To the best of our knowledge, the present study is the first analysis of an interventional ICR QA procedure prospectively performed in a clinical RT brain trial (i.e. EORTC QA level 4 ). We have observed a substantial number of deviations in approximately one third of accrued patients that may have an impact on the primary-end point (Figure 1). The impact of protocol deviations on patient’s outcome , has been shown in a number of prospective studies [6–8]. Interestingly, the successful DR-plans did not guarantee protocol compliance during subsequent ICR submissions and that the overall deviation rate did not improve with time (Figure 2). As such, ICR should be prospectively performed in a clinical trial with RT.
Our report not only presents the data of this brain trial but also gives us opportunity to challenge the current QA paradigm. In previous studies, prospective reviews could not be conducted or were considered as ineffective [6, 7, 9]. We observed that only 7% of all ICRs could not be analyzed in this trial. A substantial number (18%) of cases were however retrospectively analyzed due to late submission or corrupted files during first submission to the digital QA platform. All (n=11) major deviations and 80% (n=4) of the minor deviations were detected by prospective review (n=41) and were discussed with institutions before the start of treatment. No significant association (p=0.19) was observed between the review type, prospective vs. retrospective, and the deviation detection rate, but these data should be cautiously interpreted due to the low number of patients in the retrospective review arm (n=9).
There was a significant association (p=0.007) between the number of accrued cases per institution and the number of observed deviations. Peters et al. reported similar findings in the prospective head and neck trial, with a cut-off of 5 patients per institution . Duhmke et al. have also found similar results for early stage Hodgkin lymphoma, with a cut-off of 10 patients per institutions . It would thus be appropriate to limit the inclusion of patients into prospective RT trials from reasonably high-accruing institutions (i.e. 5 – 10 patients per institution), so as to increase the protocol-compliance rate and possibly improve patient’s outcome .
The DR is designed to identify systematic planning or delivery RT errors and recognize protocol ambiguities before study treatment starts. This procedure assures that physicians understands the protocol requirement of a given trial, delineate target volumes and OARs appropriately, produce a protocol-compliant plan and are able to transfer the digital data to the QA platform . Noteworthy, the DR deviation rate of 25% was observed at the beginning of the trial and an overall deviation rate of 32% was subsequently observed during patient’s accrual. As such, the DR procedure did not improve the protocol-compliance rate of the institutions, as no association between compliant- and non-compliant centers with deviation rates was observed. Parenthetically, the rate of i.v. contrast administration during RT planning for DR and ICR improved however from 56% to 76%. A DR-ICR correlation was observed in an EORTC prostate trial, but not in a low-grade glioma brain (EORTC 22033–26033) trial . Moreover, protocol compliance did not improve within the trial accrual period (Figure 2). Clinical trials usually take several years to be completed, institutional physicists and physicians may change and have a high turn-over rate, especially so for low-recruiting institutions. This will consequently increase the probability of protocol guidelines misinterpretation and systemic planning errors. Due to the former issue, QA analysis by the intergroup QA team should always be performed by two reviewers and inter-rater agreement should be reported. In our study there was a significant association between the two reviewers (K=0.5). Discrepancy was observed for only 5 ICR-plans with minor deviations.
During our analysis, we computed CI and TC (Table 2) to take into account both non-target tissue and PTV [12, 13]. HI was calculated for absorbed-dose distribution within the PTV according to ICRU 83 recommendations . There was a negative correlation between the PTV volume and CI value for the ICR-plans (p=0.0005). Similar findings were previously reported by Musat et al. and Knöos et al.[15, 16]. We did not observe however any association between CI value and tumor shape or OAR’s vicinity or between PTV volume and TC or HI (p=0.10). We recommend the prospective capture of the PTV indices in clinical trials, as plan evaluation parameters, for future survival/toxicity correlation analyses to define optimal and suboptimal values (minor/major violations) more accurately for the choice of ideal dosimetry.
In conclusion, we have observed a considerable number of protocol deviations that may have a substantial impact on tumor control or radiation-induced toxicity. In this trial, DR could not avoid protocol non-compliance subsequently for ICR submission. Prospective ICR should be conducted to prevent protocol deviations that may have an impact on tumor control and/or toxicity. A substantial number of ICRs could not be prospectively evaluated as per protocol.