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Diffuse-type tenosynovial giant cell tumour: Current treatment concepts and future perspectives
European Journal of Cancer 63 (2016) 34e40
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Review
Diffuse-type tenosynovial giant cell tumour: Current treatment concepts and future perspectives Eric L. Staals a, Stefano Ferrari b, Davide M. Donati a, Emanuela Palmerini b,* a b
Orthopaedic Surgery, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy Chemotherapy, Musculoskeletal Oncology Department, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy
Received 17 November 2015; received in revised form 18 April 2016; accepted 26 April 2016
KEYWORDS Giant cell tumours; Surgical procedures; Operative; Radiography; Immunotherapy; Molecular targeted therapy
Abstract At present, the optimal treatment strategy in patients with diffuse-type tenosynovial giant cell tumour (D-TGCT) is unclear. The purpose of this review was to describe current treatment options, and to highlight recent developments in the knowledge of the molecular pathogenesis of D-TGCT as well as related therapeutic implications. Epidemiology, clinical features, and the pathogenesis of D-TGCT and the most widely used treatment modalities are described. DTGCT is a benign clonal neoplastic proliferation arising from the synovium. Patients are often symptomatic and require multiple surgical procedures during their lifetime. Currently, surgery is the main treatment for patients with D-TGCT, with relapse rates ranging from 14% to 55%. Radiosynovectomy and external beam radiotherapy have been used in combination with surgical excision or as single modalities. The finding that D-TGCT cells overexpress colonystimulating factor 1 (CSF1), resulting in recruitment of CSF1 receptor (CSF1R)-bearing macrophages that are polyclonal and make up the bulk of the tumour, has led to clinical trials with CSF1R inhibitors. These inhibitors include small molecules such as imatinib, nilotinib, PLX3397, and the monoclonal antibody RG7155. In conclusion, D-TGCT impairs patients’ quality of life significantly. The evidence that the pathogenetic loop of D-TGCT can be inhibited could potentially change the therapeutic armamentarium for this condition. Clinical trials of agents that target D-TGCT are currently ongoing. In the meantime, international registries should be activated in order to provide useful information on this relatively rare tumour. ª 2016 Elsevier Ltd. All rights reserved.
* Corresponding author: Sezione di Chemioterapia, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy. Tel: þ39 051 6366400; fax: þ39 051 6366277. E-mail addresses: [email protected] (E.L. Staals), [email protected] (S. Ferrari), [email protected] (D.M. Donati), emanuela.palmerini@ ior.it (E. Palmerini). http://dx.doi.org/10.1016/j.ejca.2016.04.022 0959-8049/ª 2016 Elsevier Ltd. All rights reserved.
E.L. Staals et al. / European Journal of Cancer 63 (2016) 34e40
1. Background The term tenosynovial giant cell tumour (TGCT) refers to a family of proliferative and inflammatory diseases of benign course arising from the synovium of joint, bursae, and tendon sheaths. The lesion can either present as a single nodule (localised form: L-TGCT), or as multiple nodules (diffuse-type: D-TGCT) along a synovial layer or tendon sheath [1e6]. While previously these tumour types were classified as pigmented villonodular synovitis or giant cell tumour of the tendon sheath, in the most recent version of the World Health Organisation classification, TGCT has been suggested to replace both designations [5]. While surgery is the mainstay of treatment for TGCT, failure is frequent, with local relapse rates of up to 50% [2,7e9]. Furthermore, repetitive surgical treatment can lead to substantial morbidity to the impacted joints and impaired quality of life. Various forms of radiation therapy have been applied in an attempt to reduce the risk of local recurrence and as an alternative to surgery, although these strategies have not been rigorously tested in large, prospective clinical studies [10,11]. Historically, conventional chemotherapeutic agents have not been proven effective in TGCT, but new drugs are under investigation for this indication, with promising preliminary results [12e15]. This paper will review treatments currently applied for D-TGCT and will discuss emerging therapeutic options that are currently under investigation. 2. Epidemiology, clinical features, and pathogenesis of TGCT The annual incidence rate for TGCT has been estimated at 1.8 cases per million people in the United States [16],
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and TGCT is equally frequent in males and females. Diagnosis usually occurs between 20 and 50 years of age [5]. D-TGCT most frequently involves the knee, hip and ankle joints. Patients generally present with pain, tenderness, swelling, or limitation of motion, and haemorrhagic joint effusions are common. At diagnosis, the symptoms are usually of relatively long duration, often spanning several years. Radiographically, most tumours present as poorlydefined periarticular masses, frequently associated with degenerative joint disease and cystic lesions in the adjacent bone [17]. By magnetic resonance imaging, giant cell tumours typically show decreased signal intensity in both T1- and T2-weighted images (Fig. 1) [18]. For many years, the pathogenesis of TGCT has been poorly understood, with a number of sources hypothesised as contributing to its development, including neoplastic, inflammatory, traumatic, metabolic, and viral pathways [19]. More recently, TGCT was found to be a clonal neoplastic process associated with specific genetic changes, frequently due to a specific translocation: t(1;2) CSF1:COL6A3. There is also typically a reactive component with proliferation and recruitment of colony-stimulating factor 1 receptor (CSF1R)expressing cells including macrophages, giant cells, and osteoclasts, in what is known as the ‘paracrine landscape effect.’[6]. 3. Current treatment strategies There are several treatment options available for DTGCT, although they have varying success rates and associated morbidity. While surgical excision is currently considered the principal treatment for DTGCT [2], there is no consensus about the most
Fig. 1. T1-weighted axial (A) and T2-weighed sagittal (B) MRI-scan showing extensive D-TGCT of the knee with a large extraarticular component and bone erosion. MRI, magnetic resonance imaging; D-TGCT, diffuse-type tenosynovial giant cell tumour.
