Palmerini E, Chawla N S, Ferrari S, Sudan M, Picci P, Marchesi E, Leopardi M Piccinni, Syed I, Sankhala K K, Parthasarathy P, Mendanha W E, Pierini M, Paioli A, Chawla S P
Istituto Ortopedico Rizzoli, Bologna, Italy.
Sarcoma Oncology Center, Santa Monica, CA, USA.
Eur J Cancer. 2017 May;76:118-124. doi: 10.1016/j.ejca.2017.01.028. Epub 2017 Mar 17.
Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly 'GCTB-schedule' (120 mg per 12/year, 1440 mg total dose/year) are lacking.
Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated.
Ninety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6-45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13-76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9-115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7-15 months).
Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84-100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%).
Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.
骨巨细胞瘤（GCTB）是RANK/核因子κB受体活化因子配体（RANKL）阳性、侵袭性和进行性溶骨性肿瘤。地诺单抗是一种RANKL抑制剂，已获美国食品药品监督管理局（FDA）批准，用于治疗不可切除的GCTB或手术切除可能导致严重并发症的成年患者和骨骼成熟的青少年。目前缺乏关于地诺单抗每月“GCTB方案”（每年12次，每次120mg，每年总剂量1440mg）长期毒性和活性的数据。
纳入2006年至2015年在两个中心接受地诺单抗治疗（第1、8、15、29天各120mg，此后每4周一次）的GCTB患者。评估长期毒性。
共确定97例患者。43例患者接受了肿瘤切除术，接受地诺单抗治疗的中位时间为12个月（范围6 - 45个月）。54例患者患有不可切除的GCTB（男/女23/31，中位年龄35岁[范围：13 - 76岁]，26%有肺转移，31%原发肿瘤位于脊柱，63%既往手术后复发），接受地诺单抗治疗的中位时间为54个月（9 - 115个月）。在不可切除的GCTB组中，所有接受地诺单抗治疗的患者均观察到肿瘤控制和临床获益，而40%停用的患者在中位8个月（范围7 - 15个月）后出现肿瘤进展。
总体而言，6例（6%）患者发生颌骨坏死（ONJ）：可切除组1/43（2%），不可切除组5/54（9%），5年无ONJ生存率为92%（95%CI 84 - 100）。只有接受长期治疗的患者出现轻度周围神经病变（6/54，11%）、皮疹（5/54，9%）、低磷血症（2/54，4%）和非典型股骨骨折（2/54，4%）。
地诺单抗长期治疗对GCTB有持续活性，毒性较轻。观察到的剂量依赖性毒性提示，对于需要长期治疗的患者应进行仔细严格的监测。在不可切除的GCTB中应进一步探索降低剂量强度的方案。
