Denosumab or external beam radiation therapy: Arrows in quiver for giant cell tumor of the bone

The research article “Comparison between radiotherapy and neoadjuvant denosumab followed by surgery in the treatment of giant cell tumor of bone: A retrospective observational study,” published in Cancer Research, Statistics and Treatment, is engaging and illuminating.[1] This article directly compares the effects of denosumab followed by surgery with those of external beam radiation therapy (EBRT) in patients with giant cell tumors of the bone (GCTB).[1] The authors weighed the locoregional failure-free survival and quality of life among participants of both groups. Recently, another study evaluated the impact of denosumab on the tumor size, visual analog scale (VAS) scores, and musculoskeletal tumor society (MSTS) scores in patients with GCTB.[2] Hemosiderin deposits and highly vascularized collagen bands with foamy macrophages are the microscopic characteristics of GCTB.[3] Histologically, GCTB is characterized by three cell lineages: multinucleated osteoclastic giant cells, spindle-shaped mesenchymal stromal cells, and rounded mononuclear histiocytic cells.[3] The stromal cells have an ill-defined cytoplasm and high expression of nuclear factor-kB receptor activator ligand (RANKL). This makes RANKL a potential therapeutic target, positioning denosumab as a preferred treatment option for GCTB.[2,3] I would like to provide several observations and suggestions to enhance the comparison of the effects of denosumab with other therapeutic modalities. The omission of data on tumor size and pain may have restricted the extent of the study.[1] Including a cost-effectiveness analysis would provide a broader perspective on the pharmacoeconomics of various therapies. The rising incidence of GCTB and the skyrocketing healthcare costs in developing countries, such as India, make the treatment decisions even more difficult.[1,2] With ample data regarding efficacy, safety, quality of life, and various facets of pharmacoeconomics, the treatment decision would have been easier.[1,2] Considering the recurrent and unresectable GCTB, cost-effectiveness, and cost-utility analyses are paramount.[3] Recently, a meta-analysis advocated that the recurrence rate of GCTB increases with denosumab treatment.[4] As denosumab shrinks the tumor, it becomes easier to operate. However, the tumor borders often remain undetectable, which creates room for recurrence. The recurring nature of GCTB impacts the quality of life and aggrandizes treatment costs. It is now time to tailor treatment plans for patients with GCTB. Most GCTBs can be managed with extended intralesional curettage without the need for preoperative denosumab. This approach is suitable for Campanacci I, II, and some Stage III GCTBs. However, very large Campanacci III GCTBs or lesions in expendable bones, such as the lower end of the ulna, are often treated with resection. These patients can benefit from preoperative denosumab, which promotes tumor ossification, reduces blood loss, improves intraoperative handling, and decreases the risk of tumor spillage.[5] With the availability of definitive long-term denosumab therapy, the indications for radiotherapy have decreased. However, radiotherapy remains an option for unresectable tumors or cases where surgery would result in unacceptable morbidity.[6] Long-term denosumab, alone or in combination with embolization, effectively controls symptoms and disease activity and is now preferred over radiotherapy at most centers.[7] Typically, a patient requires 3-4 angioembolization sessions and 8-10 doses of denosumab to achieve disease control. Radiotherapy, though less commonly used, remains an option at many centers, with a dose prescription of 45-50 Gy in 1.8-2 Gy fractions for adequate control.[8] While radiotherapy offers a cost-effective strategy and durable local control, prospective studies comparing it with other non-surgical modalities are needed to determine the best approach for unresectable GCTBs or cases with high surgical morbidity. To summarize, the article illustrates a firm basis for selecting appropriate treatment options for GCTB. The article emphasizes tackling unresectable and recurrent tumors with EBRT while highlighting that most appendicular GCTBs can be effectively treated with curettage, without neoadjuvant denosumab or radiotherapy. A small fraction of appendicular GCTBs requiring resection may benefit from a short course of neoadjuvant denosumab. To address rising treatment costs and reduce morbidity in selected cases of unresectable GCTBs, a cost-effectiveness analysis comparing EBRT and denosumab should be considered. I strongly believe that future studies on the pharmacoeconomic implications of various treatment approaches for GCTB will play a vital role in making healthcare more affordable and accessible for all. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.