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appropriate type of surgery. Both arthroscopic and open surgical excision are commonly used, and synovectomy can be either partial or complete. In case of severe DTGCT, complete surgical excision can be relatively invasive, occasionally requiring a total joint replacement, arthrodesis, or even amputation in extreme cases. Radiosynovectomy and external beam radiotherapy (EBR) have been used in combination with surgical excision or as a single modality treatment for D-TGCT. 3.1. Surgical excision Surgical planning for the treatment of TGCT is based on clinical and radiological presentation. The recurrence rate for L-TGCT is below 10% [20], and there appears to be little difference in disease control following use of either arthroscopic or open surgical excision. In contrast, recurrent disease is frequent with D-TGCT, and overall relapse rates range from 14% to 55% [9,21,22]. Complete surgical excision is associated with lower recurrence rates compared to partial or incomplete excision [23e26], and this is best obtained through an open approach. A systematic literature search reviewing the surgical treatment of TGCT between 1992 and 2011 found a recurrence rate of 40% after arthroscopic synovectomy, and a recurrence rate of 14% after open synovectomy for D-TGCT of the knee [20]. Although complete surgical removal of D-TGCT offers the best outcome in terms of disease control, the procedure is technically demanding, and is frequently associated with postoperative problems such as haemarthrosis, joint stiffness, and instability, leading to loss of function. Therefore, in select cases, a partial or subtotal synovectomy might be considered, although small amounts of residual disease could remain. In the knee joint, a combined arthroscopic anterior and open posterior approach has been advocated to reduce postoperative complications [27]. Alternatively, a two-stage procedure, with anterior and posterior excision at separate times (either arthroscopic-open or open-open) may reduce postoperative complications [2,25,28,29]. Secondary osteoarthritis is frequently associated with D-TGCT, and may be directly caused by the chronic inflammatory changes of the joint following repetitive intra-articular bleeding of the vascularised pathological tissue, or may occur as an indirect consequence of multiple invasive surgeries or radiotherapy treatment. Therefore, patients with D-TGCT frequently require joint replacements at a relatively young age. Some studies show a lower recurrence rate after complete synovectomy combined with total joint replacement, compared with complete synovectomy only [30,31]. An extensive exposure of the joint, as achieved in joint replacement, ensures complete debridement of the synovial membrane. In the knee, a total knee arthroplasty that often involves a constrained or even a hinged
design, combined with a total synovectomy, is a viable option that can offer a functional and painless joint. However, prostheses implanted for secondary osteoarthritis in D-TGCT show higher revision rates than those for primary osteoarthritis, and postoperative joint stiffness is relatively frequent [32]. 3.2. External beam radiotherapy The role of EBR in the treatment of D-TGCT is currently unclear. EBR has been considered as a primary treatment for inoperable disease or as an adjuvant treatment to surgery in the case of extra-articular involvement, residual disease, or persistent recurrent disease. Several studies have reported good results after a combination of synovectomy and EBR with recurrence rates of less than 20% [10,33e36]. EBR is generally applied within 3e4 months from surgery, and total doses in the range of 30e36 Gy are recommended [10,36]. Complications reported in association with EBR include skin reactions, poor wound healing, joint stiffness, sarcomatous transformation, and pathological fractures [10,37]. Therefore, EBR should not be used routinely, but only for symptomatic residual and recurrent D-TGCT, or when limb-sparing surgery is impossible. 3.3. Radiosynovectomy Radiosynovectomy is the instillation of 90-Yttrium (90Y)-labelled colloid inside the affected joint. Its use for the treatment of D-TGCT has been debated for many years. Positive results have been reported from the use of isotopic synoviorthesis as adjuvant treatment after surgical synovectomy [7,22], and a few small series have even reported good results after the use of radiosynovectomy as a monotherapy in treating D-TGCT [25]. The largest case series on radiosynovectomy included 73 patients with a new diagnosis of TGCT who were treated by open synovectomy with additional radiosynovectomy [7]. After a mean follow-up period of 4.6 years, the relapse rates were 30% for tumours located in the knees and 9% for tumours located in other locations. However, this technique has a potential risk of radionecrosis, and harmful effects on bone and joint cartilage have been demonstrated in vitro and in vivo [38e41]. Furthermore, radiosynovectomy is not indicated in cases of extra-articular disease, which is a common finding in recurrent or residual D-TGCT. 4. New therapeutic strategies Given the relatively high recurrence rates and iatrogenic morbidity associated with surgery and radiotherapy, there has recently been increased interest in alternative
