Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone

Giant cell tumor of bone (GCTB) is a histologically benign bone tumor composed of mononuclear stromal and multinucleated giant cells that exhibit osteoclastic activity, typically arising in the metaphyseal/epiphyseal portions of long bones [1, 2]. GCTB causes significant bone destruction, leading to pain, pathologic fracture, and impaired joint structure and functionality [3, 4]. Surgical resection is the primary curative method for GCTB; however, aggressive interventions, such as adjuvant therapy with liquid nitrogen or phenol, are often required to decrease morbidity, avoid amputation, and ensure adequate local control [4, 5]. Effective treatment options are limited for patients with lesions in locations not amenable to surgical resection [4], and local recurrence develops after several years in approximately 10–50% and 5% of patients after intralesional treatment or wide resection, respectively [5‐8].

Constitutive activation of receptor activator of nuclear factor-kappa B (RANK) ligand maintains the osteolytic phenotype in GCTB [9, 10]. Denosumab (XGEVA^®, Amgen Inc., Thousand Oaks, CA, USA), a RANK ligand inhibitor, is a fully human monoclonal antibody approved for the treatment of unresectable GCTB or when resection may result in severe morbidity. Denosumab treatment of GCTB prevents further tumor progression, reduces tumor size, reforms mineralized bone, and increases intralesional bone density [10, 11].

Radiologic assessment of tumor response in bone tumors presents unique challenges, and no uniform radiographic assessment criteria to date have been advanced to specifically assess response in GCTB. To address this challenge, our analysis combined imaging assessment techniques and captured response elements from three response evaluation measures widely employed in the assessment of change in tumor burden across a variety of tumor types, with modifications to tailor the response measures specifically to the unique properties of GCTB. Imaging records from two phase 2 clinical trials that supported denosumab registration [10, 11] were analyzed with three imaging parameters to measure the changes in lesion size and density, compare available radiographic parameters, and assess treatment response to denosumab in patients with GCTB.

We observed impressive tumor control rates, with nearly all patients with GCTB showing sustained tumor control for ≥ 24 weeks, using any of the response criteria. Increases in lesion density by HU likely reflected the pharmacodynamic response to denosumab treatment (i.e., suppression of osteolysis and increased formation of dense fibro-osseous tissue and/or woven bone [9]). This clinical benefit allows patients to defer or downstage their planned surgical procedure when surgical resection is likely to result in severe morbidity [15]. In contrast, a purely size-based evaluation using RECIST is potentially insensitive in assessing response in bone lesions with a mixed osteolytic and expanding soft tissue component; the size of GCTB tumors changes little with targeted therapies. Therefore, an inverse modification of the ICDS was used to evaluate both GCTB density and size; either a decrease in size or an increase in density was considered a response to treatment. In GCTB, decreases in tumor size per LD are believed to reflect cytoreduction, in alignment with RECIST principles for solid tumor assessment. The kinetics of GCTB responses to denosumab therapy showed rapid cytoreduction that peaked by 3 months and was maintained thereafter, with responses of ≥ 24 weeks in nearly all patients. The Choi criteria were developed to monitor response in a soft tissue sarcoma undergoing targeted therapy where tumor cell viability and radiological size reduction may be uncoupled during the response to treatment [14]. Analogous to GIST, in the setting of GCTB, we believe that the ICDS criteria used in the present study perform as pharmacodynamic markers of effect and may offer an advantage to conventional RECIST.

