In response to emerging data from the US indicating that interval compressed VDC/IE was a well-tolerated, effective regimen for EFT, we selected patients who were ineligible for randomisation in Euro EWING 99 to receive this treatment in preference to the institutional standard, VIDE[16, 21]. We wished to gain preliminary experience of the feasibility of this regimen and extend its use to a population with metastatic disease and older patients, groups not represented in the randomised study from COG. The results indicate that this regimen can be safely delivered and interval compression achieved in this patient group. Although this is a small study, these data also lend support to the view that this is a tolerable regimen, even in an older patient group with considerable disease burden. Finally, we observed clinical benefit of dose compressed VDC/IE in DSRCT.
Toxicities associated with VIDE are well recorded both from the initial single institution study and from a large analysis of the first 851 patients included in EURO-E.W.I.N.G. 99. A total of 4,746 courses of VIDE in 851 patients were analysed with respect to toxicity. The rate of febrile neutropenia was 60.8% with, and 65.8% without, GCSF support.
Toxicity data from the AEWSOO31 study is currently available only in abstract but reports a rate of grade 3/4 febrile neutropenia of 6.9% in the two weekly arm. While emphasising the very small number of patients reported here, this figure is lower than that reported here (13.5%). However, the several differences in patient demographics may account for this. Firstly the AEWS0031 study was in a paediatric population with only 75 of the 587 (12.8%) patients over the age of 18, whereas in this study 12 patients were over the age of 18 (75%). Secondly, the AEWS0031 study was carried out in patients who did not have metastatic disease. Again, in our cohort, the majority of patients had metastatic disease and a large overall tumour burden, 11 (69%) patients having bone, bone marrow and lung metastases, and 7 (44%) with primary pelvic disease.
The determinants of chemotherapy tolerance in EFT require further clarification. Comparisons of the influence of factors such as age are limited by the absence of planned prospective analyses and the reporting of cohorts containing varying proportions of children, adolescents and adults. Hence studies that report the adverse influence of younger age may contain few adults; others focus exclusively on much older adults; while still others fall between these extremes[19, 24]. In the largest study, from EURO-E.W.I.N.G. 99, chemotherapy toxicity was not clearly greater in older patients but dose modifications were more frequent. Most clinicians will remain cautious when treating older patients or those with heavy tumour burden with the current intensive regimens discussed here.
The treatment interval for the two weekly regimen was successfully maintained in this patient cohort with a mean treatment interval of 16.7 days. This resulted in a shorter overall treatment time when compared to a 3-weekly regimen. For the 8 patients who completed all 14 cycles of treatment the average overall treatment time was 253 days, which is markedly shorter than the 294 days it takes to complete standard treatment with VIDE/VAI. In the EURO-E.W.I.N.G 99 clinical trial, dose modifications were recorded in 1020 of the 4746 courses (21%) of all cycles. In this study, only 26 cycles were given at a reduced dose (14%), therefore we can postulate that dose intensity was not compromised in order to maintain a shorter dose interval. Three patients terminated treatment early due to chemotherapy-related toxicity; two at cycle 11 and one at cycle 12.
The main limitation of this study is that it is a small non-randomised cohort of patients with heterogeneity of presenting clinical features. The poor prognostic factors present in several patients and the need to gain familiarity with the regimen will have had an effect on the application of clinical thresholds for decisions on dose reductions and cessation of treatment. The information on clinical outcome is provoking but should be considered only with caution. Despite this, the data do have value in supporting the premise that this may be a less toxic regimen than VIDE, which is deliverable in patients outside of the limited eligibility criteria for AEWS0031.
In conclusion, this study demonstrates that interval compression of chemotherapy is feasible in an older and higher risk cohort of patients with EFT and other small round cell sarcomas. This schedule appears well tolerated compared with the standard European treatment of VIDE followed by VAC or VAI. We also included patients who would traditionally have a poor long term survival even with intensive chemotherapy. A shorter, less toxic regimen is an attractive option for these patients in whom life expectancy is likely to be limited by their disease. Further data regarding efficacy and long term toxicity will be available in the future as this regimen will now be compared with the VIDE/VAI schedule in a multi-centre randomised controlled trial.