OSS is a malignant tumor that originates in mesenchymal tissues. It is prone to occur in the metaphysis of long bone with rich blood supply. OSS is highly malignant and has a poor prognosis. It occurs in children and adolescents, seriously threatening their health and even life. The cause of OSS is closely related to previous trauma history, genetic factors, viral infection, and radiation stimulation [9]. In clinical practice, OSS manifests as local pain and swelling, sometimes accompanied by joint dysfunction. The manifestations are relatively insidious, and some may be found early due to pathological fractures caused by trauma [10]. Whereas in other patients, some patients have had distant lung metastasis at the time of OSS diagnosis, and when distant metastasis of OSS occurs, the 5-year disease-free survival rate is less than 20% [11]. The existing mainstream mode of treatment for OSS is preoperative neoadjuvant chemotherapy plus surgical resection plus postoperative adjuvant chemotherapy [12]. The 5-year survival rate of patients has been greatly improved with the above treatment. However, further improvement of the therapeutic efficacy has fallen into a bottleneck. No unified treatment plan is currently available for patients with advanced osteosarcoma and metastases who have failed the traditional standard treatment (i.e., surgery plus chemotherapy) in China and other countries. The prognosis of these patients is usually poor. Thus, it is imperative to explore new safe and effective treatment methods and strategies for OSS.
Molecular targeted therapy has become one of the hotspots in tumor therapeutic research in recent years. Since the first targeted therapy drug, rituximab, was approved for clinical use by the United States Food and Drug Administration (FDA) in 1997, there have been more drug trials specifically targeting OSS targets and immunotherapy [13]. Sirolimus, an inhibitor of the mechanistic target of rapamycin (mTOR) signaling channel, inhibits insulin-like growth factor 1 on its downstream channel to promote tumor cell proliferation and revascularization. It has been found in experimental animals to prevent metastasis and tumor growth of OSS. Everolimus, an oral mTOR inhibitor, has the same effect as sirolimus, and the antitumor efficacy is enhanced when combined with zoledronic acid [14, 15]. Takagl et al. [16] suggested that the contact between OSS and platelets in the body may cause platelet aggregation and stimulate the release of PDGF. Platelet aggregation leads to the phosphorylation of platelet-derived growth factor receptors (PDGF-R) and protein kinase B (Akt) and promotes the proliferation of OSS cells. Breaking the binding of PDGF by ligands inhibits tumor angiogenesis to provide an anti-tumor effect. Gobin et al. [17] showed that in mouse animal models of osteosarcoma, imatinib mesylate inhibited tumor growth. However, some experiments showed that imatinib was less effective as a single drug for patients with OSS [18], and it was not appropriate to use imatinib alone to treat advanced OSS.
Angiogenesis is one of the important pathological characteristics of malignant tumors. It not only provides nutrition for the growth of tumor cells, but also secretes growth factors to promote tumor cell proliferation and to play an important role in tumor growth, invasion, and metastasis [19]. Thus, VEGF, which is involved in tumor angiogenesis, is an important antitumor target of drugs including bevacizumab, sunitinib, sorafenib, cediranib, and pazopanib. Among them, sorafenib has been recommended by the US FDA and the NCCN as a second-line drug for patients with relapsed and metastatic OSS. It prevents tumor blood vessel proliferation by inhibiting VEGF receptor 2 and PDFG-R-beta, thereby inhibiting tumor growth. The study results of Heymann et al. [20] have shown that sorafenib is expected to reduce tumor growth and inhibit lung metastasis in an OSS model. Results of Grignani et al. [21] in a phase II clinical trial of relapsed and unresectable OSS showed that the 4-month disease-free survival rate was 14% among all patients and 29% among patients with stable disease. In addition, Grignani et al. were the first to report the use of an active targeted drug in patients with OSS. However, sorafenib has not been approved in China for use in OSS patients. Moreover, the long-term application of sorafenib is very expensive. Most patients with OSS who have undergone surgery and multiple consecutive chemotherapy, especially those in developing western regions in China, cannot afford such a high medical cost. The cost burden of anlotinib is much lower than sorafenib. Anlotinib was approved by CFDA on May 8, 2018, for third-line and above treatment of lung cancer.