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treatments such as immunotherapy and targeted therapy. The clinical application of immunotherapy, specifically tumour necrosis factor-alpha (TNFa) inhibitors, is limited to a few case reports with promising initial results. However, prospective clinical studies are required to confirm these preliminary findings, with increased patient numbers and longer follow-up times. More recently, there is raised interest in the use of targeted treatments for TGCT, such as tyrosine kinase inhibitors or monoclonal antibodies. Phase IeII studies with these compounds have demonstrated promising activity, and phase III clinical trials are currently underway. 4.1. Immunotherapy Macrophages and pro-inflammatory cytokines such as TNFa are present in the synovium of patients with TGCT [42]. According to this finding, anti-TNFa drugs, such infliximab, etanercept, and adalimumab, have been tested in patients with relapsing TGCT, with relatively good results [43e45] Kroot et al. reported on a patient with recurrent TGCT of the knee, who demonstrated clinical improvement after infliximab treatment, along with a marked reduction in macrophages and TNFa expression in the synovium [43]. Fiocco et al. described two patients with recurrent disease of the knee who responded to intra-articular injection of etanercept [45]. Knee function and disease activity improved, and a regression of knee joint synovial proliferation was confirmed by ultrasound. Similarly, Kobak described a case with good clinical and radiological response to intra-articular treatment with adalimumab [44]. With only anecdotal reports available, further studies are required to determine the role of anti-TNFa in patients with D-TGCT. 4.2. Targeted therapy In 1994, a cytogenetics study of six cases of TGCT was the first to suggest that the chromosomal region lpl1-p13 may be involved in the pathogenesis of TGCT [46]. More than 10 years later, West et al. reported that chromosomal translocations involving 1p13 are present in a majority of cases of TGCT. They further demonstrated that the gene CSF1 is located at the chromosome 1p13 breakpoint. The translocation fuses CSF1 to COL6A3 (2q35), resulting in CSF1 overexpression in many TGCT cases [6]. CSF1 gene encodes for CSF1, the ligand of CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) or CD115 (cluster of differentiation 115). CSF1R is a protein found on the cell surface which controls the production, differentiation, and function of macrophages. In TGCT the translocation involves the ligand CSF1 which is overexpressed in a
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minority of tumour cells and creates a gradient of CSF1 which attracts the CSF1R expressing cells (mostly macrophages) which comprise the bulk of the tumour. Interestingly, the tumour cells also express CSF1R. This suggests that a CSF1/CSF1R autocrine loop is involved, leading to the abnormal accumulation of non-neoplastic cells that form a tumourous mass though a ‘paracrine landscape’ effect [6,47]. It is hypothesised that CSF inhibitors may disrupt this ‘paracrine landscape’ effect, which is believed to be responsible for TGCT growth [6,47,48]. The activity of a CSF1R inhibitor in TGCT was first described by Blay et al. reporting a complete response in a 34-year-old woman with right elbow TGCT recurrence treated with imatinib [49]. Subsequently, in a retrospective series of 29 patients with advanced TGCT, encouraging activity was reported following treatment with imatinib, with one (4%) complete remission, four (15%) partial remissions, and 20 (74%) patients with stable disease [50]. Two (8%) patients had metastatic disease, and both progressed. Response evaluation was not possible in two (8%) patients due to discontinuation of treatment owing to early side-effects, consisting of febrile neutropenia and grade III oedema. A number of clinical trials are currently investigating the use of CSF1R inhibitors in patients with TGCT, including tyrosine kinase inhibitors such as nilotinib [13,51] or PLX3397 [14], or monoclonal antibodies such as emactuzumab (also known as RG7155) [12]. An inhibitor of the CSF1 ligand, MSC110, is also under investigation. These trials are still in early stages, however. Promising efficacy results have been reported in abstract form in two phase II studies of nilotinib in patients with TGCT (NCT01261429 [number of patients Z 56] and NCT01207492 [number of patients Z 17]), although final results have yet to be published for either study [13,51]. The first study reported a 93.6% progression-free survival rate at 12 weeks [13], while the other reported a 82% progressionfree survival rate at 6-months, a clinical benefit rate (best response of stable disease or better) of 47%, and an overall response rate (best response of partial response or better) of 0% [51]. A phase II study of MSC110 in patients with TGCT (NCT01643850) is still recruiting patients, and efficacy and safety data have not yet been reported [15]. Data from phase I studies with PLX3397 (NCT01004861) and emactuzumab have been recently published, demonstrating impressive activity in TGCT, with 12/23 and 24/28 patients achieving an objective response, respectively, and only one patient progressing in each series [12,14]. The toxicity of these targeted agents is usually mild. Adverse events included facial oedema, asthenia, change in hair colour, nausea, dysgeusia, and periorbital oedema [12,14]. Patients with TGCT are currently being recruited for a phase III global clinical trial of PLX3397
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E.L. Staals et al. / European Journal of Cancer 63 (2016) 34e40
(NCT02371369). In part 1 of the study, eligible participants will be assigned to either PLX3397 or placebo for 24 weeks, and assessments will be completed in week 25. Patients who complete part 1 will be eligible to advance to part 2, a long-term treatment phase in which all patients will receive open-label PLX3397 [52]. Future studies with emactuzumab, such as an international collaboration with cooperative groups to ensure appropriate recruitment in D-TGCT, are currently under development [12]. The striking difference in terms of efficacy observed between PLX3397 or RG7155 and imatinib in patients with TGCT is likely attributable to the fact that imatinib is not a particularly strong inhibitor of CSF1R [12,14,53]. Also, in a preclinical xenograft model of TGCT, imatinib blocked the CSF1R pathway and monocyte or macrophage infiltration to a lesser extent than the mouse antihuman CSF1 antibody 5H4 [54]. 5. Conclusions D-TGCT is a clonal, proliferative, and inflammatory disease of benign course. Due to its high tendency to recur, D-TGCT requires repetitive, invasive, and eventually aggressive treatments. Thus, D-TGCT has a dramatic impact on quality of life. There is a lack of high-quality studies on the treatment of this disease, and the highest level of evidence is level IV, based on retrospective case series. These case series are difficult to interpret and compare due to heterogeneous study populations, including different disease locations and subtypes, and whether the disease is primary or recurrent. Various measurements, including functional assessment, imaging evaluation, or patient satisfaction, are used to assess treatment outcomes. However, open surgical excision is currently the gold standard of treatment for D-TGCT. The evidence that the pathogenetic loop can be inhibited by different classes of drugs could potentially change the therapeutic armamentarium for D-TGCT. Clinical trials of agents that target D-TGCT are currently ongoing. In the meantime, international registries should be activated in order to provide useful information on this relatively rare tumour. The development of new CSF1R/CSF1 inhibitors represents a new avenue for the management of patients with diffuse/relapsed TGCT. However, the implementation of these new therapies in the routine setting raises specific challenges. For example, the efficacy is not easily evaluated through imaging studies, by means of monodimensional criteria (i.e. response evaluation criteria in solid tumours [RECIST]), as tumour volume is difficult to measure in a multinodular- diffuse disease, often associated with bone involvement and variable quantities of joint effusion. Clinical response (use of pain scores, functional
scales and quality of life assessments) is probably a more reliable indicator of treatment efficacy, but could be biased by secondary, permanent, degenerative changes. Furthermore, it is unclear which is the optimal treatment duration, how long the response lasts or what would happen after treatment discontinuation. Finally, it would be interesting to assess the combination of CSF1R/CSF1 inhibitors with surgery, either in the neoadjuvant or adjuvant setting. Results of current trials will help to better understand the role of these new agents and solve some of the pending issues. Conflict of interest statement ES and EP serve on the Daiichi Sankyo advisory board. SF received research support form PharmaMar, MolMed, Glaxo, Morphotek, and CytRx, received honoraria from the speakers bureau for Takeda, and serves as a consultant/is on the advisory board for Novartis, Takeda, Glaxo, and Merck. DD has no conflicts of interest to declare.
