongens van de VOCA, wat waren het twee mooie jaren! Op en neer met de trein vanuit Groningen naar Utrecht, maar elke keer was dit het weer waard! Verfrissend om uit den lande te horen wat er allemaal speelt en deze unieke tijd was goud. Details kan ik voor ons allemaal beter niet noemen, maar ik vind het mooi om te zien dat Sergio en Katja nog steeds de rode draad vormen van het huidige bestuur.

Uiteraard ook heel veel dank aan mijn collega’s van de staf Orthopedie van het Radboudumc. Marinus, Maarten, Wim, Bart, Allard, Micha, Ingrid, Wim, Sebastiaan, Arno en Martin: jullie zijn een super team om mee te werken. We zetten allemaal onze schouders onder onze mooie afdeling. We hebben een stevige basis en een duidelijke missie waar we komende jaren verder aan kunnen bouwen. Als fellow voelde ik mij al snel onderdeel van de afdeling en ik prijs mezelf erg gelukkig hier nu vast onderdeel van uit te maken. Petra, Nelleke en Renate, jullie zijn van onschatbare waarde voor onze staf en hopelijk krijgen jullie vaak genoeg onze waardering die jullie toebehoort.

Heren traumatologen van de heelkunde, Michael, Jan, Vincent, Jan-Paul, Edward, Joost, Bas, Erik en Erik, onze samenwerking krijgt steeds meer vorm en het jaarlijkse kerstdiner is nu al een klein hoogtepunt. Laten we zorgen dat deze band alleen maar sterker wordt, en dat onze afdelingen elkaar nog vaker vinden, in de kliniek en binnen het onderzoek. 196 | Advances of treatment in atypical cartilaginous tumours

Alle disciplines die bij het Radboudumc expertise centrum sarcomen betrokken zijn: onze patiënten zijn op de juiste plek dankzij al jullie inspanningen. Hans en Han, Christel, Ingrid en Suzanne, Jacky en Marieke, Uta en Pètra en Marian, dank voor al jullie input, vergaderdiscipline en overwegingen tijdens ons wekelijks overleg. Het centrum heeft zijn waarde bewezen, maar laten we in beweging blijven om tot nog betere zorg te komen.

Ons team kan niet zonder haar vaste OK-medewerkers en verpleegkundigen op de poli en afdeling, jullie bepalen voor een groot deel het werkplezier! Als “buitenstaander” en jonge klare kwam ik in een warm bad, wat de start van mijn carrière als medisch specialist zeker makkelijker heeft gemaakt.

Deze veeleisende baan vraagt ook om momenten van ontlading en ik ben blij met de vriendenkring waarbij ik uit kan blazen. Joost en Diederik, als grootste maten van de JC kan ik niet eens verzinnen hoeveel we samen hebben meegemaakt. Van de pistes in Crans, tot op de Friese wateren of (in) de Prinsengracht, het is altijd een groot feest. Ondanks onze carrières en gezinnen zijn we weer die kleine jongens als we samen zijn.

Na een mooie studententijd in Groningen, zijn daar ook in de jaren daarna mooie vriendschappen ontstaan. Deze had zijn wortels tijdens de co-schappen in Zwolle en alle avonden op het podium in de discotheek (jullie weten wel welke). Michael en Janine, Sophie en Warner, Ianthe en Thomas en Ed, zo langzamerhand waaieren we steeds meer uit over het land, maar laten we minstens één keer per jaar naar het vaste honk terugkeren.

Er zijn weinig mensen die je beter leren kennen dan je oud-huisgenoten. Beste Mark, als alleroudste oud-huisgenoot hebben we een bijzondere vriendschap. Wel en wee hebben we gedeeld, en ik vind het erg bijzonder dat we deze band nog steeds hebben. En dan mijn twee paranimfen: Beste Ysbrand, koning van de filmweetjes, maar je bent gelukkig veel meer dan dat. In Zwolle hebben we een jaar de tijd van ons leven gehad en het was natuurlijk ook in die tijd dat je Martzen hebt ontmoet. Jouw promotie is alweer even geleden en ik ben blij dat je me vandaag bij wilt staan. Beste Michael, wat begon als tutor genootje en busmaat naar Mannheim leidde tot een roerig bestaan aan de Oostersingel. Martin zou jaloers zijn op jouw levensstijl, maar met Marjan heb je de vrouw van je Dankwoord | 197

leven gevonden. Je bent een multitalent dat veel verder gaat dan de psychiatrie en ik ben bijzonder trots dat jij hier ook vandaag naast me staat.

