The prognosis of RMS has been greatly improved over the last 3 decades, thanks to the series of clinical trials carried out by the COG Soft Tissue Sarcoma Committee in North America, the European pediatrics Soft Tissue Sarcoma Study Group (EpSSG), etc. [2, 5]. Although 5-year OS now exceeds 70%, survival of patients with recurrent and advanced disease is still poor, with 5-year OS about 30% [2, 5, 6]. Survival related events include disease progression, disease relapse, second tumor and death of any cause [9-11]. Treatment related second tumor and death of other cause (tumor progression or relapse unrelated cause) are rare, while disease progression and relapse comprise almost all events [9, 17, 18]. In most studies patients with disease progression and relapse were analyzed as a combined single group, using EFS rate to evaluate prognosis. The estimated EFS rate should be lower than OS rate, which is due to the fact that some patients with disease progression or relapse could still be salvaged with intensive/second-line treatment. Compared with OS, EFS is a more conservative estimation yet actually effective.
Generally, disease progression represents early treatment failure [12], which includes primary tumor enlargement, and/or new lesions, and/or metastasis during primary treatment course. Patients with disease progression respond poorly to the initial treatment, and primary tumor enlargement, local invasion, regional nodal involvement, and even metastasis can be anticipated. Disease relapse represents late treatment failure [19, 20], which means recurrence of RMS in any form after last treatment during off therapy surveillance. Patients with disease relapse usually respond well to the initial treatment and end with complete remission. Later the tumor recurs from incompletely eradicated micro residual of primary site, regional nodes, or metastatic foci.
The biological processes of disease progression and relapse are distinct, leading to distinct prognosis. Our survival results confirmed the heterogeneity of this group of patients with events, that Group PD had significantly worse survival expectation compared with Group RD. Clinical features of Group PD were not only different from Group NE, but also Group RD. Interestingly clinical features of Group NE and Group RD were more alike. Pairwise comparisons revealed that Group PD tended to have larger tumor size, higher ranks of surgical pathologic group (unresectability) and risk group (advanced disease status), which may indicate a more malignant biological behavior.
Clinically disease progression indicates resistance to current treatment, and once progression confirmed the treatment is usually enhanced or switched to second-line regimen. But disease relapse is more likely attributed to insufficient treatment to a responsive tumor, which could be inadequate local control (surgery and/or RT), and/or inadequate systemic control (intensity and/or duration of chemotherapy). A multicenter open-label randomized phase 3 trial finished by EpssG recently showed that maintenance treatment with vinorelbine and low-dose oral cyclophosphamide for patients with high-risk rhabdomyosarcoma in complete remission after standard treatment improves OS [3]. This survival improvement was the result of the lower recurrence rate. The authors explained that the improvement of OS might be attributed to prolonged chemotherapy or the combination of vinorelbine and cyclophosphamide might have killed the small amount of residual disease remaining at the end of standard treatment.
A lot of prognostic factors for survival have been reported. Considering the poor survival of Group PD, we explored these factors for disease progression. The univariate and multivariate analysis results confirmed tumor size, histology subtype and initial RT as independent prognostic factors for disease progression. Although surgical-pathologic group showed statistical significance on univariate analysis, it was not an independent prognostic factor for disease progression on multivariate analysis. This is not difficult to understand that the resectability of the primary tumor is affected by many factors, such as anatomy (site/tumor size), invasiveness (regional or distal involvement/histology subtype), etc., which makes surgical pathologic group unlikely an independent prognostic factor. Our results of the Cochran-Armitage test for trend indicated that the possibility of disease progression increased with the ranks of surgical pathologic group and risk group, which meant patients with unresectable tumor and advanced disease were more likely to develop disease progression.
We previously reported that the patterns of disease progression and relapse of this cohort were mainly local, which was consistent with other published reports [9, 21]. A cure for RMS depends firstly on local control (eradication of the primary tumor by surgery and/or RT), then on systemic control (eradication of the micro and metastatic residual) [5]. Local tumor is the main burden of the whole disease, including the primary site and regional nodes. Local eradication is more responsible for complete remission/cure of the disease, and failed local control is also more responsible for disease progression and relapse. This explains why the main pattern is local.
The importance of local control by surgery and/or RT has widely been reported and confirmed in this cohort [8, 13, 22]. We reported that non-initial RT impairs OS and EFS by causing local failure in this cohort. And it has been reported that delayed RT may cause treatment failure in parameningeal RMS patients [23, 24], also delayed RT may cause early treatment failure (mainly disease progression) in intermediate risk RMS patients [9]. This explains why initial RT was an independent prognostic factor for disease progression.
Tumor size >5cm has been widely reported as a risk factor for survival especially in refractory patients (patients with disease progression) and recurrent patients (patients with disease relapse) [25-28], and is the strongest predictor of local failure [29]. It is widely reported RMS patients with alveolar histology have worse survival than embryonal type, especially those alveolar patients with PAX-FOXO1 fusion gene [5, 10, 11]. The biological behavior is very different between the alveolar and embryonal histologic subtypes, with alveolar (especially PAX-FOXO1 positive) subtype more aggressive and easier to infiltrate and metastasize [5, 30].
From the above, we can explain these risk factors from two angles. Firstly, failed local control is prone to disease progression. If the tumor has one or more of the following features, which include large (tumor size>5cm), aggressive (alveolar type), unresectable (high surgical pathologic rank) and not receiving RT initially (non-initial RT), the local control is impossible by chemotherapy alone, which would cause disease progression. Secondly, advanced disease is prone to disease progression. If the tumor has progressed into an advance status, especially with metastasis (high rank of risk group), with infeasible surgery (high rank of surgical-pathologic group), chemotherapy would appear feeble and futile in front of such large tumor burden.