Introduction

Giant cell tumor of bone (GCTB) is classified as an intermediate malignant bone tumor by the World Health Organization (WHO) as of 2020. Predominantly affecting adults aged 20 to 40, it has a minimal potential to metastasize to the lungs.123 Initially described by Cooper and Travers in 1818, GCTB was further characterized by Jaffe et al in 1942.45 Nelaton's work highlighted the local aggressiveness of GCTB. Notably, the incidence of GCTB is significantly higher in Asian populations compared to the Western populations.5

The basic pathology of GCTB revolves around the receptor activator of nuclear factor kB (RANK), RANK ligand, and osteoclasts. These pathways have a role in bone formation and resorption. However, stromal cells overexpress RANK ligands and activate mononuclear cells to become giant osteoclast cells. These giant cells cause bone resorption and ultimately formation of GCTB.6

GCTB was classified radiographically by Campanacci into three grades, grade 1 is latent lesion with well-defined boundaries and intact cortex, grade 2 is ballooning of cortex leading to thin rim of bone, and grade 3 being cortical destruction with extraosseous soft tissue lesion with indistinct borders.7 This grading system is majorly utilized for the management of extremity GCTBs. Treatment of choice for GCTB is surgical removal of tumor. Campanacci grade 1, 2, and 3 tumors with limited soft tissue invasion are treated by extended intralesional curettage. Campanacci grade 3 tumors with extensive soft tissue invasion are treated by en bloc resection.8

Denosumab is a monoclonal antibody that inhibits RANK ligands. Denosumab has shown to inhibit proliferative stromal cells and replace them into nonproliferative, differentiated new bone along with eliminating RANK positive tumor giant cells. Thus, denosumab is utilized in the treatment of GCTB to shrink tumors that are initially unresectable, thereby making them amenable to surgical resection and enabling limb-sparing surgical approaches. It was approved by the U.S. Food and Drug Administration and the European Medicines Agency as neoadjuvant drug therapy for advanced GCTB. But there are also reports that denosumab use is associated with high local recurrence in patients undergoing extended curettage.9

In this study, we have analyzed the effect of denosumab biosimilar (DB) Esentra© in the treatment of Campanacci grade 3 GCTB.

Methods

This retrospective study focuses on patients with Campanacci grade 3 GCTB treated at our tertiary care center from January 1, 2019, to May 31, 2023, who received DB as a neoadjuvant therapy. Data were collected from the electronic medical records of the patients, with no direct contact made with any patient. All patients were followed up for at least 1 year postsurgery, provided they were alive.

Campanacci grades were determined by the treating oncologist based on X-rays of the local site. The study included patients over 18 years of age with biopsy-proven Campanacci grade 3 GCTB who received 120 mg/dose of DB subcutaneously prior to surgery between January 1, 2019, and May 31, 2023. Patients under 18 years of age, those with Campanacci grade 1 or 2 GCTB, or those with a different pathology from GCT on the final biopsy report after surgery were excluded from the study.

The primary objective of the study was to determine the effect and efficacy of DB in reducing disease burden in Campanacci grade 3 GCTB. This was determined by change in size of the lesion before and after receiving DB in magnetic resonance imaging (MRI) and formation of sclerotic bony rim around the periphery of tumor on X-ray. For pretherapy values, size of the lesion on MRI and X-rays were considered. Following therapy, the size of the lesion is determined on post-therapy MRI and X-ray; and also correlated with tumor size on resected surgical specimens as reported by an oncopathologist.

The secondary objective of the study was to analyze the effect of the DB dosing interval in patients with Campanacci grade 3 GCTB. In our study, we administered two doses 14 days apart, with the first dose on day 0 and the second on day 14. The effectiveness of DB was assessed on day 28 through clinical and X-ray examinations. Favorable outcomes included reduced pain and swelling, functional improvement, and the appearance of sclerosis on X-rays. If these favorable effects were observed, an MRI was recommended at the 6th week post-first DB dose to evaluate the response. Surgery was then planned based on the response scan. In cases of unfavorable or inadequate response, additional DB doses were administered.

