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. 2019 Nov 26;478(5):1076–1085. doi: 10.1097/CORR.0000000000001074

Is Treatment with Denosumab Associated with Local Recurrence in Patients with Giant Cell Tumor of Bone Treated with Curettage? A Systematic Review

Shinji Tsukamoto 1,2,3,4,5,✉, Yuu Tanaka 1,2,3,4,5, Andreas F Mavrogenis 1,2,3,4,5, Akira Kido 1,2,3,4,5, Masahiko Kawaguchi 1,2,3,4,5, Costantino Errani 1,2,3,4,5
PMCID: PMC7170677  PMID: 31794487

Abstract

Background

Denosumab, a monoclonal antibody that binds to receptor activation of nuclear factor-kappa ß ligand (RANKL), has been used as a drug to treat aggressive giant cell tumors of bone. It is unclear whether preoperative denosumab therapy is associated with the local recurrence risk in patients with giant cell tumors of bone treated with curettage. Early evidence suggests that denosumab treatment is associated with a reduction in local recurrence, but other studies have questioned that premise. Curettage after a short course of denosumab (3 to 4 months) has been recommended, especially for large, aggressive giant cell tumors in which complete curettage is difficult to achieve. No randomized studies have documented the benefit of this approach, and some investigators have reported higher local recurrence after denosumab treatment. Due to this confusion, we performed a systematic analysis of existing reports to attempt to answer this question and determine whether the appropriate preoperative denosumab therapy duration could be established.

Questions/purposes

(1) Is the use of preoperative denosumab associated with local recurrence risk in patients with giant cell tumors of bone treated with curettage compared with those treated with curettage alone? (2) Is the preoperative denosumab therapy duration associated with local recurrence after curettage?

Methods

We searched the PubMed, EMBASE, and CENTRAL databases on April 26, 2019 and included both randomized and non-randomized studies that compared local recurrence between patients who had giant cell tumors of bone and were treated with curettage after preoperative denosumab and patients treated with curettage alone. Two authors independently screened the studies. There were no randomized studies dealing with denosumab in giant cell tumors of bone, and generally, denosumab was used for more aggressive tumors. We assessed the quality of the included studies using the Risk of Bias Assessment tool for Non-randomized Studies, with a moderate overall risk of bias. We registered our protocol in PROSPERO (registration number CRD42019133288). We selected seven eligible studies involving 619 patients for the final analysis.

Results

The proportion of patients with local recurrence ranged from 20% to 100% in the curettage with preoperative denosumab group and ranged from 0% to 50% in the curettage-alone group. The odds ratio of local recurrence ranged from 1.07 to 37.80 in no more than 6 months of preoperative denosumab duration group and ranged from 0.60 to 28.33 in more than 6 months of preoperative denosumab duration group.

Conclusions

The available evidence for the benefit of denosumab in more aggressive giant cell tumors is inconclusive, and denosumab treatment may even be associated with an increase in the proportion of patients experiencing local recurrence. Because there are no randomized studies and the existing studies are of poor quality due to indication bias (the most aggressive Campanacci 3 lesions or those where even a resection would be difficult and result in morbidity are generally the patients who are treated with denosumab), the evidence to suggest a disadvantage is weak. Denosumab treatment should be viewed with caution until more definitive, randomized studies documenting a benefit (or not) have been conducted. Furthermore, we could not find evidence to suggest an appropriate length of preoperative denosumab before curettage.

Introduction

Giant cell tumor of bone, a rare primary benign bone tumor, accounts for approximately 5% of all primary bone tumors [11]. It usually involves the metaphyseal-epiphyseal region of the long bones [7]. There is no sex predilection, and tumors usually occur in adults aged 20 to 40 years [5, 38]. Intralesional curettage is associated with little disability, although many patients experience local recurrence [5, 13, 38]. Wide resection has been recommended for tumors that have extended through the cortex into the soft tissue to prevent local recurrence [21]. A giant cell tumor of bone close to a joint is often treated with resection and endoprosthetic replacement or bone graft reconstruction, which may cause functional impairment [38].

