Retrospective review of safety and efficacy of anlotinib in advanced osteosarcoma with metastases after failure of standard multimodal therapy

To study the safety and efficacy of anlotinib, a multitargeted tyrosine kinase inhibitor, in the treatment of advanced osteosarcoma (OSS) with metastases.

LI ET AL. e315 chemotherapeutic agents, eventually leading to treatment failure and distant metastases, such as lung and liver metastases.The most common metastatic site is the lungs, and the prognosis of metastasis is often very poor. 4Hence, there is an urgent need for a new and effective treatment method, especially for the treatment of metastatic OSS in the advanced stage.
In the process of studying the molecular mechanism of tumorigenesis, invasion, spread, and metastasis, researchers discovered related protein molecules and tried to use these protein molecules as attack targets to specifically inhibit the proliferation and spread of tumor cells.Molecular targeted therapy has become a hotspot in OSS research in recent years.The typical characteristic of a malignant tumor is continuous angiogenesis, which plays an important role in tumor invasion, growth, and metastasis.Thus, antiangiogenesis is considered to be a potential and important form of cancer treatment.Anlotinib, a new drug independently developed in China, is a small-molecule multitarget tyrosine kinase inhibitor that effectively inhibits vascular endothelial cell growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, stem cell growth factor receptor, and other kinase activities, thus inhibiting tumor blood vessel growth and consequently tumor growth. 5,6Anlotinib has shown good safety in third-line and above treatment of advanced non-small cell lung cancer and STS.The National Medical Products Administration (formerly the China Food and Drug Administration, CFDA) approved its listing on May 9, 2018. 7,8In this study, anlotinib was used as a single drug to treat metastatic advanced OSS after the failure of standard multimodal therapy to evaluate its safety and therapeutic efficacy, providing more clinical evidence for its ability to supplement and improve the treatment options for metastatic OSS.

Treatment
Therapeutic doses of anlotinib for adults and for children and adolescents were 12 and 10 mg, respectively, once a day taken orally before breakfast for 2 consecutive weeks, followed by 1 week of withdrawal.
This 3-week treatment cycle was repeated.If patients missed a dose, they were instructed to not take the missed dose if there were less than 12 h remaining before the next dose.Patients were followed to observe the performance of the medication, especially any adverse events related to the medication.Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 issued by the National Cancer Institute.Patients with uncontrolled or intolerable adverse events had their anlotinib doses reduced to 10 or 8 mg.Moreover, patients were required to stop the medication when unacceptable serious adverse events or tumor progression occurred or when the patients refused to take the medication.

Efficacy and safety assessments
The tumor response of the patients was evaluated by physical examinations, magnetic resonance imaging, and/or computed tomography (determined according to the clinical situation) every 2 months until the disease progressed.The evaluation indicators of the curative effect included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), objective response rate (ORR), and complete response (CR).PFS was defined as the time from the beginning of anlotinib treatment to disease progression or death, and OS was defined as the duration from the first use of anlotinib to the last follow-up or death, whichever came first.DCR was considered to be the percentage of stable disease (SD), CR, and partial response (PR), whereas ORR was the percentage of PRs and CRs.PD, SD, CR, and PR were determined by professional physicians based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.Adverse events related to the anlotinib treatment were evaluated according to the evaluation criteria for adverse drug events (version 4.0), from the beginning of the anlotinib application to at least 1 month after the last anlotinib application.

Statistical analysis
In this study, therapeutic safety and survival analysis was performed for patients who had finished at least one cycle of anlotinib.Kaplan-Meier survival curves were used for OS and PFS estimations.All statistical data analyses were performed using SPSS for Windows (version 20.0, IBM, Armonk, NY).

Ethics
This observational and retrospective study was approved by the ethics committee of the Southwest Hospital, the Third Military University (30 Gaotanyan Street, Shapingba District, Chongqing, China).

Patients and tumor characteristics
From June 2018 to April 2020, 15 OSS patients in our hospital received anlotinib treatment (Table 1).All patients had lung metastases before anlotinib treatment.The lung is the most common metastatic site in

Therapeutic efficacy
In this study, the median follow-up time of the patients was 10.7 months.At the last follow-up, five patients (33%) died of tumor progression.Ten patients (66.6%) showed no progress after 6 months of anlotinib treatment.Three patients (20%) received anlotinib for more than a year.The median PFS time was 9.8 ± .9 months (95% confidence interval [CI]: 8.0-10.5).The 6-and 10-month PFS rates of the patients were 73% and 33%, respectively.

