Is a Short-course of Preoperative Denosumab as Effective as Prolonged Therapy for Giant Cell Tumor of Bone?

Abstract

Background Denosumab is an inhibitor of monoclonal receptor activator of nuclear factor-ĸB ligand, approved to treat giant cell tumors of bone (GCTB). It is commonly used for unresectable tumors and for downstaging the tumor to perform less-morbid procedures. Although denosumab has been used extensively for GCTBs, there are no recommendations regarding the duration of therapy. The risk factors associated with local recurrence (LR) in patients receiving preoperative denosumab for GCTB also are unknown. Questions/purposes (1) Is short-course (three doses or fewer) preoperative denosumab treatment as effective as longer course (more than three doses) of treatment in terms of achieving a clinical, radiologic, and histologic response in patients with GCTB? (2) Is there an increased risk of LR after short-course denosumab therapy compared with long-course denosumab therapy; and after controlling for confounding variables, what factors were associated with LR after surgery for GCTB in patients receiving preoperative denosumab? Methods A retrospective study was performed using an institutional database of 161 skeletally mature patients with a histologic diagnosis of GCTB who received denosumab between November 2010 and July 2019 to downstage the tumor before surgery. In general, we used denosumab when we thought it would facilitate either resection or curettage (by formation of a sclerotic rim around the osteolytic lesion), when a less-morbid procedure than initially planned might be performed, and in patients with complex presentations like cortical breech and soft tissue extension, pathological fracture, thinning of more than three cortices of the extremity. From 2010 to late 2015, denosumab was administered for approximately 4 to 6 months; starting in late 2015 through 2020, the number of denosumab doses has been reduced. We divided patients into two groups: Those who received three or fewer doses of denosumab (short-course, n = 98) and those who received more than three doses of denosumab (long-course, n = 63). Comparing those in the long-course group with those in the short-course group whose procedures were performed at least 2 years ago, there were no differences in loss to follow-up before 2 years (3% [3 of 98] versus. 3% [2 of 63]). The mean patient age was 30 years (± 6.1) and the mean number of denosumab doses was 4.4 (range 1 to 14). Overall, 77% (37 of 48) of patients taking short-course denosumab and 75% (27 of 36) of patients on long-course denosumab underwent curettage, and the remaining patients with an inadequate bony shell around the tumor or destruction of articular cartilage in both groups underwent tumor resection. With the numbers available, the patients with short- and long-course denosumab were not different in terms of age, sex, MSTS score on presentation, lesion size, lesion location, Campanacci grade, presence of pathological fracture and pulmonary metastasis on presentation, and the type of surgery performed (curettage versus resection). We analyzed the change in the Musculoskeletal Tumor Society score, change in Campanacci grade, radiologic objective tumor response (defined as a partial or complete response, per the modified inverse Choi criteria), and histologic response (defined as reduction of more than 90% of osteoclast-like giant cells or a reduction of more than 50% of mesenchymal spindle-like stromal cells, along with evidence of lamellar or woven bone formation, when compared with the biopsy sample) between the two groups (short- and long-course denosumab). LR rates were compared between the two groups, and after controlling for confounding variables, factors associated with LR in all operated patients were analyzed with a Cox proportional hazards regression analysis. Results With the numbers available, there was no difference between the short- and long-course denosumab groups in terms of mean percentage improvement in MSTS score (20 [± 18.5] versus 24 [± 12.6]; p = 0.37), radiologic objective tumor response (90% [43 of 48] versus 81% [29 of 36]; p = 0.24) and histologic response (79% [38 of 48] versus 83% [30 of 36]; p = 0.81). With the numbers available, there was no difference between the short- and long-course denosumab groups in terms of Kaplan-Meier survivorship free from LR at 5 years after surgery (73% [95% confidence interval, 68 to 76] versus 64% [95% CI 59 to 68]; log-rank p = 0.50). After controlling for potential confounding variables like age, sex, Campanacci grade and MSTS score on presentation, number of denosumab doses administered before surgery, clinical, radiologic and histologic response to denosumab, and time duration between denosumab therapy and surgery, we found that tumors involving the bones of the hand and the foot (hazard ratio 7.4 [95% CI 2.0 to 27.3]; p = 0.009) and curettage (HR 6.4 [95% CI 2.8 to 23.0]; p = 0.037) were independently associated with a higher risk of LR. Conclusions In this preliminary, single-center study, we found that a short-course of preoperative denosumab (three or fewer doses) was associated with no differences in clinical scores, histological and radiological response, or LR-free survivorship, compared with longer-course of denosumab (more than three doses). Fewer preoperative doses can reduce the complications and costs associated with more-prolonged therapy. Denosumab must be used cautiously before curettage for GCTB, and only if the benefit of joint salvage outweighs the possibility of LR. However, given the small number of patients, potentially clinically important differences might have been missed, and so our findings need to be confirmed by larger, multicenter, prospective trials. Level of Evidence Level III, therapeutic study.