Acknowledgements Editorial assistance in the preparation of this manuscript was provided by BlueMomentum, an Ashfield Company, part of UDG Healthcare plc, and supported by Daiichi Sankyo, Inc.
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Review
Diffuse-type tenosynovial giant cell tumour: Current treatment concepts and future perspectives Eric L. Staals a, Stefano Ferrari b, Davide M. Donati a, Emanuela Palmerini b,* a b
Orthopaedic Surgery, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy Chemotherapy, Musculoskeletal Oncology Department, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy
Received 17 November 2015; received in revised form 18 April 2016; accepted 26 April 2016
KEYWORDS Giant cell tumours; Surgical procedures; Operative; Radiography; Immunotherapy; Molecular targeted therapy
Abstract At present, the optimal treatment strategy in patients with diffuse-type tenosynovial giant cell tumour (D-TGCT) is unclear. The purpose of this review was to describe current treatment options, and to highlight recent developments in the knowledge of the molecular pathogenesis of D-TGCT as well as related therapeutic implications. Epidemiology, clinical features, and the pathogenesis of D-TGCT and the most widely used treatment modalities are described. DTGCT is a benign clonal neoplastic proliferation arising from the synovium. Patients are often symptomatic and require multiple surgical procedures during their lifetime. Currently, surgery is the main treatment for patients with D-TGCT, with relapse rates ranging from 14% to 55%. Radiosynovectomy and external beam radiotherapy have been used in combination with surgical excision or as single modalities. The finding that D-TGCT cells overexpress colonystimulating factor 1 (CSF1), resulting in recruitment of CSF1 receptor (CSF1R)-bearing macrophages that are polyclonal and make up the bulk of the tumour, has led to clinical trials with CSF1R inhibitors. These inhibitors include small molecules such as imatinib, nilotinib, PLX3397, and the monoclonal antibody RG7155. In conclusion, D-TGCT impairs patients’ quality of life significantly. The evidence that the pathogenetic loop of D-TGCT can be inhibited could potentially change the therapeutic armamentarium for this condition. Clinical trials of agents that target D-TGCT are currently ongoing. In the meantime, international registries should be activated in order to provide useful information on this relatively rare tumour. ª 2016 Elsevier Ltd. All rights reserved.
* Corresponding author: Sezione di Chemioterapia, Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136, Bologna, Italy. Tel: þ39 051 6366400; fax: þ39 051 6366277. E-mail addresses: [email protected] (E.L. Staals), [email protected] (S. Ferrari), [email protected] (D.M. Donati), emanuela.palmerini@ ior.it (E. Palmerini). http://dx.doi.org/10.1016/j.ejca.2016.04.022 0959-8049/ª 2016 Elsevier Ltd. All rights reserved.
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1. Background The term tenosynovial giant cell tumour (TGCT) refers to a family of proliferative and inflammatory diseases of benign course arising from the synovium of joint, bursae, and tendon sheaths. The lesion can either present as a single nodule (localised form: L-TGCT), or as multiple nodules (diffuse-type: D-TGCT) along a synovial layer or tendon sheath [1e6]. While previously these tumour types were classified as pigmented villonodular synovitis or giant cell tumour of the tendon sheath, in the most recent version of the World Health Organisation classification, TGCT has been suggested to replace both designations [5]. While surgery is the mainstay of treatment for TGCT, failure is frequent, with local relapse rates of up to 50% [2,7e9]. Furthermore, repetitive surgical treatment can lead to substantial morbidity to the impacted joints and impaired quality of life. Various forms of radiation therapy have been applied in an attempt to reduce the risk of local recurrence and as an alternative to surgery, although these strategies have not been rigorously tested in large, prospective clinical studies [10,11]. Historically, conventional chemotherapeutic agents have not been proven effective in TGCT, but new drugs are under investigation for this indication, with promising preliminary results [12e15]. This paper will review treatments currently applied for D-TGCT and will discuss emerging therapeutic options that are currently under investigation. 2. Epidemiology, clinical features, and pathogenesis of TGCT The annual incidence rate for TGCT has been estimated at 1.8 cases per million people in the United States [16],
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and TGCT is equally frequent in males and females. Diagnosis usually occurs between 20 and 50 years of age [5]. D-TGCT most frequently involves the knee, hip and ankle joints. Patients generally present with pain, tenderness, swelling, or limitation of motion, and haemorrhagic joint effusions are common. At diagnosis, the symptoms are usually of relatively long duration, often spanning several years. Radiographically, most tumours present as poorlydefined periarticular masses, frequently associated with degenerative joint disease and cystic lesions in the adjacent bone [17]. By magnetic resonance imaging, giant cell tumours typically show decreased signal intensity in both T1- and T2-weighted images (Fig. 1) [18]. For many years, the pathogenesis of TGCT has been poorly understood, with a number of sources hypothesised as contributing to its development, including neoplastic, inflammatory, traumatic, metabolic, and viral pathways [19]. More recently, TGCT was found to be a clonal neoplastic process associated with specific genetic changes, frequently due to a specific translocation: t(1;2) CSF1:COL6A3. There is also typically a reactive component with proliferation and recruitment of colony-stimulating factor 1 receptor (CSF1R)expressing cells including macrophages, giant cells, and osteoclasts, in what is known as the ‘paracrine landscape effect.’[6]. 3. Current treatment strategies There are several treatment options available for DTGCT, although they have varying success rates and associated morbidity. While surgical excision is currently considered the principal treatment for DTGCT [2], there is no consensus about the most
Fig. 1. T1-weighted axial (A) and T2-weighed sagittal (B) MRI-scan showing extensive D-TGCT of the knee with a large extraarticular component and bone erosion. MRI, magnetic resonance imaging; D-TGCT, diffuse-type tenosynovial giant cell tumour.
