The results of our study revealed similar progression-free survival with the observation approach when compared to metastasectomy as a first-line approach in patients with metastatic GCTB. Before 2010, many authors stressed the importance of early detection of metastasis in GCTB with regular long-term follow up and recommended, where possible, appropriate immediate surgical resection, such as metastasectomy, wedge resection, or lobectomy, to prevent progressive pulmonary dysfunction [11,16,32–35]. On the other hand, a few authors suggested that pulmonary metastases has a good long-term prognosis and should be kept under observation, avoiding aggressive treatment such as lobectomy, chemotherapy, and radiotherapy [20,43]. Since 2015, authors have suggested that it is unnecessary to perform lung metastasectomy immediately after the diagnosis of metastasis and it is more appropriate to perform metastasectomy only when there is disease progression in terms of volume and number of lung metastases [12,36–38]. According to a recent systematic review regarding prognosis of metastatic GCTB, spontaneous regressions were observed in 4.5% of patients [44]. Lung metastasis of GCTB often exhibits no changes in volume [36]. Because it is impossible to predict the behavior of lung metastases from GCTB [38], it is reasonable to evaluate the tumor biology with observation in each case in order to determine further treatments such as metastasectomy or medical treatment.
The mortality of the patients who had metastases from GCTB and received metastasectomy ranged between 0% and 50% [2,12–14,20,31,32,34,37,45–50]. The recurrence rate of the patients who had metastases from GCTB and received metastasectomy ranged between 0% and 50% [2,13,14,20,31,32,37,45,46,49]. The outcome following metastasectomy varied due to unpredictable tumor behavior of lung metastases from GCTB. Literature showed that aggressive lung metastasectomy might fail to produce a cure [51].
Although the efficacy of cytotoxic chemotherapy for lung metastases from GCTB has been scarcely reported [34,52], its role is loosely determined. Thus, considering that GCTBs are borderline tumors, they are not responsive to chemotherapy even after the appearance of the lung metastases [48].
There is anecdotal evidence that interferon a-2a can be effective in stabilizing progressive GCTB refractory to other modalities such as surgery, radiation and cytotoxic chemotherapy [53–55]. Interferon may have activity in GCTB via its antiangiogenic properties. Interferon is not well-tolerated and is associated with numerous side effects, including depression and ischemic events [56].
Feigenberg et al. [57] reported 3 patients with lung metastases from GCTB who were treated with whole-lung radiotherapy. One patient’s lung metastasis progressed after treatment, and the patient soon died. The 2 other patients were long-term survivors (7.5 years and 13 years) with complete resolution of detectable disease. However, radiotherapy may induce (secondary) malignant transformation, which is of concern especially because most patients are usually relatively young. The reported risk of malignant transformation varies between 0% and 5% [58–62].
Denosumab was able to stop the progression of lung metastases in 2 patients. In 1 of the 2 patients, lung metastases progressed despite chemotherapy but denosumab halted the progression of lung metastases. Palmerini et al. [26] reported a series of 15 patients with metastatic GCTB treated with denosumab and all patients achieved tumor control under denosumab treatment. Engellau et al. [63] reported that 38 patients with metastatic GCTB, who had tumor control under denosumab treatment. Thus, denosumab could halt the disease progression in most metastatic GCTBs. In our study, 2 patients underwent denosumab treatment and achieved tumor control of lung metastases without side effects. One of these 2 patients was treated with denosumab twice before surgical treatment of the primary lesion and then for the treatment of lung nodules. To date, there has been no evidence that denosumab rechallenge could be effective.
Balke et al. [28] reported a series of 12 patients with metastatic GCTB who had a stable disease following bisphosphonate treatment. Li et al. [64] conducted a randomized study comparing the efficacy and safety of denosumab and zoledronic acid treatment in patients with surgically unsalvageable GCTB, including GCTB of the sacrum and spine, and multifocal tumor including lung metastases. In their study, 29 of 125 patients who were administered denosumab had lung metastasis, compared to 25 of 125 patients who were administered zoledronic acid. Zoledronic acid halted the progression of lung metastases as well as denosumab, with relatively manageable adverse effects [64].
This study has some limitations. Firstly, a power analysis was not performed, and there was a risk of type Ⅱ error due to the small sample size. If an adequate number of patients is gathered in the future, significant differences may appear regarding the variables in this study. However, lung metastases from GCTBs are very rare. Secondly, the study was retrospective and thus had inherent limitations and risk of selection bias. Multivariable analysis was impossible due to the small sample and we were not able to correct of the influence of confounding factors. Moreover, there are still concerns of negative effect in terms of disease control or survival by delaying metastasectomy in patients who showed progression later. Future prospective randomized controlled trials with an endpoint of not only traditional oncologic metrics such as local recurrence, progression disease by imaging and death but also impact on quality of life and respiratory function are needed to confirm the similar outcome between the patients initially treated with observation and those treated with metastasectomy at presentation. As no randomized trials have been performed yet, well-designed cohort and observational studies with strong effects may provide reliable information. Thirdly, we have a histological documentation for the lung nodules only for the patients who underwent resection of their lung metastases. However, most patients with GCTB are young patients and it is not frequent among healthy young patients to have lung lesions; therefore, these lung lesions when observed in imaging studies of GCTB patients most likely represent GCTB lung metastases.