(P 315) SALVAGE THERAPY EFFICACY IS MODIFIED BY RISK GROUP AT DIAGNOSIS IN PATIENTS WITH RELAPSED RHABDOMYOSARCOMA

Objective: Patients with relapsed rhabdomyosarcoma (RMS) have a poor overall survival (OS) and there is currently no established standard systemic salvage approach. There are multiple regimens used with varying intensity and side effect profiles, however, there are no comparative studies available in the literature assessing the efficacy and toxicity of these regimens. Utilizing a large dataset of patients with relapsed RMS from five centers in North America, we performed a retrospective comparison of various relapse regimens exploring whether more intensive regimens were associated with longer OS.

Methods: In 110 patients with relapsed RMS, we categorized treatment regimens as intensive or nonintensive based on author consensus. Treatment regimens were classified as “Intensive” if they required inpatient administration and were associated with higher risk for ≥ grade 3 toxicities, including any regimen with a high dose alkylating agent, such as, doxorubicin/cyclophosphamide/ifosfamide/etoposide, ifosfamide/doxorubicin, vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and ifosfamide/carboplatin/etoposide. “Nonintensive” regimens were those most often delivered in the outpatient setting and less often associated with ≥ grade 3 toxicities, including topotecan/cyclophosphamide, cyclophosphamide/vinorelbine +/- temsirolimus, and vincristine/irinotecan +/- temozolomide. We then compared OS between the two groups, adjusting for risk group at diagnosis and institution using Kaplan-Meier and Cox proportional hazards analyses.

Results: Median time to relapse for all patients was 1.4 years (range 0.2 – 8.9 years), with no difference between the two groups. Patients in the intensive chemotherapy group tended to have embryonal histology (56% vs 30%, p=0.006), low-risk group at diagnosis (30% vs 7%, p< 0.001), surgical resection after relapse (46% vs 24%, p=0.01), and genitourinary primary location (27% vs 7%, p=0.005) compared to patients treated with nonintensive chemotherapy. There were also differences between the five institutions for salvage therapy selection (p=0.01) and an expected correlation with the type of upfront chemotherapy regimens (p=0.02). Median follow-up in the 32 survivors was 4 years (range 1.0 - 16.7 years) with a 28% (95%CI 19% - 37%) 4-year OS. Patients treated with intensive regimens had longer OS compared to patients treated with the nonintensive combinations (4-year OS 41%, 95%CI 27% - 58%, vs 14%, 95%CI 4% - 24%, respectively, HR 2.1, 95%CI 1.3-3.2, p=0.002). Adjustment for risk group at diagnosis abrogated the association (HR 1.4, 95%CI 0.8-2.3, p=0.16). In stratified analyses, patients who had low risk at diagnosis had the highest effect size, suggesting a benefit after intensive treatment [stratified HR 4.4 (95%CI 0.96-20.3), p=0.06, reference intensive regimens] compared to intermediate [stratified HR 1.6 (95%CI 0.9-3.2), p=0.13] or high [stratified HR 0.9 (95%CI 0.4-1.8), p=0.7] risk patients.
For the high-risk group at diagnosis, the 4-year OS rate in patients treated with nonintensive regimens was 8% (95%CI 0% - 19%) vs 10% (95%CI 0% - 28%) in patients treated with intensive regimens.

Conclusion: In our cohort, we found that patients with relapsed RMS treated with intensive chemotherapy regimens experienced longer OS; however, this association was attenuated when adjusting for risk group at diagnosis. Patients with relapsed RMS in the low-risk group at diagnosis may benefit from intensive salvage chemotherapy, while the high-risk group has a dismal outcome regardless of therapy. It is inconclusive whether intermediate risk patients benefit from intensive therapy. A larger dataset is needed to improve the precision of the effect size in the low risk group and further understand the efficacy of salvage chemotherapy in the intermediate risk group patients.