Net zoals vrienden onmisbaar zijn, is familie dat ook. Lieve Miranda, daar staat je broertje dan vandaag! Twee gepromoveerd medisch specialisten die op de plek zitten die ze ambiëren, wat willen we nog meer? Met Luc, Cas en Roos heb je een hecht gezin, die je thuis tot rustpunt maken. Ik heb bewondering voor je gedrevenheid en we hebben de gezamenlijke eigenschap dat we niet opgeven voordat onze doelen bereikt zijn.

Lieve pappa en mamma, ik ben trots dat ik vandaag als jullie zoon hier sta. Dank voor alle steun die jullie me altijd hebben gegeven en een opvoeding waar ik als dokter nog dagelijks van profiteer. Ruimte geven en loslaten is niet altijd makkelijk (snap ik nu als ouder) maar dankzij jullie heb ik mij ten volle kunnen ontwikkelen. Integriteit en authenticiteit zijn twee kernwaarden die ik van jullie meegekregen heb, en deze zijn onbetaalbaar.

Lieve schoonouders en schoonfamilie, niets is te gek voor jullie en hoewel de afstand iets groter is geworden maken we nog graag van jullie gebruik als oppas. Beau is altijd dolenthousiast om met Femke te spelen, en met kleine Thom zal dat niet anders zijn!

Beau, je hebt (gelukkig) geen idee waar pappa druk mee was achter de computer, maar hopelijk kan je later een beetje trots op me zijn. Ik ben ieder geval nu al trots op jou, en ontzettend nieuwsgierig hoe dit prachtige ventje zich in de toekomst gaat ontwikkelen!

En dan mijn allerliefste Helma, wat ben ik blij dat je in mijn leven gekomen bent. Er zijn weinig mensen die zo zichzelf zijn en ik kan ook volledig mezelf zijn bij jou. Het boekje is nu eindelijk klaar en met onze vaste stek hoop ik dat we nu ook meer rust hebben als gezin. Dat het na mijn promotie minder druk gaat worden is natuurlijk een illusie, maar ik zal voor een betere balans zorgen zodat je mijn tijd en liefde die je toebehoort nog veel vaker krijgt. Jouw steun en liefde de afgelopen jaren betekenen alles voor mij, het leven met jou is een feestje dat we vanavond zeker gaan vieren. 198 | Advances of treatment in atypical cartilaginous tumours

LIST OF PUBLICATIONS

Dierselhuis EF, Jutte PC, van der Eerden PJ, Suurmeijer AJ, Bulstra SK. Hip fracture after radiofrequency ablation therapy for bone tumors: two case reports. Skeletal Radiol. 2010 Nov;39(11):1139-43.

Dierselhuis EF, Maathuis PGM. Conservative treatment of a pathological fracture in a 3-year-old boy with primary hyperoxaluria type I. J Pediatr Orthop B. 2013 Mar;22(2):175- 7

Dierselhuis EF, van den Eerden PJ, Hoekstra HJ, Bulstra SK, Suurmeijer AJ, Jutte PC. Radiofrequency ablation in the treatment of cartilaginous lesions in the long bones: results of a pilot study. Bone Joint J. 2014 Nov;96-B(11):1540-5

Dierselhuis EF, Gerbers JG, Ploegmakers JJW, Stevens M, Suurmerije AJH, Jutte PC. Local treatment with adjuvant of central atypical cartilaginous tumors in the long bones: Analysis of outcome and complications in 108 patients with a minimum follow-up of two years. J Bone Joint Surg Am. 2016 Feb 17;98(4):303-13

Gerbers JG, Dierselhuis EF, Stevens M, Ploegmakers JJW, Bulstra SK, Jutte PC. Computer assisted surgery for curettage of atypical cartilaginous tumors / chondrosarcoma grade 1 in the long bones compared to fluoroscopic guidance. PLoS One. 2018 May 17;13(5)

Dierselhuis EF, Goulding KA, Stevens M, Jutte PC. Intralesional treatment versus wide resection for central low-grade chondrosarcoma of the long bones. Cochrane Database Syst Rev. 2019 Mar 7;3 List of publications | 199

Dierselhuis EF, Overbosch J, Kwee TC, Suurmeijer AJH, Ploegmakers JJW, Stevens M, Jutte PC. Radiofrequency ablation in the treatment of atypical cartilaginous tumours in the long bones: lessons learned from our experience. Skeletal Radiol. 2019 Jun;48(6):881- 887

BOOK CHAPTER

J.G. Gerbers, E.F. Dierselhuis, P.C. Jutte. Local Tumor Ablation Using Computer- assisted Planning and Execution. Chapter 12 – Computer Assisted Muskuloskeletal Surgery, pp 151-62. ISBN 978-3-319-12943-3 200 | Advances of treatment in atypical cartilaginous tumours

RESEARCH INSTITUTE SHARE

This thesis is published within the Research Institute SHARE (Science in Healthy Ageing and healthcaRE) of the University Medical Center Groningen / University of Groningen. Further information regarding the institute and its research can be obtained from our internet site: http://www.share.umcg.nl/

