G. Scoccianti, F. Totti, M. Scorianz, D. A. Campanacci, Department of Orthopaedic Oncology and Reconstructive Surgery, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy G. Baldi, Department of Medical Oncology, Hospital of Prato, Prato, Italy G. Roselli, Department of Radiology, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy G. Beltrami, Department of Paediatric Orthopaedic Oncology, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy A. Franchi, Department of Translational Research and New Technologies, Department of Anatomic Pathology, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy R. Capanna, Department of Orthopaedics and Traumatology, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.
Clin Orthop Relat Res. 2018 Sep;476(9):1783-1790. doi: 10.1007/s11999.0000000000000104.
Denosumab is a monoclonal RANKL antibody, which was originally introduced for the treatment of osteoporosis and bone metastases from solid tumors, but more recently has been used for treatment of giant cell tumor of bone (GCTB). In GCTB, denosumab has been used as a single agent in patients with inoperable tumors; it also has been used before surgery in some patients with the aim to downstage the tumor to facilitate a joint-preserving procedure (curettage) rather than a resection. However, few studies are available evaluating the benefits and risks of denosumab for the latter indication.
QUESTIONS/PURPOSES: (1) Does preoperative treatment with denosumab reduce the risk of local recurrence in patients treated for GCTB? (2) Are there adverse effects of short-term denosumab use before surgery and, if so, what are they?
All patients with a diagnosis of GCTB surgically treated at our institution from June 2009 to June 2016 with curettage and cryotherapy were retrospectively evaluated to compare patients treated with curettage alone versus patients treated with curettage after preoperative therapy with denosumab. During that period, we treated 97 patients for GCTB; 30 patients were excluded because they received a resection; 34 patients were excluded because they received curettage without cryotherapy. Of the remaining 33 patients, four were excluded because they received denosumab only after surgery, one because she received zoledronic acid, one because she received a curettage after her refusal of a resection that was the advised procedure, two because they were lost to followup early, and four because they were treated for recurrence rather than a new diagnosis of GCTB. The remaining 21 patients were included. Twelve lesions had been treated with surgery after denosumab and nine with surgery alone. During the study period, we preferentially used denosumab for the more aggressive-looking lesions. After curettage, cryotherapy of the residual bone walls was performed with argon cryoprobes to -150° C after pouring gel into the cavity, and we then used cement (17 patients) or morcellized allograft (four patients). Tumors were Campanacci Grade 3 in eight of 12 patients in the denosumab group and in two of nine patients in the surgery-only group (p = 0.08), but the extent of epiphyseal juxtaarticular bone involvement was not different between the groups with the numbers available. Median followup was 39 months (range, 14-55 months) in the denosumab group and 27 months (range, 18-92 months) in the surgery-only group. We used chart review to record the proportion of patients in each treatment group who had a local recurrence and to tally adverse events.
With the numbers available, there was no difference in the proportion of patients experiencing a recurrence (five of 12 in the denosumab group and one of nine in the surgery-only group; p = 0.18). We found no adverse effects associated with denosumab either during or after treatment; specifically, we found no alterations in electrolyte levels, blood count, or liver and renal function parameters. In this small series, no patient has developed osteonecrosis of the jaw.
In this small series, use of denosumab before surgery for GCTB appeared to allow the reforming of a bone peripheral rim around the tumor, perhaps facilitating curettage rather than osteoarticular resection in some patients. However, we did not observe a decrease in the risk of local recurrence with the use of denosumab, suggesting that it may not decrease the aggressiveness of the disease; according to our preliminary results, we cannot exclude that the rate of local recurrence could be even higher after curettage in denosumab-treated patients than in nontreated patients, and until or unless larger studies demonstrate such a reduction, primary intralesional surgery without denosumab seems more prudent when curettage is feasible at presentation. We did not observe any adverse effects with denosumab, but we caution readers that this study was underpowered to detect even relatively common complications and relatively large differences in the risk of local recurrence. Future studies should evaluate denosumab prospectively; given the relative rarity of this tumor, we suspect multicenter studies are needed to achieve this.
Level III, therapeutic study.
地舒单抗是一种单克隆 RANKL 抗体，最初用于治疗骨质疏松症和实体瘤的骨转移，但最近也用于治疗骨巨细胞瘤 (GCTB)。在 GCTB 中，地舒单抗已被用于不可手术肿瘤的患者；在某些患者中，它也被用于术前，目的是使肿瘤降级，以便于保留关节手术（刮除术）而不是切除术。然而，很少有研究评估术前使用地舒单抗治疗对后者的益处和风险。
问题/目的：(1) 术前使用地舒单抗治疗是否会降低 GCTB 患者局部复发的风险？(2) 手术前短期使用地舒单抗是否有不良反应，如果有，是什么？
回顾性评估 2009 年 6 月至 2016 年 6 月期间在我院接受手术治疗的所有 GCTB 患者，比较单纯刮除术组和术前用地舒单抗治疗组患者。在这段时间内，我们治疗了 97 例 GCTB 患者；30 例患者因接受切除术而被排除；34 例患者因接受刮除术而未接受冷冻疗法而被排除。在剩下的 33 名患者中，有 4 名因术后仅接受地舒单抗治疗而被排除，1 名因接受唑来膦酸治疗而被排除，1 名因拒绝接受建议的切除术而接受刮除术而被排除，2 名因早期失访而被排除，4 名因治疗复发而不是新诊断的 GCTB 而被排除。剩下的 21 名患者被纳入研究。12 例病变在接受地舒单抗治疗后行手术治疗，9 例仅行手术治疗。在研究期间，我们更倾向于使用地舒单抗治疗更具侵袭性的病变。刮除后，将凝胶注入空腔中，然后使用氩气冷冻探针将残余骨壁冷冻至-150°C，然后使用水泥（17 例）或切碎的同种异体移植物（4 例）。在地舒单抗组的 12 例患者中，有 8 例为 Campanacci 3 级，在单纯手术组的 9 例患者中，有 2 例为 Campanacci 3 级（p=0.08），但两组的骺板关节旁骨受累程度无差异。地舒单抗组的中位随访时间为 39 个月（范围，14-55 个月），单纯手术组为 27 个月（范围，18-92 个月）。我们通过病历回顾记录了每组患者中局部复发的比例，并记录了不良反应。
在现有的病例数量下，两组患者的复发比例无差异（地舒单抗组 5 例，单纯手术组 1 例；p=0.18）。我们没有发现地舒单抗治疗期间或治疗后有任何不良反应；具体来说，我们没有发现电解质水平、血细胞计数或肝肾功能参数的改变。在这个小系列中，没有患者发生颌骨坏死。
在这个小系列中，术前使用地舒单抗治疗 GCTB 似乎可以在肿瘤周围形成一个骨缘，这可能会使一些患者更容易进行刮除术，而不是关节切除术。然而，我们没有观察到使用地舒单抗降低局部复发的风险，这表明它可能不会降低疾病的侵袭性；根据我们的初步结果，我们不能排除在接受地舒单抗治疗的患者中，刮除术后局部复发的风险甚至更高，除非或直到更大规模的研究表明这种风险降低，否则当在初次就诊时可行刮除术时，主要采用肿瘤内切除术而不使用地舒单抗似乎更为谨慎。我们没有观察到地舒单抗的任何不良反应，但我们提醒读者，本研究的效力不足，无法检测到甚至是相对常见的并发症和局部复发风险的较大差异。未来的研究应该前瞻性地评估地舒单抗；考虑到这种肿瘤的相对罕见性，我们怀疑需要多中心研究才能实现这一目标。
3 级，治疗性研究。