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appropriate type of surgery. Both arthroscopic and open surgical excision are commonly used, and synovectomy can be either partial or complete. In case of severe DTGCT, complete surgical excision can be relatively invasive, occasionally requiring a total joint replacement, arthrodesis, or even amputation in extreme cases. Radiosynovectomy and external beam radiotherapy (EBR) have been used in combination with surgical excision or as a single modality treatment for D-TGCT. 3.1. Surgical excision Surgical planning for the treatment of TGCT is based on clinical and radiological presentation. The recurrence rate for L-TGCT is below 10% [20], and there appears to be little difference in disease control following use of either arthroscopic or open surgical excision. In contrast, recurrent disease is frequent with D-TGCT, and overall relapse rates range from 14% to 55% [9,21,22]. Complete surgical excision is associated with lower recurrence rates compared to partial or incomplete excision [23e26], and this is best obtained through an open approach. A systematic literature search reviewing the surgical treatment of TGCT between 1992 and 2011 found a recurrence rate of 40% after arthroscopic synovectomy, and a recurrence rate of 14% after open synovectomy for D-TGCT of the knee [20]. Although complete surgical removal of D-TGCT offers the best outcome in terms of disease control, the procedure is technically demanding, and is frequently associated with postoperative problems such as haemarthrosis, joint stiffness, and instability, leading to loss of function. Therefore, in select cases, a partial or subtotal synovectomy might be considered, although small amounts of residual disease could remain. In the knee joint, a combined arthroscopic anterior and open posterior approach has been advocated to reduce postoperative complications [27]. Alternatively, a two-stage procedure, with anterior and posterior excision at separate times (either arthroscopic-open or open-open) may reduce postoperative complications [2,25,28,29]. Secondary osteoarthritis is frequently associated with D-TGCT, and may be directly caused by the chronic inflammatory changes of the joint following repetitive intra-articular bleeding of the vascularised pathological tissue, or may occur as an indirect consequence of multiple invasive surgeries or radiotherapy treatment. Therefore, patients with D-TGCT frequently require joint replacements at a relatively young age. Some studies show a lower recurrence rate after complete synovectomy combined with total joint replacement, compared with complete synovectomy only [30,31]. An extensive exposure of the joint, as achieved in joint replacement, ensures complete debridement of the synovial membrane. In the knee, a total knee arthroplasty that often involves a constrained or even a hinged
design, combined with a total synovectomy, is a viable option that can offer a functional and painless joint. However, prostheses implanted for secondary osteoarthritis in D-TGCT show higher revision rates than those for primary osteoarthritis, and postoperative joint stiffness is relatively frequent [32]. 3.2. External beam radiotherapy The role of EBR in the treatment of D-TGCT is currently unclear. EBR has been considered as a primary treatment for inoperable disease or as an adjuvant treatment to surgery in the case of extra-articular involvement, residual disease, or persistent recurrent disease. Several studies have reported good results after a combination of synovectomy and EBR with recurrence rates of less than 20% [10,33e36]. EBR is generally applied within 3e4 months from surgery, and total doses in the range of 30e36 Gy are recommended [10,36]. Complications reported in association with EBR include skin reactions, poor wound healing, joint stiffness, sarcomatous transformation, and pathological fractures [10,37]. Therefore, EBR should not be used routinely, but only for symptomatic residual and recurrent D-TGCT, or when limb-sparing surgery is impossible. 3.3. Radiosynovectomy Radiosynovectomy is the instillation of 90-Yttrium (90Y)-labelled colloid inside the affected joint. Its use for the treatment of D-TGCT has been debated for many years. Positive results have been reported from the use of isotopic synoviorthesis as adjuvant treatment after surgical synovectomy [7,22], and a few small series have even reported good results after the use of radiosynovectomy as a monotherapy in treating D-TGCT [25]. The largest case series on radiosynovectomy included 73 patients with a new diagnosis of TGCT who were treated by open synovectomy with additional radiosynovectomy [7]. After a mean follow-up period of 4.6 years, the relapse rates were 30% for tumours located in the knees and 9% for tumours located in other locations. However, this technique has a potential risk of radionecrosis, and harmful effects on bone and joint cartilage have been demonstrated in vitro and in vivo [38e41]. Furthermore, radiosynovectomy is not indicated in cases of extra-articular disease, which is a common finding in recurrent or residual D-TGCT. 4. New therapeutic strategies Given the relatively high recurrence rates and iatrogenic morbidity associated with surgery and radiotherapy, there has recently been increased interest in alternative