Other secondary objectives included determining the 1-year local and distant recurrence rates in Campanacci grade 3 GCTB patients who received DB prior to surgery, and assessing nononcological complications of DB such as hypocalcemia, osteonecrosis, and pathological fractures during the peritreatment period.

Descriptive statistics were calculated using MS Excel, with means and standard deviations for normally distributed continuous variables, medians and ranges for nonnormal continuous variables, and percentages for categorical variables; missing data were deleted, and the last observation was carried forward for lost to follow-up cases.

Results

Seventeen cases were eligible for the study, all with at least 1 year of follow-up. The mean and median ages were both 31 years (range 20–47). The male-to-female ratio was 1.57:1, with 11 males and 6 females. At presentation, 11 cases were primary GCTB and 6 were recurrent GCTB previously operated elsewhere. GCTB sites included distal femur (3), proximal tibia (3), distal tibia (2), distal radius (4), distal ulna (2), proximal humerus (2), and proximal femur (1). Of the 6 recurrent cases, 4 had undergone prior curettage. Campanacci grades at initial presentation were unavailable for recurrent cases.

All cases received two doses of DB on days 0 and 14, resulting in a mean lesion size reduction of 17.75% ± 8.029%. One case showed progression and received an additional dose on day 30. Radiological examinations before surgery showed complete sclerotic rim formation in all 17 cases. Wide excision was performed in 10 cases, all with free resection margins postsurgery. The remaining 7 cases underwent intralesional extended curettage. Postoperatively, 2 cases experienced flap necrosis and 1 had implant failure, managed by revision surgery.

The median follow-up duration for the 17 cases was 16 months (range 12–24), calculated from the date of surgery. During follow-up, there was an 11% (2/17) local and 11% (2/17) distant recurrence rate. No recurrences were observed in the wide excision group (0/10) or in patients who underwent primary extended curettage (0/7) within 1 year.

However, two recurrent cases that underwent repeat extended curettage experienced a second local recurrence at 19 and 20 months. The first re-recurrent case, initially misdiagnosed and treated at secondary care center as a traumatic fracture with plating, was later identified as GCTB. After DB therapy, the patient underwent plate removal, extended curettage, and bone cement with plating. At 19 months postsurgery, the patient presented with pain and swelling, and a biopsy revealed malignant GCT with axillary and neck node and lung nodules, leading to the patient's death. The second case had a second local recurrence and lung nodules at 20 months and is currently alive, receiving definitive denosumab treatment and now with stable lung nodule. No cases experienced hypocalcemia or osteonecrosis postoperatively.

Discussion

GCTB is one of the most common neoplasms of the skeletal system accounting for around 20% of cases. Incidence of GCTB is found to be higher in the Asian population compared to Caucasians.10 GCTB usually presents in the 3rd and 4th decade of life and is seen more in females.11 In our cohort, the average age of presentation is around 31 years with male predominance compared to gender equation reported elsewhere.

GCTB generally manifests in mature skeletons, primarily affecting the epiphysio-metaphyseal regions of long bones. It commonly occurs in the distal femur, proximal tibia, and distal radius. Less frequently, it can be found in the proximal femur, distal tibia, pelvis, bones of the hands and feet, and vertebrae.12 In our study, the distal end of the radius was the most prevalent site, representing approximately 23.5% of cases.

GCTB is classified by the WHO as an intermediate malignant neoplasm. It is considered a locally aggressive tumor that rarely metastasizes. Multicentricity in GCTB is uncommon, and none of our cases exhibited this characteristic.13 Malignant transformation of GCTB is rare and can be categorized into primary and secondary malignant GCTB. Primary malignant GCTB refers to a sarcoma developing within a benign GCTB, while secondary malignant GCTB occurs post-treatment, primarily after radiation therapy.14 Therefore, we recommend that any patient who does not respond to denosumab within 30 days of initiation should undergo a repeat biopsy from the heterogeneous area of the tumor for further evaluation.

