Ethics statement
No ethical approval from the Ethics Committee of Witten/Herdecke University was required because this work was a literature search.
Patients
After an intensive literature search for trials in Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and MEDLINE/PubMed until February 28, 2018, the efficacy and safety of denosumab as a monoclonal antibody with a recent approval extension were determined in the patients with GCBT with tumor progression and compared with the efficacy and safety of denosumab observed in patients with tumor regression. For this present evaluation, the age and gender of the subjects were assessed from the results of previously published studies of patients with GCBT. The tool “clinicaltrials.gov” was also checked for studies about denosumab treatment of GCBT.
Endpoints of this review
This meta-analysis considered the following nine events as relevant to the definitions of the endpoints of this systematic review: pulmonary metastases, tumor progression, secondary tumor development, GCBT death, death from other cancers, treatment-related death, rejection of treatment, non-compliance, and loss of follow-up. The following seven endpoints were considered relevant to the assessment of the effects of treatment with denosumab: disease-free survival, local recurrence of GCBT, treatment failure of denosumab, adverse effects of denosumab, recurrence-free survival, survival without tumor progression, and overall survival.
Cohort 1: Tumor progression during treatment with denosumab
Cohort 1 included all the patients with GCBT who had tumor progression, with possible lung metastases, during treatment with denosumab. Another criterion was treatment failure with denosumab.
Cohort 2: Tumor controlled by denosumab
Cohort 2 included all patients with GCBT who had tumor regression during treatment with denosumab. Cohort 2 was used as the comparison group.
Data collection
Suitable studies that included patients with GCBT who were undergoing drug treatment with denosumab were searched by entering the search terms “denosumab” and “giant cell tumors of the bone” into the search consoles of Embase, CENTRAL, and MEDLINE/PubMed, followed by the filters “humans” and “text availability in abstract.” The systematic review and meta-analysis were performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [14].
Study choice
No randomized controlled trials for denosumab treatment of GCBT were found in the literature. Therefore, this review included all the non-randomized, uncontrolled, and open-label phase II studies, as well as case series and case reports, concerned with the efficacy of denosumab in patients with GCBT. The selection criteria for the studies used in the analysis were as follows: the study should report on (a) the outcome of the treatment with denosumab in addition to the demographic data, (b) the location of the tumor, (c) the surgical treatment, (d) the adverse reactions to denosumab, (e) the duration of treatment with denosumab, and (f) the follow-up time. The studies were evaluated after they were classified according to the study design. Within each category of the study design, the data were compared between the cohort 1 and cohort 2. Published studies were excluded if the effectiveness of the administration of denosumab in patients with GCBT was not stated.
Definition of giant cell tumor of the bone
A giant cell bone tumor is a rare tumor that is often found in the epiphysis of the long bone. It is an aggressively growing tumor but is considered benign [15]. Raised radiographic findings of a cystic, juxta-articular, non-reactive mass lead to a biopsy. After tumor removal, a high risk of relapse remains [16]. In the present study, GCBT were identified and referred to as a primary or recurrent tumors, in addition to being recurrently unresectable [17].
GCBT occur mainly in the knee joint area, in the proximal humerus, and in the distal radius. For the sake of brevity, these areas were identified as the lower and upper extremities in the present study [18]. Other less frequent localizations also considered here include the skull, the spine, the trunk, the pelvis, and the sacrum [19‒22]. Metastases to the lungs are less common but have been included in the present study [23]. GCBT usually occur in patients between 20 and 40 years of age [24]; in the present study, age is expressed as the mean in years in the demographic data of the patients. Bone-destroying GCBT often cause fractures, which are reported as being among the unwanted side effects of denosumab [25, 26].
Radiological imaging
A giant cell bone tumor was initially diagnosed upon detecting osteolytic areas in X-ray radiographic images. Thereafter, computerized tomography (CT) and magnetic resonance imaging (MRI) were performed on the patients with GCBT [27].
Pathohistology
The radiographic findings of a cystic [28], juxta-articular [29], and non-reactive mass led to a biopsy [30]. The diagnosis of a GCBT was made by examining the biopsy tissue under a microscope after hematoxylin-eosin staining. A GCBT showed very characteristic multinuclear osteoclast-like giant cells, and the actual tumor cells were similar to mesenchymal mononuclear fibroblast-like cells [31].
