Takeuchi Akihiko, Endo Makoto, Kawai Akira, Nishida Yoshihiro, Terauchi Ryu, Matsumine Akihiko, Aiba Hisaki, Nakamura Tomoki, Tandai Susumu, Ozaki Toshifumi, Hoshi Manabu, Kayano Daiki, Okuda Miho, Yamamoto Norio, Hayashi Katsuhiro, Miwa Shinji, Igarashi Kentaro, Yoshimura Kenichi, Nomura Akihiro, Murayama Toshinori, Tsuchiya Hiroyuki
Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Front Oncol. 2022 Sep 21;12:900010. doi: 10.3389/fonc.2022.900010. eCollection 2022.
A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, categorized as localized (L-TGCT, solitary lesion) and diffuse (D-TGCT, multiple lesions) TGCT. Surgical excision is the mainstay of the treatment, and a high local recurrence rate of approximately 50% has been reported. We focused on zaltoprofen, a nonsteroidal anti-inflammatory drug that can activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the proliferation of TGCT stromal cells. Therefore, we conducted a randomized trial to evaluate the safety and effectiveness of zaltoprofen in patients with D-TGCTs or unresectable L-TGCTs.
This randomized, placebo-controlled, double-blind, multicenter trial evaluated the safety and efficacy of zaltoprofen. In the treatment group, zaltoprofen (480 mg/day) was administered for 48 weeks; the placebo group received similar dosages without zaltoprofen. The primary outcome was progression-free rate (PFR) 48 weeks after treatment administration. Disease progression was defined as the following conditions requiring surgical intervention: 1) repetitive joint swelling due to hemorrhage, 2) joint range of motion limitation, 3) invasion of the adjacent cartilage or bone, 4) severe joint space narrowing, and 5) increased tumor size (target lesion).
Forty-one patients were allocated to the zaltoprofen (n=21) or placebo (n=20) groups. The PFR was not significant between the zaltoprofen group and the placebo group at 48 weeks (84.0% and 90.0%, respectively; p=0.619). The mean Japanese Orthopedic Association knee score significantly improved from baseline to week 48 in the zaltoprofen group (85.38 versus 93.75, p=0.027). There was a significant difference between the values at 48 weeks of placebo and zaltoprofen group (p=0.014). One severe adverse event (grade 3 hypertension) was observed in the zaltoprofen group.
This is the first study to evaluate the efficacy and safety of zaltoprofen in patients with TGCT. No significant differences in PFR were observed between the groups at 48 weeks. Physical function significantly improved after zaltoprofen treatment. The safety profile of zaltoprofen was acceptable. This less invasive and safer treatment with zaltoprofen, compared to surgical removal, could be justified as a novel approach to treating TGCT. Further analysis of long-term administration of zaltoprofen should be considered in future studies.
University Hospital Medical Information Network Clinical Trials Registry, identifier (UMIN000025901).
腱鞘巨细胞瘤（TGCT）是一种起源于关节内或关节外组织的局部侵袭性良性肿瘤，分为局限性（L-TGCT，孤立性病变）和弥漫性（D-TGCT，多发性病变）TGCT。手术切除是主要治疗方法，据报道局部复发率高达约50%。我们关注到扎托洛芬，一种非甾体抗炎药，可激活过氧化物酶体增殖物激活受体γ（PPARγ）并抑制TGCT基质细胞的增殖。因此，我们进行了一项随机试验，以评估扎托洛芬对D-TGCT或不可切除L-TGCT患者的安全性和有效性。
这项随机、安慰剂对照、双盲、多中心试验评估了扎托洛芬的安全性和有效性。治疗组给予扎托洛芬（480毫克/天），持续48周；安慰剂组给予相似剂量但不含扎托洛芬。主要结局是治疗给药48周后的无进展率（PFR）。疾病进展定义为需要手术干预的以下情况：1）因出血导致的反复关节肿胀，2）关节活动范围受限，3）侵犯相邻软骨或骨，4）严重关节间隙变窄，5）肿瘤大小增加（靶病变）。
41名患者被分配到扎托洛芬组（n = 21）或安慰剂组（n = 20）。48周时，扎托洛芬组和安慰剂组的PFR无显著差异（分别为84.0%和90.0%；p = 0.619）。扎托洛芬组从基线到第48周日本骨科学会膝关节评分平均显著改善（85.38对93.75，p = 0.027）。安慰剂组和扎托洛芬组48周时的值有显著差异（p = 0.014）。扎托洛芬组观察到1例严重不良事件（3级高血压）。
这是第一项评估扎托洛芬对TGCT患者疗效和安全性的研究。48周时各治疗组间PFR无显著差异。扎托洛芬治疗后身体功能显著改善。扎托洛芬的安全性可接受。与手术切除相比，扎托洛芬这种侵入性较小且更安全的治疗方法可作为治疗TGCT的一种新方法。未来研究应考虑对扎托洛芬长期给药进行进一步分析。
大学医院医学信息网络临床试验注册中心，标识符（UMIN000025901）。