In giant cell tumors of bone, neoplastic stromal cells highly express receptor activation of nuclear factor-kappa ß (RANK) ligand and induce receptor activation of RANK-positive osteoclast-like giant cells and their precursors [2, 14, 15, 22, 31, 35, 36]. Denosumab is a fully human monoclonal antibody that inhibits the RANK ligand (RANKL), thereby preventing RANK–RANKL interactions and the subsequent giant cell tumor of bone-induced bone destruction [4, 20, 31]. In 2013, based on the results of a single arm, Phase 2 study, the US Food and Drug Administration approved denosumab for treating adults and skeletally mature adolescents with an unresectable giant cell tumor of bone or patients in whom resection can cause severe morbidity [6]. Rutkowski et al. [32] reported that of 85 patients with planned en bloc resection, 45.9% (n = 39) were able to have curettage and 36.5% (n = 31) did not undergo surgery after preoperative denosumab therapy. They also reported that for patients with resectable giant cell tumors of bone, preoperative denosumab therapy resulted in beneficial surgical downstaging [32]. Traub et al. [37] reported that at a median of 30 months of follow-up after preoperative denosumab therapy and curettage, local tumors recurred in 17% of patients. They noted that local recurrence of giant cell tumor of bone after curettage did not seem to be affected by denosumab treatment and remained a concern [37]. We previously reported that preoperative denosumab therapy increased the local recurrence risk in patients treated with curettage, and these patients had longer follow-up than the patients treated with denosumab who Rutkowski et al. [32] and Traub et al. [37] reported [9]. This may have been caused by thickened cortical bone after denosumab treatment, making it difficult to determine whether removal of diseased tissue was complete, resulting in a higher proportion of patients with local recurrence [9]. Thus, there are conflicting reports regarding whether preoperative denosumab therapy increases the local recurrence risk in patients with a giant cell tumor of bone treated with curettage. No results of randomized studies have been published so far. Moreover, recently, some authors recommended performing curettage earlier after a short course of denosumab (3 to 4 months) to prevent the development of a thick rim of peripheral bone [24, 41]. This approach might decrease the chance that neoplastic tissue will be left behind post-curettage in the thickened rim of perilesional new bone, thus facilitating complete tumor removal [24, 41]. However, the duration (number of doses) of preoperative denosumab therapy was not standardized. We therefore performed a systematic review of comparative studies reporting on the proportion of patients with local recurrence treated with preoperative denosumab therapy combined with curettage compared with those treated with curettage alone. We thought this might provide useful information to physicians treating giant cell tumors of bone.

We performed this systematic review of comparative studies to determine whether preoperative denosumab therapy has any effect on the local recurrence of giant cell tumor of bone. We asked: (1) Is the use of preoperative denosumab associated with the local recurrence risk in patients with giant cell tumors of bone treated with curettage compared with those treated with curettage alone? (2) Is the preoperative denosumab therapy duration associated with local recurrence after curettage?

Materials and Methods

We followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement [26]. We registered our protocol with the International Prospective Register of Systematic Reviews (PROSPERO, an international database of systematic reviews in health and social care: http://www.crd.york.ac.uk/PROSPERO/; registration number CRD42019133288).

Eligibility Criteria

All comparative reports examining local recurrence in patients with giant cell tumors of bone who were treated with curettage, with or without denosumab, were included. We included human studies and articles with clearly defined local recurrence following curettage. We excluded studies without a comparison group, those without or unclear reporting of local recurrence, isolated case reports or case series including fewer than five patients, and non-English, non-Japanese, non-Italian, and non-Greek-language abstracts. We did not restrict the date of publication.

Literature Search and Study Selection

We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) on April 26, 2019. We used a systematic search strategy (see Table 1, Supplemental Digital Content, http://links.lww.com/CORR/A268) and searched for relevant publications via online sources of published studies. Moreover, the bibliographies of retrieved trials were used to identify other relevant studies. Publication bias was assessed with a funnel plot and Egger’s test.

Table 1.

