Outcome
After the initial three cycles, CR was evident in 3 patients, PR in 15, and MR in 1. SD was evident in the 2 children with RMS and PD in 2 patients with Ewing sarcoma. Considering the CR and PR alone, the response rate was 88.2% (15/17) in cases of RMS. PR was evident in 2/4 patients with relapsed ES and 1/2 patients with DSRCT. The response rates were 84.6% (11/13) and 70% (7/10) for patients treated with IrIVA and IrVAC, respectively.
With a median follow-up of 2.6 years (range 0.2 -5.0), 12 patients were still alive at the time of writing, 9 in CR (3 metastatic at diagnosis and 6 with the relapsing disease) and 3 were alive with disease.
DISCUSSION
In this study, we evaluated the feasibility of a dose density approach using a chemotherapy combination that aimed to include irinotecan in the chemotherapy regimens currently used to treat patients with sarcoma, and especially RMS.
The IVA regimen is now considered the standard chemotherapy in European trials for non-metastatic RMS. In North America, cyclophosphamide is used instead of ifosfamide in the VAC regimen. The most significant toxicity of these two combinations is myelotoxicity in the 2-3 weeks following their administration. Irinotecan is a drug active against RMS and, when administered with a continuous schedule (i.e., over 5 days for 1 week), its worst side effect is diarrhea, while myelotoxicity is low.
The IrIVA or IrVAC regimens are, therefore, rational combinations of the standard IVA/VAC scheme with irinotecan because the activity of the drugs and their different toxicity profiles theoretically allow an increase of the chemotherapy intensity without increasing the risk of toxicity.
This was confirmed in our study. Most of the patients were able to complete their treatment within a reasonable time. Although IrIVA/IrVAC are intensive combinations, toxicity was not significantly worse than in patients treated with IVA in the RMS2005 protocol, where grade 3-4 infections were reported in 57% of patients, and renal and gastrointestinal toxicity in 2% and 8%, respectively (10). It should be noted that 47.8% of the patients in our present study had a relapsed tumor, so they had already received previous treatments, meaning that a more significant toxicity might have been expected.
There is limited experience of the dose-density approach against pediatric sarcoma. An attempt to reduce the interval between cycles proved feasible, and possibly beneficial, in patients with metastatic RMS included in the COG protocol ARST0431study was based on the concept of dose-compression: the cycles of chemotherapy were administered with an interval of 14 days instead of the 21 as it is used in the standard treatment. The results showed a possible improvement for patients with embryonal RMS, but not for those with high-risk features (Oberlin score >1) (7). More promising results were achieved in localized ES by adopting the same chemotherapy-intensifying approach and reducing the interval between cycles to 2 weeks. A randomized study reported a significantly better outcome in patients treated with chemotherapy administered after shorter intervals than in those given the same chemotherapy according to the standard interval (6). New combinations are under study using the same approach (11).
In our high-risk population, 52% of patients were alive in CR at the time of writing, although some have only a short follow-up. This result, and the limited toxicity reported, indicate that the IrIVA or IrVAC combinations deserve further testing, possibly in a more homogenous group of patients with less unfavorable features-as already done for ES patients (6) (11).
A limitation of our study is that we tested only one dose of irinotecan (20 mg/m2/day for 5 days). The recommended dose of irinotecan, when it is used alone or with vincristine, is 50 mg/m2 for 5 days. Therefore a proper phase I study is needed to establish the maximum tolerated dose of irinotecan within this novel regime.
In conclusion, our study demonstrates that it is feasible to include irinotecan in the standard chemotherapy regimens used to treat sarcoma, and its use in this setting deserves further investigation. This will be one of the goals of the next EpSSG study.