Survival benefits and challenges of adjuvant chemotherapy for high-grade osteosarcoma: a population-based study

Osteosarcoma is the most common primary malignant bone tumor, which tends to occur in children and adolescents. The predilection site of osteosarcoma is long bone epiphysis, which is prone to early lung metastasis [1]. The prognosis for patients with osteosarcoma is poor, with a dismal 5-year survival rate of less than 20% before the 1970s. It was not until the emergence of chemotherapy drugs, such as methotrexate, doxorubicin and leucovorin, that the survival rate of osteosarcoma increased to more than 50% [2]. The original surgical method of osteosarcoma is mainly amputation. With the application of chemotherapy, limb-salvage surgery has become the mainstream treatment method for osteosarcoma and further improves the 5-year survival rate of patients [3]. Currently, the survival rate of patients without metastatic osteosarcoma can reach 60–70% with surgical and chemotherapy therapy, but the overall survival time of metastatic osteosarcoma is less than 30% [4]. In the past few decades, although advanced treatments have been used to improve the survival of osteosarcoma patients, the long-term survival rate has not been further improved [5].

Chemotherapy is an important treatment to improve the survival of patients with osteosarcoma. Cisplatin, doxorubicin, methotrexate and ifosfamide are first-line drugs for osteosarcoma. However, chemotherapy is unsuitable for all patients with osteosarcoma, and many factors can affect patients receiving chemotherapy. With the increase in age, the chemotherapy acceptance rate also gradually decreased. Longhi et al. [6] reviewed 43 osteosarcoma patients over 65 and found that stage, tumor volume, and surgery were important prognostic factors, but chemotherapy was not significant. Okada et al. [7] analyzed the prognosis of 64 patients with osteosarcoma over 50 years old and found that chemotherapy could not improve the prognosis of these patients. For low-grade tumors, the absence of chemotherapy can also result in high survival rates. Righi et al. [8] found that high-grade components appeared in low-grade central osteosarcoma, chemotherapy was unnecessary as long as it was less than 50%, and radical surgical resection could achieve a high survival rate. In addition, other factors may affect patients’ acceptance of chemotherapy, such as gender, race and insurance [9].

Chemotherapy regimens for osteosarcoma have been improved in recent years. A combination chemotherapy regimen of cisplatin, doxorubicin, methotrexate, and ifosfamide is used in most bone tumor treatment centers but varies from center to center. The European Osteosarcoma Intergroup (EOI) recommended the combination of cisplatin and doxorubicin (6 treatments for 18 weeks), and Memorial Sloan Kettering Cancer Center, on the other hand, uses a modified T10 regimen (eight drugs combined for 44 weeks) [10]. In addition, neoadjuvant chemotherapy also plays an important role in limb-salvage surgery. However, neoadjuvant chemotherapy did not significantly improve prognosis, and a randomized controlled trial by the Pediatric Oncology Group (POG) showed no significant difference in survival between patients receiving neoadjuvant chemotherapy and those undergoing immediate surgery after diagnosis [11]. In addition, clinical second-line chemotherapeutics such as docetaxel, gemcitabine and cyclophosphamide are also used for refractory, multi-drug-resistant and recurrent osteosarcoma. In addition, the efficacy of chemotherapy is related to a variety of factors, such as the cycle of adjuvant chemotherapy or neoadjuvant chemotherapy, the type of drugs used and the dose of drugs.

However, whether chemotherapy treatment rates for osteosarcoma have changed in recent years or 5-year survival rates have increased is unclear. In this study, we used population-based osteosarcoma patient data from The Surveillance, Epidemiology, and End Results (SEER) database to analyze the influencing factors for osteosarcoma patients receiving chemotherapy and to identify the benefit population of chemotherapy. We also analyzed changes in chemotherapy treatment rates in recent years in patients with osteosarcoma and trends in 5-year overall survival in all patients with osteosarcoma and patients receiving chemotherapy. This study aimed to determine the survival benefits of adjuvant chemotherapy in different populations of osteosarcoma and to explore current challenges to chemotherapy.

Although osteosarcoma is the most common bone tumor, its incidence is still low, about 3 per 1 million [12]. There has been little progress in treating osteosarcoma since adjuvant chemotherapy began in the 1970s [13]. Due to off-target effects and uncontrolled release, powerful anticancer drugs have limited dosage and low patient compliance. Many studies are currently aimed at developing new chemotherapy agents for osteosarcoma to improve patient survival, but the results have been unsatisfactory. A Phase 3 trial using zoledronate sodium in combination with chemotherapy and surgery for osteosarcoma did not yield favorable results [14]. Although many studies have used drug delivery systems to control the release of chemotherapy drugs to reduce their side effects, most of them are still confined to preclinical studies [15]. Therefore, new treatment strategies and new chemotherapy drugs are needed, and clinical trials must be conducted to find more promising treatments.

This study analyzed the differences between patients who received chemotherapy for osteosarcoma and those who did not. In both difference analysis and influence factor analysis, we found that age was an important factor. In younger patients, osteosarcoma is more likely to occur in the distal femur, proximal tibia, and humerus, whereas, in older patients, osteosarcoma often occurs in the axial bone [16]. The efficacy of adjuvant chemotherapy in middle-aged and elderly patients with human osteosarcoma differs. Bacci et al. [17] found that adjuvant chemotherapy was effective for patients over 40 with high-grade limb osteosarcoma. Grimer et al. also reported 238 cases of non-metastatic high-grade osteosarcoma in the extremities aged 40–60. The survival rate in the chemotherapy group was significantly higher than that in the non-chemotherapy group [18]. In contrast, some studies have found no significant prognostic benefit of adjuvant chemotherapy in middle-aged and elderly patients with osteosarcoma. Iwata et al. reported on 86 patients over 40 with high-grade osteosarcoma and found that adjuvant chemotherapy did not significantly improve 5-year survival [19]. In our study, osteosarcoma patients under 60 years of age who received chemotherapy had a lower survival rate, which may be due to selection bias, because patients with advanced stage or higher malignancy are more likely to receive chemotherapy. In addition, there was no significant difference in survival rate between chemotherapy group and non-chemotherapy group in patients over 60 years old, indicating that chemotherapy could not improve the survival of elderly patients. Although the SEER database does not provide details of chemotherapy, such as chemotherapy regimens and dosages, poor prognosis after chemotherapy in elderly patients should be associated with adverse chemotherapy reactions. In middle-aged and elderly patients, chemotherapy often leads to myelosuppression and renal toxicity [20]. Therefore, adjuvant chemotherapy should be carefully selected for elderly patients with osteosarcoma.

