Definitive treatment strategies for STSs, which vary based on histological characteristics, have not been fully determined. Moreover, the various subtypes of STS are rare, and it is difficult to deduce meaningful results. Therefore, we analyzed data from the largest soft-tissue tumor-specific database in Japan to determine the risk factors associated with SS outcomes. Notably, we identified distant metastasis after primary resection, surgical margins, and local recurrence after primary resection and surgical margins as risk factors that affect the oncologic outcomes of OS, LC, and D-RFS, respectively. In contrast, previous studies had identified distant metastasis at diagnosis, SS subtype (poorly differentiated < biphasic type and monophasic < biphasic type), tumor depth (deep < superficial), tumor size (> 5 cm), and local recurrence as independent prognostic factors [6, 7, 9, 14–16]. These findings indicated the importance of complete surgical resection to avoid micro/macro-residues of the tumor in the post-resection margins. To verify improvements in the surgical outcome, we further attempted to demonstrate the efficacy of neoadjuvant chemotherapy for SS by comparing the oncologic outcomes between the cx + and cx- groups.
Theoretically, neoadjuvant therapy for locally advanced and high-risk STS has several advantages over adjuvant chemotherapy. First, this modality could potentially reduce possible invasion around the tumor and thus prevent micro-residual resection. In cases where a tumor arises near neurovascular bundles, neoadjuvant chemotherapy improves the likelihood that resection will spare the neurovascular bundles and may allow the patient to forgo amputation, which allows the preservation of muscle function [22]. Second, neoadjuvant chemotherapy can potentially improve patient survival by eradicating micro-metastatic disease without delaying adjuvant chemotherapy. Finally, neoadjuvant therapy can provide guidance for postoperative therapeutic strategies.
Currently, the role of neoadjuvant chemotherapy in SS remains controversial [19] because of the challenges associated with prospective studies and the potential for various selection biases in retrospective studies. Therefore, to reduce the possible bias of the retrospective analysis, we examined the oncologic outcomes of SS using an MPA of a relatively large population and thus present a novel report. We found that the cx + population was more likely to have monophasic-type disease, a large tumor size, and distant metastasis at diagnosis, suggesting that selection bias might affect the oncologic outcomes. However, we did not observe a significant difference in the oncologic outcomes of patients in the cx + and cx- groups, despite propensity matching to reduce intergroup differences. Possibly, similar numbers of patients in both groups derived benefits from chemotherapy. Although we did not identify significant intergroup differences, our data suggested that patients with large tumors (> 5 cm) and those with monophasic-type disease would benefit from neoadjuvant chemotherapy (Appendices A and B). These characteristics might affect oncologic outcomes and may explain the controversial results of previous reports.
In a previous study of the analysis of resectable SS, the 5-year OS rate was 64%, and age > 35 years, Grade 3 tumor, and margins other than R0 were identified as significant independent predictive factors for improved survival. Despite adjustments based on these factors, we did not observe any significant impact of chemotherapy on survival in the present analysis. The HRs for OS with neoadjuvant chemotherapy and adjuvant therapy were 1.01 (p = 0.358) and 1.62 (p = 0.099), respectively [12]. Similarly, 52% of patients with localized SS in an Italian study were treated with a combination of ifosfamide and doxorubicin or epirubicin, and the 5-year OSs of those who did or did not receive chemotherapy were 69% and 82%, respectively (p = 0.20). In that study, the negative impact of chemotherapy was explained by the exclusive administration of this treatment modality to patients with larger tumors (> 5 cm) and re-excision cases. These preconditions may have influenced the outcomes [9].
In contrast, an analysis of 14 trials reported that doxorubicin-based chemotherapy significantly improved oncologic outcomes. Although the SS subgroup extracted from these trials was better oriented for chemotherapy, that analysis identified no significant improvement in OS (57.5% and 47.3% for the chemotherapy and control groups, respectively) [20]. Eilber et al. reported favorable outcomes with ifosfamide-based chemotherapy for SS in a dataset limited to patients with tumors > 5 cm, deep tumors, as well as primary and extremity tumors and were treated between 1990 and 2002. In that study, the 4-year disease-specific survival rates were 88% and 67% in the chemotherapy and no-chemotherapy groups, respectively (p = 0.01). Additionally, treatment with an ifosfamide-based regimen was reported to improve D-RFS (HR = 0.4, p = 0.03) [13]. Ferrari et al. suggested that younger patients and those with tumors larger than > 5 cm achieved better outcomes with chemotherapy [21]. These retrospective studies indicate that high-risk patients might benefit from neoadjuvant chemotherapy, which supports our findings.
Few published reports have focused on neoadjuvant therapy for the treatment of SS. One randomized phase 2 trial of adult patients with high-risk STS (tumor size > 8 cm of any grade, tumor size < 8 cm of grade 2/3, or locally recurrent sarcoma/after inadequate surgery of grade 2/3) did not indicate that a regimen of three cycles of neoadjuvant chemotherapy was superior to surgery alone in patients (5-year disease-free survival rates of 56% and 52% for the neoadjuvant chemotherapy and surgery-alone arms, respectively; p = 0.354) [23]. With regard to the comparison between neoadjuvant and adjuvant chemotherapy, a retrospective analysis reported that neoadjuvant chemotherapy (doxorubicin + ifosfamide + dacarbazine) for SS had a significant advantage over adjuvant chemotherapy (5-year OS rates of 84.5% and 55.6% for the neoadjuvant chemotherapy and adjuvant chemotherapy groups, respectively) [3]. However, that study did not sufficiently balance patients who received neoadjuvant chemotherapy with those who received adjuvant therapy. Therefore, it remains difficult to draw meaningful conclusions on the actual contribution of neoadjuvant chemotherapy to patient outcomes.
This study had several limitations. First, the design was retrospective and, therefore, many biases, including selection and recall bias, may have influenced the results despite a propensity-score adjustment. Second, the BSTT database covers only patients treated at orthopedic departments; thus, our dataset did not include patients treated at other departments. Third, we could not evaluate the exact intensity of chemotherapy. Consequently, patients who received attenuated chemotherapy were included in the cx + group. Fourth, we did not analyze differences in genotype. As fusion proteins resulting from the SYT-SSY1 or SYT-SSY2 fusions have been associated with the histological subtype and clinical behavior, these biomarkers should be reviewed in a further analysis of this database [24]. Finally, in Japan, the standard treatment protocol for SS involves a doxorubicin-based chemotherapy regimen. However, the different participating institutions do not use identical protocols. Accordingly, although 60.1% of patients received neoadjuvant chemotherapy via the AI regimen, many patients were treated with AI-IE, VDC/IE, MAID, or other regimens. These differences might have affected the study outcomes. We further note that, currently, new drugs are being approved rapidly in Japan, and pazopanib, trabectedin, and eribulin have been proven to yield improved oncologic outcomes in patients. These newly approved drugs may influence patient outcomes and, therefore, potential changes in treatment strategy should be considered when applying our findings.