(P 209) PROGNOSTIC VALUE OF EARLY RADIOLOGIC TUMOUR VOLUME RESPONSE IN RHABDOMYOSARCOMA; RESULTS OF THE EUROPEAN PAEDIATRIC SOFT TISSUE SARCOMA STUDY GROUP RMS 2005 STUDY

Objective: In rhabdomyosarcoma (RMS), there is an ongoing search for early prognostic markers predicting outcome. First, to identify high-risk patients and therefore be able to intensify or de-intensify treatment at an early stage. Second, to early recognize effective new treatment strategies, and bring promising treatment to phase III while dropping inferior regimens. Currently, the only endpoint for trials available is survival, taking up to a decade to give results. In previous publications the prognostic value of early radiologic tumor size response has shown to be controversial.
We present the prognostic value of early tumor size response in a large cohort of non-metastatic RMS patients with residual disease after initial surgery or biopsy, Intergroup Rhabdomyosarcoma Studies (IRS) postsurgical Group III, treated according to state-of-the-art guidelines in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 cohort.

Methods: For this post-hoc analysis, IRS Group III patients from the EpSSG RMS 2005 cohort with tumor volume measurements available at diagnosis and after three courses of induction chemotherapy were included. Measured tumor response was grouped according to the EpSSG RMS 2005 imaging protocol: complete response (CR), partial response (PR), minor partial response (mPR), stable disease (SD) and progressive disease (PD) (Figure 1). Overall survival (OS) was defined as time from tumor evaluation to death from any cause, and failure free survival (FFS) as time from tumor evaluation to disease progression, a second malignancy, or death. In FFS analyses, PD patients were excluded, as disease progression is within the definition of FFS. OS and FFS were estimated using the Kaplan-Meier method and comparisons between the response groups were made using the log-rank test. The prognostic impact was assessed using a univariate Cox proportional hazards model. Multivariate Cox regression analysis was used to evaluate the independent prognostic factors

Results: Of 1306 IRS Group III patients, 618 had all measurements available after three courses of induction chemotherapy and were included for analysis. 49 patients (8%) achieved CR, 373 patients (60%) PR, 140 patients (23%) mPR, 47 patients (8%) SD, and nine patients (2%) PD. The estimated five-year FFS and OS for all patients were respectively 67.3% (95% CI 63.4%-70.9%) and 80.7% (95% CI 77.4%-83.7%). No significant differences were observed for FFS or OS between the different response groups (Figure 2). Univariate Cox proportional hazards model showed no significant difference for FFS (p=0.140) and OS (p=0.252) between the different response groups. Hazard ratios (HR) for PR, mPR and SD were 0.97 (95% CI, 0.59-1.61), 1.05 (95%CI, 0.60-1.82) and 1.5 (95%CI, 0.79-2.79), respectively, for FFS and 1.17 (95% CI, 0.61-2.24), 1.35 (95% CI, 0.67-2.71) and 1.85 (95%CI, 0.85-4.04), respectively, for OS. In the multivariate cox regression analysis site (unfavorable; HR 1.54, 95% CI, 1.08-2.22), histology (unfavorable; HR 1.51, 95% CI, 1.13-2.01), and loco-regional lymph node involvement (N1; HR 1.48, 95%CI: 1.07-2.03) were identified as independent prognostic factor for FFS. Site (unfavorable; HR 2.92, 95% CI, 1.69-5.06 and loco regional lymph node involvement (N1; HR 2.39, 95%CI: 1.70-3.36) were identified as independent prognostic factor for OS as well. For both FFS and OS, tumor volume response was not identified as an independent prognostic factor.

Conclusion: This study confirms that radiological tumor volume response after three courses of induction chemotherapy does not predict FFS or OS in IRS Group III patients treated according to the EpSSG RMS 2005 protocol and cannot be considered as an early surrogate marker in pediatric RMS. Therefore, there remains an urgent need to develop new imaging markers prognostic for outcome in RMS patients. This is the subject of imaging biomarker studies in the current Frontline and Relapse Rhabdomyosarcoma (FaR-RMS) study.