In addition, tumor grade is also a factor influencing chemotherapy in patients with osteosarcoma, and survival analysis shows that patients with high-grade osteosarcoma can significantly benefit from adjuvant chemotherapy. The onset of multi-drug chemotherapy has significantly improved the prognosis of patients with high-grade osteosarcoma [21]. Previous studies have shown that adjuvant chemotherapy combined with surgery can improve the survival rate of patients with high-grade osteosarcoma from 10–20% to more than 60% compared with surgery alone [22, 23]. In our study, most patients with high-grade osteosarcoma received chemotherapy and significantly extended their survival compared to the non-chemotherapy group. Therefore, our findings suggest that adjuvant chemotherapy is an effective treatment for patients with high-grade osteosarcoma and that adequate chemotherapy should be given simultaneously with surgery.

The Cox regression analysis revealed that female patients were a protective factor for survival. These results indicate that there may be sex differences in the treatment of osteosarcoma. The treatment rate of women has also been reported in other diseases or tumors. Rose et al. reported the difference in the chemotherapy treatment rate of 23,981 patients with advanced bladder cancer, and the results showed that the chemotherapy treatment rate of women was significantly lower than that of men, and the overall survival rate of women was significantly lower than that of men [24]. Similarly, some studies have found that women are significantly less likely than men to use aspirin and statins to treat cardiovascular disease [25, 26]. However, these studies did not specify a direct relationship between treatment rates and survival. Therefore, further research is needed to explore the low treatment and survival rates in women with osteosarcoma.

The primary site of the tumor is also a factor influencing the rate of chemotherapy, especially the low rate of chemotherapy in patients with cranial and facial osteosarcoma. Because the risk of distant metastasis of craniofacial osteosarcoma has been considered low by previous studies, the role of chemotherapy is unclear [27, 28]. However, Salvati et al. found that chemotherapy could reduce low local recurrence and metastasis of cranial osteosarcoma [29]. Therefore, chemotherapy is an indispensable treatment for craniofacial osteosarcoma. In addition, our study also found that the later the tumor stage, the larger the tumor size, and the more important the role of chemotherapy. Adjuvant chemotherapy can significantly improve the prognosis of patients with advanced osteosarcoma.

However, there are many factors that can influence the effectiveness of chemotherapy in patients, such as the chemotherapy cycle, dosage, and drugs used. Min et al. [30] collected data from 333 patients with high-grade osteosarcoma and found that the chemotherapy cycle significantly affects patient survival. The median survival time for patients with a chemotherapy cycle of less than 4 cycles was 20 months, while it was 57 months for patients with a chemotherapy cycle of more than 4 cycles. Additionally, patients who responded well to chemotherapy had significantly higher survival rates. Huvos et al. [31] quantified the degree of tumor necrosis in patient tumor specimens, where a tumor necrosis rate of > 90% was defined as high necrosis, and < 90% was defined as low necrosis. The degree of tumor necrosis is an important factor in evaluating the effectiveness of chemotherapy.

We analyzed time trends in chemotherapy treatment rates for all osteosarcoma patients over the last 15 years. Although the results showed a slight upward trend in the rate of chemotherapy for osteosarcoma, it was still not significant. At the same time, we analyzed the time change trend of 5-year survival for all patients and patients receiving chemotherapy over the 15 years. There was no significant change in survival for patients. These results indicate that adjuvant chemotherapy for osteosarcoma has not progressed significantly in the past 15 years. Further research on new drugs or drug delivery systems is urgently needed to increase the effectiveness of chemotherapy treatment and thus improve the prognosis of patients with osteosarcoma.

The study still has some limitations. First, this study is a retrospective analysis, and there is still some bias in patient selection. Second, the lack of comorbidities and insurance data in the SEER database may influence the outcome of chemotherapy choices and survival differences. The SEER database lacks specific parameters regarding patient chemotherapy, such as chemotherapy cycles, drugs, and dosages, which are crucial factors in assessing prognosis after chemotherapy. Additionally, we also lack variables to assess the degree of tumor necrosis, which is important for evaluating chemotherapy effectiveness. Therefore, we need to conduct single-center studies to collect chemotherapy parameters from patients in order to assess the role of chemotherapy in osteosarcoma. Finally, it should be noted that our conclusions are based on retrospective research, and further confirmation is required through prospective studies.

We analyzed the factors influencing chemotherapy treatment in patients with osteosarcoma. The results showed that age, primary tumor site, tumor size, N stage, M stage, and surgery influenced chemotherapy treatment. We then analyzed the benefits of adjuvant chemotherapy in patients with osteosarcoma. The results indicate that younger patients benefit more from chemotherapy. In addition, we analyzed the changes in chemotherapy treatment rate and 5-year overall survival rate of patients over the past 15 years. The results showed no significant progress in the chemotherapy of osteosarcoma, suggesting that the treatment of osteosarcoma still faces great challenges.