Although GCTB was classified as a benign tumor, the lung metastases rate differed from 1-21.1% and show a rising trend recently [3, 4]. Currently, the treatment of pulmonary metastasis for GCTB patients is still controversial. According to the National Comprehensive Cancer Network (NCCN) guidelines, surgical excision is the mainstay of the treatment for patients with resectable metastases. Denosumab therapy is a recommended regimen for patients with unresectable metastatic lesions [1, 5, 7]. Other alternatives include interferon alfa-2b, radiation therapy, or observation. However, interferon therapy had limited efficacy to treat metastases in most patients, and radiation therapy may increase the risk of malignant transformation.
The role of denosumab in controlling unresectable (local or metastatic) tumors has been well established [1, 5]. Luo et al reported seven patients with pulmonary metastatic GCTB who received denosumab treatment. None of their patients with metastatic disease progression was found during an average of 28.6 months follow-up period. Three patients showed partial response and four patients got stable disease after denosumab treatment [8]. An open-label, phase II study divided GCTB patients into 3 cohorts. Cohort 1 incorporated 169 patients including 43 pulmonary diseases with unresectable GCTB treated with denosumab. After a median follow-up of 13 months, 96% (163 of 169) of evaluable patients had no disease progression [9]. However, they also mentioned that six unresectable GCTB cases were determined to have disease progression after denosumab therapy, only one patient who had radiological progression continued denosumab therapy because of a good clinic response, one died of pulmonary complications, the other four stopped denosumab treatment, whereas the subsequent therapy was not documented.
In the presented case, denosumab alone was invalid in managing pulmonary metastases and the disease progressed after four months of denosumab therapy. As specimens of lung metastases were not available, it is hard to determine the pathological features of the metastatic lesions. We speculate whether the pathological changes had occurred in the metastatic lesions according to the rapid radiological progression despite previous literature indicated that pulmonary metastatic tumors maintained benign histological features [10]. In other words, if denosumab is still effective in malignant or sarcomatous GCTB. At the same time, the immunohistochemistry result of the recurrence in the patient was positive for VEGFR-2, indicating the antiangiogenetic therapy might be the potential therapeutic targets. As denosumab seems invalid to control the pulmonary metastases, but a cessation of denosumab therapy might lead to local recurrence of the tumor and critical hypercalcemia [11, 12], therefore, we decided to tentatively treat the patient with apatinib but did not rule out the denosumab treatment completely.
Pathological angiogenesis has been demonstrated to be a key role in the progression, invasion, and metastasis of tumor cells. Vascular endothelial growth factor (VEGF), overexpressed in many solid tumors including GCTB, is one of the central triggers for angiogenesis[13, 14]. VEGFR-2 presenting a strong tyrosine kinase activity towards pro-angiogenic signals is the key mediator of recognized VEGF induced phenotypes [15]. Most anti-angiogenic therapy in treating tumors mainly targets the VEGF-VEGFR system so far. Apatinib is a novel tyrosine kinase inhibitor (TKI) that selectively competes for VEGFR-2 ATP binding site, blocking downstream signaling and inhibiting tumor angiogenesis [16]. This therapy is effective for a wild range of primary malignancies and metastatic lesions, such as advanced gastric cancer, osteosarcoma, rhabdomyosarcoma, synovial sarcoma, and alveolar soft part sarcoma [17–19]. Wang et al showed a satisfactory result of the application of apatinib in 6 cases of pulmonary metastatic alveolar soft part sarcoma, leading to one complete response and five PRs [19]. Zhu et al reported an objective response rate of 33.3% and clinical benefit rate of 75.0% when apatinib was administered for 31 advanced sarcoma patients including 18 pulmonary metastases [18]. To our knowledge, there were limited reports discussed the efficiency of TKI and denosumab in the treatment of GCTB. Wang, G et al presented a case of GCTB with pulmonary and bone metastases that were treated with denosumab and sunitinib, and their patient achieved stable disease after four years of treatment [20]. Li, J et al reported a multicentric GCTB patient treated with apatinib and CT in the fourth month identified a partial response [21]. However, no study has previously used denosumab and apatinib for pulmonary metastases of GCTB.
In summary, when denosumab was invalid, the treatment strategy was unclear for patients with multiple pulmonary GCTB metastases. VEGFR-2 may provide an effective therapeutic target. We have shown that the novel combination of denosumab and apatinib can be used to treat pulmonary metastatic GCTB. However, long-term safety and the optimal duration of this therapy are still to be determined.