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treatments such as immunotherapy and targeted therapy. The clinical application of immunotherapy, specifically tumour necrosis factor-alpha (TNFa) inhibitors, is limited to a few case reports with promising initial results. However, prospective clinical studies are required to confirm these preliminary findings, with increased patient numbers and longer follow-up times. More recently, there is raised interest in the use of targeted treatments for TGCT, such as tyrosine kinase inhibitors or monoclonal antibodies. Phase IeII studies with these compounds have demonstrated promising activity, and phase III clinical trials are currently underway. 4.1. Immunotherapy Macrophages and pro-inflammatory cytokines such as TNFa are present in the synovium of patients with TGCT [42]. According to this finding, anti-TNFa drugs, such infliximab, etanercept, and adalimumab, have been tested in patients with relapsing TGCT, with relatively good results [43e45] Kroot et al. reported on a patient with recurrent TGCT of the knee, who demonstrated clinical improvement after infliximab treatment, along with a marked reduction in macrophages and TNFa expression in the synovium [43]. Fiocco et al. described two patients with recurrent disease of the knee who responded to intra-articular injection of etanercept [45]. Knee function and disease activity improved, and a regression of knee joint synovial proliferation was confirmed by ultrasound. Similarly, Kobak described a case with good clinical and radiological response to intra-articular treatment with adalimumab [44]. With only anecdotal reports available, further studies are required to determine the role of anti-TNFa in patients with D-TGCT. 4.2. Targeted therapy In 1994, a cytogenetics study of six cases of TGCT was the first to suggest that the chromosomal region lpl1-p13 may be involved in the pathogenesis of TGCT [46]. More than 10 years later, West et al. reported that chromosomal translocations involving 1p13 are present in a majority of cases of TGCT. They further demonstrated that the gene CSF1 is located at the chromosome 1p13 breakpoint. The translocation fuses CSF1 to COL6A3 (2q35), resulting in CSF1 overexpression in many TGCT cases [6]. CSF1 gene encodes for CSF1, the ligand of CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) or CD115 (cluster of differentiation 115). CSF1R is a protein found on the cell surface which controls the production, differentiation, and function of macrophages. In TGCT the translocation involves the ligand CSF1 which is overexpressed in a
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minority of tumour cells and creates a gradient of CSF1 which attracts the CSF1R expressing cells (mostly macrophages) which comprise the bulk of the tumour. Interestingly, the tumour cells also express CSF1R. This suggests that a CSF1/CSF1R autocrine loop is involved, leading to the abnormal accumulation of non-neoplastic cells that form a tumourous mass though a ‘paracrine landscape’ effect [6,47]. It is hypothesised that CSF inhibitors may disrupt this ‘paracrine landscape’ effect, which is believed to be responsible for TGCT growth [6,47,48]. The activity of a CSF1R inhibitor in TGCT was first described by Blay et al. reporting a complete response in a 34-year-old woman with right elbow TGCT recurrence treated with imatinib [49]. Subsequently, in a retrospective series of 29 patients with advanced TGCT, encouraging activity was reported following treatment with imatinib, with one (4%) complete remission, four (15%) partial remissions, and 20 (74%) patients with stable disease [50]. Two (8%) patients had metastatic disease, and both progressed. Response evaluation was not possible in two (8%) patients due to discontinuation of treatment owing to early side-effects, consisting of febrile neutropenia and grade III oedema. A number of clinical trials are currently investigating the use of CSF1R inhibitors in patients with TGCT, including tyrosine kinase inhibitors such as nilotinib [13,51] or PLX3397 [14], or monoclonal antibodies such as emactuzumab (also known as RG7155) [12]. An inhibitor of the CSF1 ligand, MSC110, is also under investigation. These trials are still in early stages, however. Promising efficacy results have been reported in abstract form in two phase II studies of nilotinib in patients with TGCT (NCT01261429 [number of patients Z 56] and NCT01207492 [number of patients Z 17]), although final results have yet to be published for either study [13,51]. The first study reported