Toxicity and safety
The median duration of anlotinib was 7.1 months.Table 2

DISCUSSION
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.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. 9However, 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%. 10The existing mainstream mode of treatment for OSS is preoperative neoadjuvant chemotherapy plus surgical resection plus postoperative adjuvant chemotherapy. 11The 5-year survival rate of patients has been greatly improved with the above treatment.How- In a multicenter, 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 vs. 6.3 months), the PFS was significantly prolonged (5.4 vs. 1.4 months), and the ORR and DCR were heightened (9.18% vs. .70%and 80.95% vs. 37.06%, respectively), with all showing significant improvement. 16series 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%. 7,17Based 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 treatments for metastatic OSS.Tian et al. 18  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 metastatic OSS, apatinib seems to be more effective than anlotinib.Nevertheless, in our current study, the PFS was 9.8 ± .9 months, and the OS was 11.4 ± .6 months.Ten patients (67%) exhibited SD, and 2 patients (13%) had PR.Comparing the results of the average PFS of sorafenib and apatinib, 15,18  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 one patient stopped anlotinib treatment due to economic reasons.7][18][19] However, four patients in our study developed pneumothorax, among which one 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. 20 believed 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 1-2, and no drugrelated 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 OSS that has metastasized after the failure of surgery and chemotherapy to receive anlotinib treatment.To further evaluate the value of anlotinib in the treatment of OSS with metastases, a multicenter, prospective, randomized controlled study is needed.
shows the side effects and toxicity experienced by the patients.The most common toxic reactions included hand-foot syndrome (n = 8, 53.3%), diarrhea (n = 5, 33.3%), hypertension (n = 6, 40%), fatigue (n = 4, 26.7%), pneumothorax (n = 4, 26.7%), weight loss (n = 4, 26.7%), anorexia (n = 3, 20%), and elevated transaminase (n = 3, 20%).In general, drug-related adverse events were limited to Grade 1 or Grade 2. Grade 3 adverse events of the patients included hand-foot syndrome (n = 2, 13.3%), pneumothorax (n = 2, 13.3%), and hypertension (n = 1, 6.7%).No drugrelated deaths or Grade 4 adverse events occurred among the patients.The drug toxicity was generally well tolerated by the patients.Anlotinib was discontinued in one patient due to hand-foot syndrome during treatment, and the drug was discontinued for economic reasons after symptoms improved.One patient had to reduce the dose of anlotinib to 10 mg due to pneumothorax.This patient was treated with closed thoracic drainage and other symptomatic treatment outside our hospital, and the therapeutic dose of anlotinib dose was restored after their condition improved.One patient stopped taking anlotinib due to pneumothorax.
anlotinib seems to be superior to apatinib and sorafenib in the treatment of 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 are needed to further confirm this observation.Compared with other literature reports, the patients in our study were younger.If the anti-angiogenic drugs such as anlotinib are more effective for children or adolescents, we do not know and need clinical comparison trial to further evaluate the value of anlotinib in the treatment of advanced OSS patients of different ages.In addition, based on previous literature, an antitumortargeted 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 CR.Anlotinib was effective in treating metastatic 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 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, because 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 an 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.
Characteristics of 15 advanced osteosarcoma patients with metastases treated with anlotinib TA B L E 1Abbreviations: ADM, doxorubicine; DDP, cisplatin; GEM, gemcitabine; IFO, ifosfamide; MTX, methotrexate; OS, overall survival; PFS, progression free survival; PR, partial response; SD, stable disease; TXT, docetaxel; VP-16, etoposide.OSS.The mean age of patients with OSS was 15.2 years (ranging from 10-to 21-year old), and 60% of the patients in this study were male.radiotherapy in other hospitals before amputation.Three patients underwent two surgeries, one of which was due to postoperative superficial incision infection, which was healed after debridement, and the other two patients underwent incision biopsies in another hospital.No local recurrence occurred in all 15 patients during follow-up.None of them underwent lung surgery.All patients received the anlotinib treatment for at least a month.
Drug-related adverse events that arose in at least one patient The median OS time was 11.4 ± .6 months (95% CI: 10.3-12.5).None of the patients achieved CR.However, 10 patients (66.6%) had SD, and 2 patients (13%) had PR.After 6 months of follow-up, the DCR and ORR of the patients were 80% and 13%, respectively.Similar to other targeted drugs, clinical observations showed that an interruption of anlotinib treatment could lead to disease progression.Resuming anlotinib treatment may once again LI ET AL. e317 TA B L E 2 bring about disease control.Previous local treatments, such as surgery or radiotherapy, had no significant effect on the therapeutic efficacy of anlotinib.