In our study, patients had unresectable tumors or tumors requiring highly invasive or disabling surgery in an attempt to achieve surgical cure; therefore, there was a large number of pelvic, spine, and pulmonary lesions that complicated radiographic evaluation of response. Using ICDS, four patients had a ≥ 10% increase in LD, two of whom sustained increases in tumor size after study enrollment but before administration of denosumab. These two patients experienced sustained disease control lasting several months while receiving denosumab continuously, and for one patient, 12 additional months of disease control following discontinuation of denosumab. The remaining two patients had atypical GCTB. One had multiostotic and metastatic GCTB with lesions in the pelvis, rib, and lung at study entry and received denosumab for 8 months before being lost to follow-up. Multiostotic GCTB accounts for < 1% of all GCTB and has a different clinical presentation than solitary lesions; typically, patients are younger, suggesting a germ-line component that confers susceptibility to the disease [16‐21]. The other patient with atypical GCTB with an increased tumor size had a clinically aggressive disease with ten previous attempts at surgical resection before enrollment. While these patients met all histological entry criteria and had pathologically confirmed GCTB, it remains unclear whether their atypical courses before and during denosumab treatment suggest an aggressive clinical variant of classical GCTB or an alternative diagnosis. Because true nonresponse to denosumab in GCTB is rare, patients with nonresponse may deserve more comprehensive sampling for histological disease assessment. The best percentage change in density for target lesions in the ICDS evaluation showed that 80% of the 124 patients evaluable for density had a ≥ 15% increase in density, reflecting the desired outcome of denosumab therapy.

Our results confirm and extend findings reported in a smaller study [22] where 88% patients (n = 17) had an objective tumor response using any response criteria after denosumab treatment (median duration of 13.1 months). In the present study, the proportions of patients with an objective tumor response were 35% per RECIST, 82% per PET scan criteria, and 71% per ICDS criteria (size/density). The median time to objective tumor response using any of the response criteria was 3.0 months (95% CI, 2.9–3.1). The benefit of denosumab in GCTB has already been established [10, 11]; our results provide clinicians with additional information on imaging and monitoring patients with GCTB treated with denosumab.

The single-arm study design limits our analysis; however, the central independent review of images was conducted to minimize this limitation. Furthermore, this study had a large number of unevaluable patients, there was no protocol-defined imaging schedule or methodology (which is standard for this type of study), and only a few PET scans were done, as PET was optional. We also limited our definition of sustained tumor control to a time frame of 24 weeks, which may be considered short by some clinicians; however, there are no well-established tumor response criteria for patients with GCTB [22]. We also did not examine any association between response and extent of prior treatment or other factors. The retrospective nature of this analysis made obtaining historical images difficult.

There are inherent limitations associated with using RECIST alone for assessment of denosumab response in GCTB because of the sometimes modest reduction in tumor size despite clinical benefit. Reduction in ¹⁸FDG-PET avidity predicted a favorable tumor response and sustained tumor control with denosumab treatment. Given the rarity of denosumab refractoriness in typical GCTB, new or continued high SUV_max levels while on denosumab should alert clinicians to the possibility of an aggressive clinical variant or an alternate diagnosis such as sarcoma.

Our data do not suggest an increase in the risk of osteosarcoma following denosumab treatment. There are recent case studies of patients with GCTB treated with denosumab who have developed osteosarcoma [23, 24]; three patients were diagnosed with osteosarcoma during denosumab treatment in primary reports of the studies used for our analysis [10, 11]. Patients with GCTB are at higher risk for developing osteosarcoma than the general population, with approximately 2–5% of patients developing secondary sarcoma following radiotherapy or surgical resection [25‐27]. There also remains the previously reported, equally difficult task of identifying patients with small foci of sarcomatous change within the large field of otherwise benign-appearing GCTB [28]. The incidence of pathologic fracture is up to 30% in patients with GCTB; data to date do not indicate an increased rate with denosumab [8, 29, 30].

Modified PET scan criteria and ICDS criteria showed responses in most patients in our analysis, indicating a substantially higher benefit rate compared to that assessed by modified RECIST. PET or CT with ICDS provided an early indication of treatment response. Moreover, all response criteria indicated tumor control ≥ 24 weeks to denosumab. Loss of ¹⁸FDG-PET avidity may have a dual role in both predicting long-term disease control and offering clinicians some reassurance that there is not a focus of sarcoma with the GCTB lesion, which would likely remain ¹⁸FDG-PET avid despite denosumab treatment. Further research is required to determine the appropriate imaging technique to be used longitudinally in a given patient, although many practitioners favor a combination of plain radiographs and CT. Regardless of the modality used, careful evaluation of nonresponders is necessary.