Characteristics of denosumab
The human monoclonal antibody denosumab was used to treat the GCBT in all the patients in this study if the tumors could not be surgically removed or if surgical resection was likely to lead to severe frailty (e.g., loss of limbs). The aim of denosumab treatment was to reduce the activity of osteoclasts, and thus bone resorption, in all the patients with GCBT in this investigation [32, 33].
Dosage and method of denosumab administration
Denosumab was administered as a subcutaneous injection of 120 mg in the thigh, the abdominal region, or the upper arm in all the participants. The drug was injected every four weeks, with additional 120 mg single doses on days 8 and 15 of the first month of treatment [34]. The second cycle started on day 29 or 4 weeks after day 15. The patients who underwent a complete resection of the GCBT also received an additional six months of denosumab treatment after surgery. When an additional surgical intervention was required for the patients whose tumor showed incomplete regression, denosumab was used as a neoadjuvant treatment. The goal of this neoadjuvant therapy was to achieve an improved starting situation for the operation, to make the disease operable, or to forgo mutilating surgery. The time of denosumab application before and after surgery or as a neoadjuvant treatment was addressed in the evaluations in this study.
All patients in this study, except those with existing hypercalcemia, also had to receive at least 500 mg of calcium and 400 IU of vitamin D per day [35]. Existing hypocalcemia had to be corrected before the start of therapy. Hypocalcemia could occur at any time during therapy, requiring regular control of calcium levels [36]. Hypocalcemia was considered one of the side effects of denosumab in this study. The duration of denosumab treatment and follow-up in patients with GCBT was determined individually by the treating physicians, depending on the drug response and tolerability of the treated patients. When this information was indicated in the examined studies, data on the duration of denosumab therapy and follow-up were collected.
Definition of therapy success with denosumab
The objective response rate of GCBT was expressed based on the best response rate to denosumab, as determined by MRI or CT in the control record in the follow-up at an interval of six months. Response was determined by radiological measurement of the longest diameter of the GCBT and comparison to the measurement obtained at the initial MRI or CT examination. The disappearance of all GCBT was considered a complete response, disappearance by at least 30% in diameter was considered a partial response, the same tumor size was considered a stable disease, and an increase of 20% in tumor size was considered progression of the disease, according to the modified Response Evaluation Criteria in Solid Tumors [37]. GCBT were detected using 18F-fluorodeoxyglucose, a radioactively labeled tracer, by recording the metabolic processes with positron emission tomography, according to the modified European Organization for Research and Treatment of Cancer [38].
Definition of treatment failure with denosumab
In this review, treatment failure with denosumab in GCBT was established when radiology or histology demonstrated local recurrences of GCBT, when GCBT progressed by metastasis to the lungs, or when patients had progression ≥ 20% during denosumab treatment of GCBT [37].
Side effects of denosumab
The evaluation of the side effects of denosumab served to establish the possible connection with the progression of GCBT. The comparison of the frequency of side effects of denosumab reported here refers to the comparison of the two cohorts and is not a frequency indication of the side effects of denosumab in general. The common side effects of denosumab considered in this study were hypocalcemia, hypophosphatemia, osteonecrosis of the jaw, pain extremities, and skin rash [39, 40, 41]. Rare side effects, such as anemia, headache, hypercalcemia, hyperparathyroidism, parathyroid adenoma, pathological bone fracture, and peripheral neuropathy, as well as serious adverse events —which could occur at any time—were also identified in this study [42]. The severe adverse events that were described as life-threatening during treatment with denosumab for GCBT included the need for life-saving interventions, a high risk of death, and the need for hospitalization, as indicated by the Common Terminology Criteria for Adverse Events developed by the US National Cancer Institute [43].
Types of surgery
Amputation and joint or prosthesis replacement
Left untreated, GCBT can lead to the complete destruction of the affected bone, deformities, joint disorders, and even amputations. The frequency of amputation and joint or prosthesis replacement was examined among the operative measures in this study [44].