Neoplastic mononuclear stromal cells activate osteoclasts, playing a central role in the pathogenesis of GCTB. Osteoclasts, derived from hematopoietic cells, are regulated by various tumor necrosis factors, including RANK and its ligand, as well as osteoprotegerin and its ligand. Denosumab, a monoclonal antibody against the RANK ligand, prevents these ligands from binding to their receptor, thereby inhibiting the differentiation and function of osteoclasts. This suppression leads to the inhibition of bone destruction.13 Radiologically, the effects of denosumab can be observed on X-rays as osteosclerosis in the area of tumor osteolysis, characterized by intralesional sclerosis and the formation of a neocortex15 (Fig. 1). Pathologically, the primary histologic efficacy endpoint is defined as a reduction of 90% or more of tumor giant cells within the tumor.3

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Fig. 1: (A) X-ray showing pre-denosumab right proximal humerus lesion. (B) Represents shrunken and sclerosis of the lesion post-denosumab therapy.

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Various dosing regimens of denosumab are documented in the literature. The traditional regimen involves doses on days 0, 7, 14, and 28, followed by monthly doses for up to 6 months. In our approach, we employed a low-dose, short-duration regimen, administering 120 mg of DB subcutaneously on days 0 and 14, with a 14-day interval between doses. The decision to use DB instead of denosumab was made by the surgeon after careful consideration, as DB is more cost-effective.

Campanacci grade 1 and 2 lesions are confined to the bone, with intralesional extended curettage being the preferred treatment. Grade 3 lesions, however, break through the bony cortex and involve surrounding soft tissues, often leading to pathological fractures. In these cases, curettage and defect filling have a high recurrence rate, so wide excision and reconstruction are preferred.16

Denosumab/DB is effective in downsizing tumors, making inoperable tumors resectable and transforming initially resectable tumors into cases suitable for curettage. For grade 3 GCTB undergoing resection, it induces peripheral sclerosis and prevents tumor spillage during surgery. In cases of pathological fractures due to GCTB, denosumab/DB not only causes sclerosis of the tumor but also provides a time interval for bony union. Preoperative denosumab therapy has been shown to facilitate surgical excision in aggressive GCTB, turning surgically unsalvageable lesions into salvageable ones.17 In our analysis, DB regimen of two doses with a 14-day gap led to a mean reduction of 17.75% in lesion size.

Denosumab therapy can have several adverse effects, including hypocalcemia, osteonecrosis of the jaw, pathological fractures, urinary tract infections, upper respiratory tract infections, dyspnea, and sciatica.17 Before initiating denosumab therapy as part of our institutional protocol, our dental surgery team evaluates the patient's teeth. Therapy is only started after receiving their clearance. Additionally, we prescribe 250 mg of calcium citrate malate and 100 IU of cholecalciferol daily. None of our patients experienced hypocalcemia, osteonecrosis of the jaw, pathological fractures, fever, or dyspnea following the therapy.

The recurrence risk in GCTB ranges from 0 to 65%, depending on the type of treatment received and the local presentation of the tumor.18 The rate of local recurrence is higher in cases treated with curettage compared to excision.19 Reports indicate that denosumab therapy is associated with a significantly higher risk of local recurrence when only curettage is done. This may be due to the entrapment of tumor cells in the thickened new bone after therapy, making curettage insufficient to remove these cells. Therefore, curettage is not preferred in cases where denosumab has been used for prolonged periods. Early extended curettage is advised in post-denosumab/DB patients to avoid excessive sclerosis around the margins, which complicates the curettage process.820 Imaging techniques utilized during surgery assist in determining the necessary extent of curettage.

In our cohort, wide excision is typically performed after DB therapy. Only two cases of local recurrence (11%) were observed in the repeat extended curettage category. This low recurrence risk is attributed to the use of wide excision as the surgical method for Campanacci grade 3 lesions that underwent neoadjuvant DB therapy.

There are many shortcomings on our side like small sample size, retrospective analysis, and short interval of follow-up.

Conclusion

A cost-effective DB therapy for Campanacci grade 3 GCTB effectively reduces lesion size without raising the risk of local or distant recurrence. It also has minimal significant side effects. This therapy can be utilized preoperatively in aggressive GCTB cases to aid in smoother surgical procedures.