A comprehensive search of Medline, Embase and the Cochrane Library yielded 648 articles. 10 studies with 1082 cases (169 in denosumab group, 913 in control group) were eventually included after careful screening title, abstract, and full texts by two independent researchers.(Figure 1). Basic characteristics and quality assessment of included studies are listed in table 1. Parameters including recurrence, indication to administer denosumab, administration time and dosage, surgical approach, lesion site, primary/recurrent lesion Campannaci grade, denosumab related complication and malignant transformation of lesion are recorded and analyzed.
Histopathological diagnosis of giant cell tumor was all achieved in included studies. The indications for denosumab are specified in 6 studies, including: lesions in distal radius, invasive radiographic findings, unresectable lesions and possible severe morbidity after surgery.
As the primary outcome of this meta-analysis, local recurrence is recorded in all included studies. Administration dosage was 120mg per injection and interval was once a month with 0-3 additional dosage in the first month. The total dosage given prior to surgery was inconsistent among included studies. 4 studies[13, 15-17] administered denosumab pre-operatively and post-operatively. Overall, 61 cases in the denosumab group and 175 cases in the control group had local recurrence. Pooled analysis showed significantly higher risk of recurrence in the denosumab group(OR: 2.37, 95% CI: 1.16 to 4.85, p=0.02, I2=57%)(figure2) . Surgical choice was taken into account by comparing cases underwent curettage with denosumab and curettage alone in 4 studies[9, 16-18](OR: 2.13, 95% CI: 0.95 to 4.76, p=0.07, I2=29%)(Figure 3), though the result was not statistically significant. 7 studies[9, 15-20] reported outcome on primary lesions, which also suggest significantly higher risk of local recurrence in the denosumab group(OR: 1.91, 95% CI: 1.17 to 3.09, p=0.009, I2=36%)(Figure 4). In 4 studies[13, 15-17] denosumab was administered both preoperatively and postoperatively, no statistically significant difference was found when comparing pre and post denosumab administration group and control group in terms of local recurrence(OR: 1.96, 95% CI: 0.63 to 6.07, p=0.24, I2=79%)(Figure 5).
Recurrence free survival
Recurrence free survival analysis was conducted in 4 studies[13, 16, 20, 21], pooled analysis including 754 cases with at least 12 months of follow-up showed that denosumab is associated with unfavorable 5 year recurrence free survival(ES: 3.707, 95% CI: 2.30 to 5.98, p=0.000, I2=0%).
Complications and others
6 studies[9, 13, 15, 19, 21, 22] reported denosumab-related complications, in the 388 cases treated with denosumab, no osteo-necrosis of jaw or hypocalcemia was observed. 1 study reported a periapical abscess and a periodontal disease during the course of denosumab administration. No other denosumab-related complications were reported in all included studies. Prior to administration of denosumab, dental check, blood test for renal function and calcium level were conducted by Agarwal et al. Scoccianti et al conducted dental check before denosumab administration. Oral supplementary of Vitamin D and calcium is administered in 4 studies[3, 9, 13, 19].Generally, Vitamin D was given more than 400IU/day and calcium more than 500mg/day. Administration of denosumab were similar, most studies administered denosumab once a month with 1-3 additional doses during the first month, the duration of administration prior to surgery differs for various reasons. Yang et al reported significant decreased VAS score, intraoperative blood loss and CT enhancement after administration.
Galbraith test(Figure6) and L’abbe test(Figure7) was conducted to assess heterogeneity among different studies in terms of local recurrence, which showed low heterogeneity among different studies.
Sensitivity analysis was conducted by excluding study with fewer than 10 cases and studies with less than 12 months of follow up, which did not have a significant impact on our result in terms of local recurrence.