title: Current Systemic Treatment Options for Tenosynovial Giant Cell Tumor/Pigmented Villonodular Synovitis: Targeting the CSF1/CSF1R Axis.
abstract: Adequate surgical resection remains the treatment of choice for tenosyovial giant cell tumor (TGCT). However, diffuse type TGCT (D-TGCT) is more difficult to resect and has a higher rate of recurrence (up to 50 %), which is often multiple. D-TGCT is rarely lethal and only rare cases of metastases have been described. Nevertheless, patients might have a significant decline in their quality of life due to multiple operations, which may sometimes result in a partial loss of function of the affected joint and may also be associated with perioperative morbidity and secondary arthrosis. As of today, no systemic treatment is approved for this rare disease. The aims of systemic therapy in the context of a non-lethal tumor are to reduce surgical morbidity and to preserve function and patient quality of life. Because TGCT is associated with characteristic cytogenetic abnormalities resulting in the overexpression of CSF1, systemic therapies targeting the CSF1/CSF1R axis (imatinib, nilotinib, emactuzumab, and PLX3397) have been tested in patients with locally advanced or relapsed D-TGCT. The more recent and more specific CSF1R inhibitors have shown a very interesting clinical activity with acceptable toxicity in early phase trials. These results will need to be confirmed in larger, ideally randomized, trials. But the high rate of clinical and functional improvement seen in some patients with advanced D-TGCT, often after multiple operations, suggests that these inhibitors will likely have a role in the management of patients with an inoperable disease; the definition of "inoperable TGCT" still requires refinement to reach a consensus. Another point that will need to be addressed is that of "the optimal duration of therapy" for these patients. Indeed, we and others have observed often prolonged clinical benefit and symptomatic relief even after treatment was stopped, with both monoclonal antibodies and tyrosine kinase inhibitors. Responses were observed very early on with emactuzumab and PLX3397, and patients experienced significant symptom improvement within a few weeks of starting therapy (2-4 weeks). Another possible application of CSF1R inhibitors could be used either as a preoperative or postoperative therapy for patients with operable TGCT. However, we currently lack sufficient follow-up to adequately address these questions which will each require specific trial designs. Overall, the striking clinical activity of CSF1R specific inhibitors in TGCT has created great enthusiasm among clinicians, and further development of these agents is clearly medically needed. Nevertheless, further investigations are necessary to validate those treatments and assess how to best incorporate them among other treatment modalities into the overall therapeutic strategy for a given patient.
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, Lyon, 69008, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Brahmi
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, Lyon, 69008, France.|Department of Medical Oncology, Centre Hospitalier Universitaire Bretonneau, Tours, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Vinceneux
authors.affiliation: Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, Lyon, 69008, France. philippe.cassier@lyon.unicancer.fr.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Cassier
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D005870:Giant Cell Tumors / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013586:Synovitis, Pigmented Villonodular / Q000175:diagnosis / Q000188:drug therapy* / Q000601:surgery
chemical_list: D000970:Antineoplastic Agents; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: Anti-TNF-alpha; Colony-stimulating factor 1; Colony-stimulating factor 1 receptor; Emactuzumab; Imatinib; Nilotinib; PLX3397; Pigmented villonodular synovitis; Systemic therapy; Tenosynovial giant cell tumor
references.citation: Clin Orthop Relat Res. 1982 Sep;(169):139-44
references.pmid: 7105568
references.citation: Cancer. 2002 Jun 25;96(3):157-65
references.pmid: 12115304
references.citation: Z Orthop Unfall. 2011 Dec;149(6):677-82
references.pmid: 21271510
references.citation: Clin Sarcoma Res. 2013 May 13;3(1):8
references.pmid: 23668619
references.citation: Ann Rheum Dis. 2014 May;73(5):947-8
references.pmid: 24401993
references.citation: Blood. 2005 Apr 15;105(8):3127-32
references.pmid: 15637141
references.citation: Am J Clin Oncol. 2006 Dec;29(6):548-50
references.pmid: 17148989
references.citation: Leukemia. 2008 Mar;22(3):649-52
references.pmid: 17851554
references.citation: Rheumatology (Oxford). 2014 Nov;53(11):2063-70
references.pmid: 24917565
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 May;111(5):e30-6
references.pmid: 21444225
references.citation: Rheumatology (Oxford). 2002 Oct;41(10 ):1113-8
references.pmid: 12364629
references.citation: Arch Orthop Trauma Surg. 1999;119(7-8):401-4
references.pmid: 10613228
references.citation: Clin Rheumatol. 2004 Feb;23(1):31-4
references.pmid: 14749979
references.citation: Hum Pathol. 2003 Jan;34(1):65-73
references.pmid: 12605368
references.citation: J Bone Joint Surg Br. 2000 May;82(4):571-3
references.pmid: 10855885
references.citation: Hum Pathol. 1992 Jul;23(7):729-35
references.pmid: 1319390
references.citation: Cancer Cell. 2014 Jun 16;25(6):846-59
references.pmid: 24898549
references.citation: Iowa Orthop J. 1998;18:26-34
references.pmid: 9807705
references.citation: Clin Sarcoma Res. 2015 Jun 06;5:15
references.pmid: 26052431
references.citation: Oncogene. 2006 Jan 5;25(1):147-51
references.pmid: 16170366
references.citation: Ann Oncol. 2008 Apr;19(4):821-2
references.pmid: 18296418
references.citation: Eur J Cancer. 2015 Jan;51(2):210-7
references.pmid: 25465190
references.citation: N Engl J Med. 2015 Jul 30;373(5):428-37
references.pmid: 26222558
references.citation: Am J Surg Pathol. 2006 Jun;30(6):734-8
references.pmid: 16723851
references.citation: Reumatismo. 2006 Oct-Dec;58(4):268-74
references.pmid: 17216015
references.citation: Semin Arthritis Rheum. 2011 Jun;40(6):539-46
references.pmid: 20884045
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):690-5
references.pmid: 16407111
references.citation: PLoS One. 2015 Mar 23;10(3):e0121451
references.pmid: 25799575
references.citation: J Bone Joint Surg Am. 2008 Feb;90(2):326-8
references.pmid: 18245592
references.citation: Target Oncol. 2014 Mar;9(1):73-9
references.pmid: 23430345
references.citation: Cancer. 2012 Mar 15;118(6):1649-55
references.pmid: 21823110
references.citation: Lancet Oncol. 2015 Aug;16(8):949-56
references.pmid: 26179200
references.citation: Am J Surg Pathol. 2007 Jun;31(6):970-6
references.pmid: 17527089
references.citation: Oncol Rep. 2000 Mar-Apr;7(2):413-9
references.pmid: 10671695
references.citation: Ann Rheum Dis. 2005 Mar;64(3):497-9
references.pmid: 15297283
references.citation: Arthroscopy. 1995 Feb;11(1):91-5
references.pmid: 7727018