a 93.6% progression-free survival rate at 12 weeks [13], while the other reported a 82% progressionfree survival rate at 6-months, a clinical benefit rate (best response of stable disease or better) of 47%, and an overall response rate (best response of partial response or better) of 0% [51]. A phase II study of MSC110 in patients with TGCT (NCT01643850) is still recruiting patients, and efficacy and safety data have not yet been reported [15]. Data from phase I studies with PLX3397 (NCT01004861) and emactuzumab have been recently published, demonstrating impressive activity in TGCT, with 12/23 and 24/28 patients achieving an objective response, respectively, and only one patient progressing in each series [12,14]. The toxicity of these targeted agents is usually mild. Adverse events included facial oedema, asthenia, change in hair colour, nausea, dysgeusia, and periorbital oedema [12,14]. Patients with TGCT are currently being recruited for a phase III global clinical trial of PLX3397
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(NCT02371369). In part 1 of the study, eligible participants will be assigned to either PLX3397 or placebo for 24 weeks, and assessments will be completed in week 25. Patients who complete part 1 will be eligible to advance to part 2, a long-term treatment phase in which all patients will receive open-label PLX3397 [52]. Future studies with emactuzumab, such as an international collaboration with cooperative groups to ensure appropriate recruitment in D-TGCT, are currently under development [12]. The striking difference in terms of efficacy observed between PLX3397 or RG7155 and imatinib in patients with TGCT is likely attributable to the fact that imatinib is not a particularly strong inhibitor of CSF1R [12,14,53]. Also, in a preclinical xenograft model of TGCT, imatinib blocked the CSF1R pathway and monocyte or macrophage infiltration to a lesser extent than the mouse antihuman CSF1 antibody 5H4 [54]. 5. Conclusions D-TGCT is a clonal, proliferative, and inflammatory disease of benign course. Due to its high tendency to recur, D-TGCT requires repetitive, invasive, and eventually aggressive treatments. Thus, D-TGCT has a dramatic impact on quality of life. There is a lack of high-quality studies on the treatment of this disease, and the highest level of evidence is level IV, based on retrospective case series. These case series are difficult to interpret and compare due to heterogeneous study populations, including different disease locations and subtypes, and whether the disease is primary or recurrent. Various measurements, including functional assessment, imaging evaluation, or patient satisfaction, are used to assess treatment outcomes. However, open surgical excision is currently the gold standard of treatment for D-TGCT. The evidence that the pathogenetic loop can be inhibited by different classes of drugs could potentially change the therapeutic armamentarium for D-TGCT. Clinical trials of agents that target D-TGCT are currently ongoing. In the meantime, international registries should be activated in order to provide useful information on this relatively rare tumour. The development of new CSF1R/CSF1 inhibitors represents a new avenue for the management of patients with diffuse/relapsed TGCT. However, the implementation of these new therapies in the routine setting raises specific challenges. For example, the efficacy is not easily evaluated through imaging studies, by means of monodimensional criteria (i.e. response evaluation criteria in solid tumours [RECIST]), as tumour volume is difficult to measure in a multinodular- diffuse disease, often associated with bone involvement and variable quantities of joint effusion. Clinical response (use of pain scores, functional
scales and quality of life assessments) is probably a more reliable indicator of treatment efficacy, but could be biased by secondary, permanent, degenerative changes. Furthermore, it is unclear which is the optimal treatment duration, how long the response lasts or what would happen after treatment discontinuation. Finally, it would be interesting to assess the combination of CSF1R/CSF1 inhibitors with surgery, either in the neoadjuvant or adjuvant setting. Results of current trials will help to better understand the role of these new agents and solve some of the pending issues. Conflict of interest statement ES and EP serve on the Daiichi Sankyo advisory board. SF received research support form PharmaMar, MolMed, Glaxo, Morphotek, and CytRx, received honoraria from the speakers bureau for Takeda, and serves as a consultant/is on the advisory board for Novartis, Takeda, Glaxo, and Merck. DD has no conflicts of interest to declare.
Acknowledgements Editorial assistance in the preparation of this manuscript was provided by BlueMomentum, an Ashfield Company, part of UDG Healthcare plc, and supported by Daiichi Sankyo, Inc.
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