Bone sarcomas: ESMO–EURACAN–GENTURIS–ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up

“…92,93 Denosumab, a human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK)-ligand (RANK-L), known to be overexpressed in GCTB, is the standard treatment in unresectable or metastatic GCTBs [III, A]. [93][94][95] Its use in the preoperative setting for GCTBs that are potentially resectable with high morbidity is debated and should be reserved for complex cases [II, C]. 96 There is increasing evidence that, if used preoperatively and before curettage, surgery is best carried out after a few months of J o u r n a l P r e -p r o o f treatment, although the most appropriate length of preoperative treatment has not been established yet [V, C].…”

“…96 There is increasing evidence that, if used preoperatively and before curettage, surgery is best carried out after a few months of J o u r n a l P r e -p r o o f treatment, although the most appropriate length of preoperative treatment has not been established yet [V, C]. 93,94 The optimal schedule and duration of treatment with denosumab in metastatic or surgically unsalvageable GCTs is also undefined, and the possible long-term side-effects are still largely unknown. Preliminary evidence suggests that denosumab interruption can be followed by disease progression.…”

Denosumab in Giant Cell Tumor of Bone: Current Status and Pitfalls

“…Maximum 3–4 months was deemed as the optimum time frame before intralesional surgery, considering that 6 months made the possibility of recurrence rate higher by getting the bony shell thicker and trapping more tumor cells. Hindiskere et al ( 51 ) found that there were no significant differences between short-course (there or fewer doses) and long-course (more than three doses) groups of preoperative denosumab in terms of clinical scores, histological and radiological response or local recurrence survivorship. Short-course could reduce costs and complications linked with long-course therapy.…”

What’s new in musculoskeletal oncology

“…Hindiskere et al analyzed 161 patients with GCTB who received preoperative denosumab treatment for downstaging prior to surgery. They reported that there was no difference between short-term and long-term administration of denosumab in terms of radiologically objective tumor response (90 % [43 of 48] vs. 81 % [29 of 36]; p = 0.24), histological response (79 % [38 of 48] vs. 83 % [30 of 36]; p = 0.81), and local recurrence-free survival rate at five years after surgery (73 % vs. 64 %; p = 0.50) [ 10 ]. They suggested that reducing the preoperative dose of denosumab can reduce the complications and costs of denosumab [ 10 ].…”

“…They reported that there was no difference between short-term and long-term administration of denosumab in terms of radiologically objective tumor response (90 % [43 of 48] vs. 81 % [29 of 36]; p = 0.24), histological response (79 % [38 of 48] vs. 83 % [30 of 36]; p = 0.81), and local recurrence-free survival rate at five years after surgery (73 % vs. 64 %; p = 0.50) [ 10 ]. They suggested that reducing the preoperative dose of denosumab can reduce the complications and costs of denosumab [ 10 ]. These studies suggest that physicians should carefully consider the use of denosumab before curettage of GCTB, and confirm that a short course of denosumab before resection can make surgery easier, with a lower risk of local recurrence.…”