Overall study characteristics

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Data Collection and Presentation

Two study authors (ST, AK) independently selected the studies and extracted data. In cases of disagreement, a consensus was either achieved between them, or by consulting a third author. We used a data collection sheet to collate the following data: (1) basic data: authors, year of publication, name of publishing journal, type of study, number of patients, and length of follow-up; (2) characteristics of the denosumab and the non-denosumab groups, such as the site and Campanacci stage; and (3) chemical adjuncts, treatment regimen, preoperative and postoperative denosumab therapy duration, number of patients in the denosumab and non-denosumab groups, and proportions of patients with local recurrence in the denosumab and non-denosumab groups.

Data Summary

We summarized the data of the selected studies. The datasets included the first author’s name, year of publication, preoperative denosumab therapy duration, number of patients who received curettage with or without denosumab, and number of patients who experienced local recurrence. Because all the studies included in this review were non-randomized, data pooling (meta-analysis) was not appropriate, and thus, not performed. All statistical analyses were made using Review Manager 5.3 (The Cochrane Collaboration, Oxford, UK) and ProMeta software Version 3 (INTERNOVI di Scarpellini Daniele s.a.s., Cesena FO, Italy).

Assessment of Methodological Quality

Two authors (ST, AK) independently assessed the quality of the included studies. When they disagreed, they reached a consensus or they consulted a third author. We independently graded the articles selected for the final analysis according to the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS tool) for assessing the quality of nonrandomized studies in meta-analyses [17]. Moreover, we summarized the data of variables that are related to local recurrence such as the site of the distal radius [29], use of chemical adjuncts [3, 18, 19], and Campanacci stage [5], because indication bias was expected (Table 1).

Search Results

Of the 460 relevant studies found by the search strategy, seven studies were finally selected for this review (Fig. 1). The characteristics of the seven studies were summarized (Table 1) [1, 9, 10, 25, 34, 40, 42]. There was no randomized study among these seven studies. Two of the excluded 453 studies had no clear information about the distinction between curettage and en bloc resection. We contacted the authors to request original data; however, we received no responses. For one of the seven studies selected for the systematic review, we obtained a poster presented at the American Society of Clinical Oncology’s Annual Meeting 2018 [10]. A funnel plot of odds ratios seemed to be asymmetric (Fig. 2); however, Egger’s test was impossible because only seven studies were included. Thus, there was possible publication bias.

Fig. 1.

Fig. 1

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This flow chart shows the search for relevant articles.

Fig. 2.

Fig. 2

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This funnel plot shows detection of publication bias.

Demographic Data and the Ratio of Patients Who Were Treated with Curettage and Preoperative Denosumab Therapy

The study population consisted of 619 patients, 21% of whom (127 of 619) received curettage and preoperative denosumab therapy; 80% (492 of 619) were not treated with denosumab (Table 1).

Methodological Quality of Included Studies

The assessment of the quality of individual studies using the RoBANS tool showed that overall risk of bias was moderate (Table 2).

Table 2.

RoBANS tool for assessing the quality of studies included in this systematic review

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Results

Comparison of the Proportion of Patients with Local Recurrence Between the Curettage with Preoperative Denosumab and Curettage Without Preoperative Denosumab Groups

The proportion of patients with local recurrence ranged 20% to 100% in the curettage with preoperative denosumab group and ranged 0% to 50% in the curettage-alone group. This indicates that there might be an increased local recurrence risk in the denosumab group compared with the non-denosumab group, but because these were poor quality, non-randomized studies, we could not pool data and perform a statistical analysis to determine whether or not there was a difference in local recurrence between the two treatment options.

Association Between the Duration of Preoperative Denosumab Therapy and the Odds Ratio of Local Recurrence

The odds ratios of local recurrence were 1.07, 2.76, and 37.80 (range 1.07 to 37.80) in the studies of Urakawa et al. [40], Agarwal et al. [1], and Yang et al. [42], respectively, where preoperative denosumab duration was no more than 6 months. The odds ratios of local recurrence were 0.60, 5.71, 7.75, and 28.33 (range 0.60 to 28.33) in the studies of Fedenko and Tararykova [10], Scoccianti et al. [34], Errani et al. [9], and Medellin et al. [25], respectively, where preoperative denosumab duration was more than 6 months.