The results of phase I/II/III clinical trials of anlotinib in the treatment of advanced non-small cell lung cancer show that it has good efficacy and safety. In a multi-center, double-blind, randomized controlled phase III clinical trial study that included a total of 439 patients who were randomly assigned to an anlotinib group (296 cases) and a placebo group (143 cases) at a ratio of approximately 2:1, the OS time of the anlotinib group was significantly longer than that of the placebo group (9.6 months vs. 6.3 months); the PFS was significantly prolonged (5.4 months vs. 1.4 months); and the ORR and DCR were heightened (9.18% vs. 0.70% and 80.95% vs. 37.06%, respectively), with all showing significant improvement [22]. A series of clinical studies have also confirmed that anlotinib is equally effective for many types of STS, as its PFS and OS are significantly prolonged; the ORR and DCR see obvious benefits; and the risk of disease progression is reduced by 67.0% [7, 23]. Based on the excellent efficacy and safety of anlotinib in the treatment of a variety of malignant tumors, we have gradually begun to try the second- and third-line treatment for metastatic advanced OSS. Zhichao et al. [24] retrospectively studied 110 patients who received apatinib or anlotinib alone, including 32 OSS and 78 STS. In the treatment of OSS, ORRs were 15.79% (3/19) in the apatinib group and 7.69% (1/13) in the anlotinib group, and DCRs were 63.16% (12/19) in the apatinib group and 30.77% (4/13) in the anlotinib group. The m-PFSs were 4.67 ± 3.01 months in the apatinib group and 2.67 ± 1.60 months in the anlotinib group. These results indicate that both apatinib and anlotinib are effective in the treatment of sarcoma. However, the specific efficacy and adverse events are based on the tissue type of the sarcoma. For advanced metastatic OSS, apatinib seems to be more effective than anlotinib. Nevertheless, in our current study, the PFS was 9.81 ± 0.9 months, and the OS was 11.43 ± 0.58 months. Ten patients (66.6%) exhibited SD, and 2 patients (13.3%) had PR. Comparing the results of the average PFS of sorafenib in April and OS in July [21], anlotinib seems to be superior to apatinib and sorafenib in the treatment of advanced metastatic OSS, indicating that anlotinib can be used as a potential new treatment option. However, the number of patients in our study is relatively small, and a larger number of patients is needed to further confirm this observation. In addition, based on previous literature, an antitumor targeted drug with more targeted receptors has better clinical effects. Anlotinib is a multitarget drug that inhibits multiple receptors and has shown certain advantages in the treatment of malignant tumors. Our research also obtained evidence in support of its clinical efficacy. Most patients’ tumors were under control after taking the medication, and some patients benefited for a long time, but none achieved complete response (CR). Anlotinib was effective in treating advanced OSS, although its underlying mechanism needs to be clarified by further study.
Importantly, in some patients with PR and SD, we found that tumor cavities formed in lung metastases (Figure 3) for unknown reasons. It is possible these cavities were caused by ischemic necrosis of tumor cells after tumor angiogenesis was interrupted. Because of the short follow-up duration, no repair of tumor cavity was found. However, we still believe that the formation of metastatic tumor cavities is a positive signal for tumor cell necrosis and metastasis control and can be used as a criterion for tumor control instead of relying on the change in tumor volume alone. Moreover, like other targeted antiangiogenesis drugs reported in the previous literature, we also treated OSS with anlotinib as a single agent due to the following reasons: (1) Most patients had received a variety of chemotherapeutics in the past, with relatively poor tumor control effect. In addition, the interference of other drugs in observing the efficacy of anlotinib was excluded. (2) As with any chemotherapeutic agent, we wanted to identify the side effects of anlotinib, since severe side effects may result in patients losing the benefits of anlotinib treatment. (3) Most chemotherapeutic agents are transported through blood vessels to the tumor site to exert antitumor effects, and anlotinib inhibits tumor angiogenesis. In metastatic advanced OSS, it is effective application of antiangiogenesis targeted drugs like anlotinib is not clearly understood and the effectiveness of anlotinib combination with other chemotherapeutic agents and immunotherapy drugs is unclear.
Regarding the adverse events caused by anlotinib treatment in this study, the most common toxic reactions were hand-foot syndrome, hypertension, diarrhea, fatigue, and pneumothorax. None of these adverse events caused serious consequences in this study. After active symptomatic treatment, these adverse events basically returned to normal. A very small number of patients had to be given a lower dose of anlotinib (reduced the dosage to 10 mg), and 1 patient stopped anlotinib treatment due to economic reasons. It is noteworthy that the incidence of pneumothorax in previous literature on the adverse events of anlotinib was relatively low [7, 22, 23, 24, 25]. However, 4 patients in our study developed pneumothorax, among which 1 patient had to have their dosage of anlotinib reduced to 10 mg due to pneumothorax. Symptomatic treatment, including closed-thoracic drainage, was provided to this patient outside our hospital. This patient resumed anlotinib treatment after their condition improved. Another patient had to stop taking anlotinib due to pneumothorax. There are many reasons for the occurrence of pneumothorax. For example, Nakamura et al. [26] believe that it may be related to the pleural invasion of lung metastases and tumor necrosis and tumor cavity formation caused by targeted therapy. Previous literature has also shown that anlotinib is mainly used for the treatment of lung cancer and STS. This study observed the efficacy and safety of anlotinib in the treatment of OSS. Further study by increasing the sample size is necessary to confirm whether the occurrence of pneumothorax may be related to the subtypes of the tumor. In general, this retrospective study found that most adverse events after the treatment were Grade 1 to 2, and no drug-related deaths occurred, indicating that anlotinib was safe and well tolerated by the patients, except for hand-foot syndrome, diarrhea, and hypertension. Adverse events such as pneumothorax should be discovered and dealt with promptly to improve patient compliance.
This study has some limitations. First, this is an observational and retrospective study without a control group. Data provided by other similar studies can be used to compare the toxicity and effectiveness of anlotinib. Second, before the application of targeted drug therapy, target detection is an important process to obtain better curative effects. However, most patients in our study did not undergo target detection. Third, the number of patients in this study is relatively small. It should be recognized that OSS is a rare malignant tumor. It is not common for patients with advanced OSS that has metastasized after failure of surgery and chemotherapy to receive anlotinib treatment. To further evaluate the value of anlotinib in the treatment of advanced osteosarcoma with metastases, a multicenter, prospective, randomized controlled study is needed.