Authors’ reply to Pruthi and Sahoo

At the outset, we would like to thank both authors for their constructive review[1,2] of our study, “Comparison between radiotherapy and neoadjuvant denosumab followed by surgery in the treatment of giant cell tumor of bone: A retrospective observational study.”[3] Giant cell tumor of bone (GCTB) has uncommon characteristics as it is a benign tumor with local aggressiveness and malignant potential.[4] Microscopically, GCTB consists of RANKL receptor activator of nuclear factor kappa-B ligand (RANKL)-positive mononuclear stromal cells and receptor activator of nuclear factor kappa (RANK)-positive multinucleated giant cells. This RANK/RANKL pathway is important in enhancing osteoclastic activity, which is required in the pathogenesis of GCTB.[5] Denosumab halts this effect by inhibiting RANKL. One of the largest studies on the role of denosumab in GCTB, conducted by Chawla et al.,[6] showed that recurrence or progression after denosumab followed by surgery occurred in 11% of cases (28 patients), which the authors considered favorable.[3] As the authors correctly point out, Grade I and II tumors are primarily treated with intralesional curettage.[1,7,8] In our study, among the 18 patients in arm 2 (with Grade I or II tumors), 15 (83.3%) were treated with neoadjuvant denosumab followed by extended curettage along with cementing and/or bone grafting. In this arm, the median tumor volume was greater than that observed in arm 1 (376.2 cc compared to 301.2 cc in arm 1). Surgery of eight patients with Grade III tumors, treated with en-bloc resection, was also aided by denosumab through tumor size reduction. The study by Niu et al.[9] showed that denosumab also reduces blood supply to the tumor, which helps in tumor downstaging.[7] Thus, we conclude that denosumab, by reducing tumor size, facilitated the surgical approach. A study by Puri et al. has shown good local control along with preservation of neurological function after short-term denosumab, angioembolization, and radiotherapy in various combinations.[8,10] Thus, we suggest that angioembolization plays a critical role in the treatment of GCTB.[3] Some studies have shown the effect of denosumab in downstaging tumors for proper resection while preserving function.[9-12] Therefore, both denosumab and angioembolization contribute to tumor size reduction by decreasing the tumor’s blood supply. The study by Errani et al. indicated that denosumab might increase the incidence of local recurrence. This retrospective study included treatment details of 408 patients. Of these, 247 (60.5%) patients underwent curettage, with phenol used as an adjuvant in 221 cases, while 161 patients underwent resection. Among these, 30 patients received denosumab followed by surgery. The joint preservation rate was 80% in patients treated with denosumab followed by curettage and 94% in those treated with curettage alone. However, recurrence rates were higher in patients treated with denosumab followed by surgery. Overall, the minimum duration of follow-up was 24 months. Due to substantial differences in the cohorts and the lack of randomization, the study underscores the need of further research to establish a causal relationship between denosumab and increased local recurrence.[11,13] The radiotherapy doses in studies evaluating radiotherapy effects ranged from 35-55 Gy, with fractions of 1.67-2.33 Gy, delivered as a single fraction per day.[12,14] In our study, the radiotherapy dose was 54 Gy with conventional fractionation. The authors have rightly emphasized the need for a cost-effectiveness analysis in the study to provide a broader perspective on the pharmaco-economics of various treatment approaches, particularly in our country.[2,15] While it is correct that we have not performed any cost-effectiveness analysis between the two treatment approaches, the goal of our study was to evaluate the role of radiotherapy in comparison to denosumab.[3] Needless to say, radiotherapy is a more cost-effective treatment compared to denosumab. Despite its limitations, this study has attempted to establish the role of radiotherapy as a definitive treatment, compared to denosumab followed by surgery.[3] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.