BACKGROUND

Giant cell tumour of bone (GCT) is a bone neoplasm which is locally aggressive and can rarely metastasize [1]. It is more prevalent in women than in men, that is 1.5:1 ratio [2] and typically affects skeletally mature adults up to 40 years of age [3]. Clinically, patients present with localised pain, tenderness, swelling, decreased joint motion, and in some cases with pathological fractures. 50% of cases involve the region of the knee and other long bones while some may involve the spine [4].

Malignancy is rare at time of diagnosis but GCT may undergo malignant transformation after radiation therapy or several recurrences [5]. This is often suspected if atypical mitotic figures are present. Surgery is the definitive therapy with 80% of patients presenting with primary GCT responding to surgical intervention [6]. This includes curettage, en bloc resection, and amputation. However, surgical intervention may cause substantial morbidity. Morbidity is often balanced against risk of recurrence which under the influence of size, location and surgical intervention ranges from approximately 50% with curettage to less than 10% with other aggressive procedures [6].

In light of this variability and high recurrence rate due to surgical intervention, the role of Denosumab, a human monoclonal antibody that inhibits RANK-L, continues to be explored [7], allowing inhibition of osteoclast mediated bone destruction. Subcutaneous administration provides rapid and sustained suppression of bone turnover in patients with multiple myeloma and osteolytic bone disease, and in patients with breast and prostate cancer with bone metastases Inhibition of RANKL by denosumab in patients with Giant cell tumor of bone (GCTB) might inhibit bone destruction and eliminate giant cells [89]. In addition, it provides for a calcified rim surrounding the soft tissue component often seen in advanced GCTB, facilitating curettage with local adjuvants, or en-bloc resection, at a later stage, in previously uncurettable GCTB [1011]. Recent literature indicates that continued denosumab may have a therapeutic role in cases of unsalvageable GCT, particularly with pulmonary metastases, but also in the neoadjuvant setting where the drug might improve surgical outcomes in both primary and recurrent disease cases [11]. This claim requires further investigation; hence our present study aims to show the role of denosumab along with surgery when given as neo-adjuvant drug to South-Asian patients of GCT for their treatment.

METHODOLOGY

A retrospective study was planned, and all patients (adult and paeds) diagnosed with GCT were included in this study from January 2016 – December 2019 and all of these patients had received neo -adjuvant Denosumab dose of 120 mg SC on day 0, 15, 30 & 45 [20]. Only those patients who were treated at the section of Orthopedics, department of surgery, Aga Khan University hospital (AKUH), Karachi were included. All patients had minimum 6 months follow up. Patients presented with ambiguous biopsy results/other benign lesions were excluded. No sampling technique was required, as all the patients meeting the inclusion criteria were enrolled for study. Patients were identified from orthopedic tumor registry data \ health information management system and data collection forms were filled through review of medical records. Study was reviewed by ethics review committee of AKUH, and exemption from ERC was granted. The following data was reviewed: demographic data (patient age at operation, gender, tumor type, and histologic diagnosis), surgical details (reconstructive procedures, lesion resected, and surgical margins), neo-adjuvant therapy and post-operative status of patients (alive, expire, tumor recurrence). Data was entered on statistical software SPSS 21 for analysis. All quantitative variables were reported as means and standard deviation while frequencies were reported for qualitative variables. For measuring histological outcomes, standard criteria for reviewing pathological slides were followed and all biopsies prior to neo-adjuvant Denosumab dose and post-surgery were evaluated for outcomes. This study has been registered in the research registry, the number is researchregistry4695 and it is being reported in line with STROCSS research reporting guidelines [19].

RESULT

There were 23 patients that matched the inclusion criteria of our study. Out of these 23 patients, there were 12 males (52.2%) and 11 females (47.8%). The mean age of our patients was 34±13.8 years and mean follow up duration of all patients was 20.5 ± 10.7 months (Table 1). There were 15 (65.2%) primary cases of GCT while 8 (34.8%) were recurrent cases. In 8 (34.8%) of the cases primary site of lesion was distal femur followed by 7(30.4%) proximal tibia cases and 3 distal radius cases (Figure 1: Primary site of lesions). There were no side effects of denosumab in our patients. The side effects can be observed immediately after administration of denosumab injection which includes redness, swelling or bone pain and none of our patient showed such signs and symptoms. In surgical procedure 20 (87%) patients underwent wide margin excision and only 3 (13%) had intralesional curettage. Reconstruction was performed in 21(91.3) patients which consist of bone grafting in 9 patients and mega prosthesis insertion in 12 patients (Figure 2: Giant Cell tumor of proximal tibia after wide margin excision and mega-prosthesis insertion).