Curettage
The traditional surgical treatment for GCBT is intralesional aggressive curettage, which involves using an additional mechanical high-speed milling cutter, followed by the application of bone cement to fill the surgical defect. This cement could be replaced with bone after one or two years if the GCBT shows no recurrence. In addition, chemically toxic substances (e.g., alcohol or phenol) are often added to kill the remaining GCBT cells [45].
En bloc resection
A high probability of recurrence of GCBT inevitably leads to a radical surgical procedure in the form of en bloc resection, in which the actual GCBT, as well as the affected neighboring tissue or the lymph node, are removed in one piece [46].
En bloc excision
A tissue part that has been affected by GCBT is removed as an en bloc excision in some cases [46]. In the most favorable cases, the surgeon can perform a marginal excision to remove the GCBT, along with the surrounding margin of the tissue [48].
Spondylectomy
Rare localizations in the spine and sacral areas are treated with the difficult surgical procedure of spondylectomy [49]. Spondylectomy is an operative removal of one or more vertebral bodies, with subsequent replacement and stabilization of the spinal column section.
No surgery
The use of denosumab can circumvent an operation in the very best of cases.
Embolization
Preoperative radiologic-interventional elective embolization is sometimes useful to control a difficult GCBT and is conducted by administering liquid plastics via a catheter into the patient’s artery. This procedure was also investigated in this study [50].
Mortality
The number of deaths among denosumab-treated patients with GCBT was surveyed after a review of the studies in this analysis.
Quality assessment study tool
For open-label phase II studies
The non-randomized, uncontrolled, and open-label phase II studies were evaluated and validated using the risk assessment tool for non-randomized studies (RoBANS) [51]. The studies were evaluated based on the following three characteristics: (a) high risk of bias, (b) low risk of bias, and (c) unclear risk of bias. RoBANS covers aspects such as participant selection, confounding variables, intervention measurement, blinding of the outcome assessment, incomplete data results, and selective outcome reporting.
For case series
The Joanna Briggs Institute is an international membership-based research and development organization within the Faculty of Health Sciences of the University of Adelaide in Australia [52]. The institute developed a critical appraisal tool for systematic reviews, and this tool was used to evaluate the case series in this work [53]. Using 10 questions, the tool rates each case series with the answers “yes,” “no,” or “unclear,” where “yes” corresponds to a low risk of bias, “no” to a high risk of bias, and “unclear” to an unclear risk of bias [53]. The 10 questions focus on the following: clear criteria for inclusion in the case series, measurement of the condition in a standard and reliable way for all the participants included in the case series, use of valid methods for the identification of the condition of all the participants included in the case series, consecutive inclusion of the participants in the case series, complete inclusion of the participants, clear reporting of the participants’ demographics in the study, clear reporting of the participants’ clinical information, clear reporting of the outcomes or follow-up results of the cases, clear reporting of the demographic information of the presenting clinics, and the use of appropriate statistical analysis.
For case reports
The evaluation of the case reports also used the critical appraisal tool of the Joanna Briggs Institute [54]. This checklist for the case reports consists of eight questions [54, 55]. The questions focus on the assessment methods; the patients’ demographic characteristics, history, current clinical condition, and post-intervention clinical condition; the treatment procedure; adverse events; and the case report’s takeaway lessons. These case report questions are rated either “yes” for a low risk of bias, “no” for a high risk of bias, or “unclear” for an unclear risk of bias.
Statistical analysis
The numbers studied in proportions were expressed as percentages (%). Mean and standard deviation (SD) were used to calculate the mean age, the duration of treatment, and the follow-up of the patients in the analysis of GCBT therapy with denosumab [56]. For the evaluation of the results in this systematic review, a P value of < 0.05 was determined to be statistically significant.
A Mann–Whitney U test for unpaired data of two samples was used to compare age differences, duration of treatment, and follow-up time [57]. Chi-square analysis was used to examine the gender difference between the published studies, classification of tumors, time of administration of denosumab, localization of tumors, course of treatment, outcome of treatment, side effects of denosumab, surgery procedures, and embolization [58]. A confidence interval (CI) of proportions was computed from the observed data for the comparison of the number of patients in cohort 1 and cohort 2, as well as the number of patients according to the study design [59].