Discussion

Denosumab may make the treatment of aggressive (Campanacci Stage 3) giant cell tumors of bone more effective and has yielded potentially positive results in initial studies [6, 32]. More recently, the drug’s effectiveness has been doubted, and we showed in the current study that its use might even increase the proportion of patients with local recurrence after curettage and denosumab treatment. We showed that preoperative denosumab therapy seemed to be associated with an increase in the proportion of patients with giant cell tumors of bone treated with curettage who had a local recurrence compared with those who did not receive denosumab preoperatively. We did not find any correlation between the preoperative treatment duration and local recurrence.

This study has limitations. First, five of seven analyzed studies had an indication bias [9, 10, 25, 34, 40]. Patients treated with denosumab had more tumors in the distal end of the radius (which is associated with a higher proportion of local recurrence) and had more Campanacci Stage 3, aggressive, or unresectable tumors, which are expected to have a higher proportion of local recurrence. Phenol was used less frequently in the denosumab group (Table 1). In the other two studies, patients in the denosumab and control groups were matched for size, Campanacci stage, recurrent or primary tumor, and site (Table 1) [1, 42]. Randomized controlled trials can avoid many of these biases by randomly allocating participants into two groups. As no randomized trials were found, well-designed cohort and observational studies with strong effects may provide reliable information. Until randomized studies are performed, our results may be the nearest available equivalent. Second, one study did not report the follow-up periods but clearly reported the outcome of local recurrence in a large number of patients [40]; therefore, we included it in this systematic review.

In this systematic review comparing the proportion of patients with local recurrence after curettage between 127 denosumab-treated patients and 492 nontreated patients, we observed that preoperative denosumab therapy seemed to be associated with an increased incidence of local recurrence. An open-label Phase 2 trial evaluated the reduction in surgical invasiveness after denosumab treatment in 222 patients with resectable giant cell tumors of bone [32]. Of 115 patients who underwent surgery after preoperative denosumab (median duration, 14.2 months), 17 (15%) experienced local recurrence during a median follow-up of 13 months [32]. A prospective nonrandomized study of patients with giant cell tumors of bone who received denosumab preoperatively for a median of 5 months reported that all patients underwent intralesional surgery, with local recurrence in three of 18 patients; the median follow-up was 30 months [37]. The proportion of patients who achieved local control was comparable to those in other studies in which denosumab was not used before curettage [8]. A European multicenter retrospective analysis that excluded clinical trials observed that after curettage and denosumab therapy for 8 months, 16 of 50 patients (32%) had local recurrence during a median follow-up of 23 months [33]. A single-institution study of patients with giant cell tumors of bone treated with denosumab with a minimum postoperative follow-up of 24 months reported that local recurrence after curettage and denosumab therapy for an average of 2 months was observed in 11 of 25 (44%) patients during a mean follow-up of 34 months [30]. These two studies showed a relatively high proportion of local recurrence in patients treated with preoperative denosumab and curettage, despite lacking a control group [30, 33]. We previously reported a higher proportion of recurrence in patients treated with preoperative denosumab and curettage than in a historical control [9]. Four studies reported relatively high proportions of local recurrence in patients treated with curettage and denosumab than in nontreated patients, but the numbers of patients were too small to draw definitive conclusions [1, 25, 34, 42]. Jamshidi et al. [16] performed a systematic review of the effectiveness and safety of denosumab in patients with giant cell tumors of bone; however, they did not investigate local recurrence. Luengo-Alonso et al. [23] subsequently performed a systematic review to investigate the proportion of patients with local recurrence after surgery and denosumab therapy. However, they did not separate curettage and en bloc resection or compare the denosumab group with a control group [23]. Thus, these systematic reviews cannot determine whether preoperative denosumab therapy is associated with the local recurrence risk in patients with giant cell tumors of bone treated with curettage compared with those treated with curettage alone. It has been postulated, but not definitively shown, that newly formed bone on the periphery of the lesion, although offering a mechanical scaffold against which curettage can be performed, could continue harboring neoplastic cells that may reactivate and result in recurrence if this shell is not completely excised [37]. Currently, based on our findings and those of other studies mentioned above, we do not use preoperative denosumab in patients with Campanacci stage 1/2 or stage 3 giant cell tumors of bone with limited soft tissue invasion where curettage is feasible. In a giant cell tumor of bone of the extremity, with a large soft-tissue component in proximity to neurovascular structures, we use preoperative denosumab before en bloc resection because the osseous rim that forms after denosumab helps decrease the possibility of injury to these adjacent neurovascular structures, and further, denosumab seems also to facilitate intraoperative manipulation and prevents inadvertent spreading of the tumor [9, 25, 27]. We use denosumab for 3 months before en bloc resection to decrease the risk of denosumab-related complications. In a Campanacci stage 3 giant cell tumors of bone with a large soft-tissue component located in the pelvis or spine in which it is possible to perform en bloc resection, we use denosumab for 3 months before en bloc resection. In a large giant cell tumor of bone located in the pelvis or spine, in which it is impossible to perform en bloc resection due to the complex anatomy and the potential extreme blood loss, or for lung metastatic lesions with increasing size, we administer denosumab without surgery once every 4 to 6 months to reduce the risk of complications because the elimination half-life of denosumab is around 32 days, but concentrations of the drug can be found up to 9 months after cessation of denosumab treatment [28].