Table 1:

Descriptive Analysis Of Age And Follow Up Of Patients.

Figure 1:

Primary Sites of Lesion.

Figure 2:

Giant Cell tumor of proximal tibia after wide margin excision and mega-prosthesis insertion.

Only two patients had no reconstruction. In bone grafting, 4(17.4%) patients had non-vascular fibula grafting,3(13%) had vascular fibula, 1 (4.3%) had iliac crest bone graft, 1 had iliac crest bone graft with strut fibula. On final histopathology, there was no residual GCT and we observed no denosumab induced adverse effects. Post-operative complications included wound infection and peri prosthetic infection in 3 patients. On follow-up we had 4(17.4%) cases of recurrence that were offered revision surgery while 19 (82.6%) were disease free.

DISCUSSION

The results of this study propose that denosumab, which particularly targets RANKL, hence hindering the interplay between RANK-positive osteoclast-like giant cells and RANKL-positive stromal cells, has activity as a therapeutic agent for GCT of bone. The unearthing of giant cells in GCTB expressing RANKL [1213] has brought about the clinical utilization of denosumab in the management of tumor which were previously deemed unresectable or led to bigger disability after resection. Inevitably Thomas el al conducted the first open-label phase II proof of concept study [11]. He reported 90% histological elimination of giant cells in 30 of 35 (86%) patients. However, in our study all patients underwent wide margin excision with or without reconstruction after receiving denosumab and the final histopathology reported complete response to tumor, defined as no residual tumor cells in final histological evaluation, in all 23 (100%) patients. A second phase II study containing 282 patients claims that denosumab is safe and efficient for GCTB [10]. 163 of 169 (96%) patients with unresectable disease (cohort 1) had no progress in disease following denosumab treatment.in second cohort of 100 patients planned for surgery, majority (16 of 26) encountered less morbid procedure than initially planned and no surgery was needed in the rest of the 74% patients [10]. The authors stated that denosumab was both effective and safe along with the ability to prevent or reduce morbidity of the scheduled procedure. Safety profile can also be witnessed in our study as we observed no denosumab induced adverse effects in any of our patients. However, 3 patients had post op surgical site infection which were completely unrelated to denosumab use and were duly treated with surgical debridement and antibiotics.

Data retrieved from another clinical trial of open-label phase II shows reduction in incursive nature of surgery after denosumab use [14]. 48 percent of two hundred and twenty two patients underwent no surgical intervention or a less morbid procedure. 17 (15%) of the 116 patients who had surgery developed local recurrence with a median follow up of 13 months. We observed recurrence in 4 out of 23 patient (17.4%) with a mean follow up of 20.5 months. This number is slightly higher than the above mentioned study, however it may attributed to our small sample size. Further prospective study with larger sample size may be needed to estimate the actual recurrence rate in our population. Longitudinal institutional cases and collaborative group studies showed that local recurrence was inclined to occur principally within the first 12–18 months after surgery [151617]. Notably, the mean follow-up of our study was sufficient compared to published data.

Recently, Chawla et al. [18] completed the biggest clinical trial to date, evaluating 532 patients. The authors presented that only a mere 11% patients with inoperable disease had progression after 65.8 month follow up. However 31 of 90 (34%) of patients with operable GCTB had recurrence after surgery [10].

CONCLUSION

In conclusion, even though our study and these clinical trials show promising results of denosumab in GCTB, it should be illuminated with vigilance due to short follow-ups, high risk of recurrence, potential malignant transformation and possible influence by funder.

DATA ACCESSIBILITY STATEMENTS

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

ABBREVIATIONS

GCT

GCTB

AKUH

ETHICS AND CONSENT

This study was conducted as per relevant guidelines and regulations or declaration of Helsinki.

Written informed consent was obtained from all subjects and/or their legal guardian(s) in ethical approval. The waiver for approval of study protocol is granted Aga khan University hospital ethics review committee (ERC). ERC reference number is 2018-0416-287.)

An informed consent from all subjects and/or their legal guardian(s) was taken for publication of identifying information/images in an online open-access publication.

COMPETING INTERESTS

The authors have no competing interests to declare.

AUTHOR CONTRIBUTIONS

1. JS contributed in data collection, data management, data analysis and results writing

2. ZS contributed in discussion writing

3. KSA contributed in initial parts of manuscript writing

4. MU reviewed manuscript critically

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