More recent theses can be found in the list below. ((co-) supervisors are between brackets)

2019

Vrijen C . Happy faces and other rewards; different perspectives on a bias away from positive and toward negative information as an underlying mechanism of depression (prof AJ Oldehinkel, prof CA Hartman, prof P de Jonge)

Moye Holz DD. Access to innovative medicines in a middle-income country; the case of Mexico and cancer medicines (prof HV Hogerzeil, prof SA Reijneveld, dr JP van Dijk)

Woldendorp KH. Musculoskeletal pain & dysfunction in musicians (prof MF Reneman, prof JH Arendzen, dr AM Boonstra)

Mooyaart JE. Linkages between family background, family formation and disadvantage in young adulthood (prof AC Liefbroer, prof F Billari)

Maciel Rabello L. The influence of load on tendons and tendinopathy; studying Achilles and patellar tendons using UTC (prof J Zwerver, prof RL Diercks, dr I van den Akker-Scheek, dr MS Brink) Research Institute SHARE | 201

Holvast F. Depression in older age (prof PFM Verhaak, prof FG Schellevis, prof RC Oude Voshaar, dr H Burger)

Leving MT. Understanding the motor learning process in handrim wheelchair propulsion (prof LHV van der Woude, dr S de Groot, dr RJK Vegter)

Riethmeister V. Sleep and fatigue offshore (prof U Bültmann, prof S Brouwer, dr MR de Boer)

Maters GA. Lungs under a cloud; psychological aspects of COPD (prof R Sanderman, dr JB Wempe, dr G Pool)

Timmeren EA van. Physical health in adults with severe or profound intellectual and motor disabilities (prof CP van der Schans, prof HMJ van Schrojenstein Lantman-de Valk, prof AAJ van der Putten, dr A Waninge)

Berghuis KMM. Age-related changes in neural plasticity after motor learning (prof T Hortobayi, prof G Koch, dr CAT Zijdewind)

Ploegmakers JJW. Grip on prognostic factors after forearm fractures (prof SK Bulstra, dr CCPM Verheyen, dr B The)

Sas AA. (Genetic) epidemiology of inflamation, age-related pathology and longevity (prof H Snieder, dr H Riese)

Joustra ML. Similar but different; implications for the One versus Many Functional Somatic Syndromes Discussion (prof JGM Rosmalen, prof SJL Bakker, dr KAM Janssens)

Nandi T. Neural control of balance in increasingly difficult standing tasks (prof T Hortobagyi, prof BE Fisher, dr CJM Lamoth, dr GJ Salem)

For earlier theses visit our website 202 | Advances of treatment in atypical cartilaginous tumours

CURRICULUM VITAE

Edwin Dierselhuis was born on November 4th 1983 in Rotterdam. He grew up in Soest, where he attended de Nieuwe Baarnsche School and Gymnasium at Het Baarnsch Lyceum. After finishing high school in 2002, he first went to the Technical University Delft to study Marine Engineering. After an eventful year, he decided to study Medicine at the Rijksuniversiteit Groningen in 2003. During his student years he employed many extracurricular activities with several board memberships, working as a student assistant for organ transplantation, but also in scientific research. During his rotations at the Department of Orthopaedic Surgery of the University Medical Center Groningen in 2008, he was gripped by the oncologic orthopaedics, which resulted in several research projects, and finally this thesis. During his clerkships, he also went to the Oncological Department of the Rizzoli Institute in Bologna, Italy. After graduation in 2010, he started working as a resident not-in-training at the University Medical Center Groningen and Orthopedisch Centrum Oost-Nederland (OCON). By the end of 2011, he started with his training for general surgery at the Treant zorggroep (supervisor dr. M. van den Berg), after which he completed his orthopaedic surgical training at Medisch Centrum Leeuwarden (supervisor: dr. P.C. Rijk), Isala klinieken (supervisor: dr. C.C.P.M. Verheyen) and University Medical Center Groningen (supervisor: prof. dr. S.K. Bulstra). At the end of his residency he went back to Isala klinieken for an internship in traumatology (supervisors: dr. S.H. van Helden and dr. R.G. Zuurmond). Besides working on this thesis in those years, he also was treasurer of the Vereniging Orthopedisch Chirurgische Assistenten (VOCA). During his training years, he met his girlfriend Helma, and by 2016, their son Beau was born. After finishing his residency in 2017, he was employed at the Radboudumc, currently as consultant orthopaedic surgeon, with fields of interest oncology and traumatology. Curriculum Vitae | 203 Advances of treatment in atypical cartilaginous tumours - Edwin F. Dierselhuis 2019

Advances of treatment in atypical cartilaginous tumours

Edwin F. Dierselhuis