This systematic review showed that the preoperative denosumab therapy duration did not seem to be associated with local recurrence after curettage. In properly selected patients with a high local recurrence risk after curettage, short-duration preoperative denosumab treatment (3 to 4 months) may play a role in creating a mechanical scaffold against which curettage may be performed without seriously compromising the ability to clear the tumor [1, 12, 24, 30, 33, 41]. In the data we previously reported [9], a univariate Cox proportional hazards regression analysis showed that the preoperative denosumab therapy duration was not associated with local recurrence-free survival after curettage in 25 patients with giant cell tumors of bone in a limb and were treated with preoperative denosumab and curettage (hazard ratio 0.81 [95% CI 0.57 to 1.17]; p = 0.26). Thus, even if the preoperative denosumab therapy duration is shortened, it may increase the local recurrence risk.

In conclusion, denosumab administered to patients before curettage of a giant cell tumor of bone may not decrease the likelihood of local recurrence and may actually increase the likelihood thereof. Because the studies performed to date were not randomized and there is indication bias in how patients receive or do not receive denosumab, the association between denosumab treatment and the local recurrence risk after curettage could not be proven. Furthermore, we could not find evidence suggesting an appropriate length of preoperative denosumab before curettage. The Japan Clinical Oncology Group is currently conducting a randomized Phase 3 trial with a standardized dose of preoperative denosumab for 2 months for patients with giant cell tumors of bone treated with curettage [39]. Although the primary aim of the study is to confirm the effects of preoperative denosumab on recurrence after curettage, the secondary endpoints include joint preservation survival, local recurrence-free survival, and metastasis-free survival [39]. This Phase 3 study will resolve the limitations of our systematic review. However, until the result of this randomized trial is published, the result of our systematic review suggests that physicians should consider the potential risks and benefits of denosumab when treating patients with giant cell tumors of bone. This study also suggests that denosumab should be used with caution and probably only for patients with a specific, high-recurrence risk, such as those with a tumor with a large soft-tissue component close to neurovascular structures (use of denosumab before en bloc resection), patients with a large tumor located in the pelvis or spine, in whom it is impossible to perform en bloc resection due to the complex anatomy and the potential for extreme blood loss, or those with aggressive lung metastatic lesions (maintenance denosumab treatment).

Acknowledgments

We thank Mr Takaaki Suzuki, of the Library at Nara Medical University, Japan, for his help with the literature search.

Footnotes

Each author certifies that neither he, nor any member of his immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.

Each author certifies that his institution waived approval for the reporting of this investigation and that all investigations were conducted in conformity with ethical principles of research.

This work was performed at Nara Medical University, Nara, Japan.

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