This retrospective trial compared the objective response rate for treated nodules as well as the best overall response in our population of HCC patients that underwent treatment with radioembolization using standard predictive dosimetry versus personalized predictive dosimetry. For patients treated after standard-dosimetry-based simulation, the activity that would have been administered by SIRT determined using a personalized dosimetry software with multicompartment MIRD technique (Simplicit90Y®) was compared to the activity actually administered determined by the classical non-compartmental dosimetry planning, using a target volume based on the 99mTc-MAA SPECT (patients treated before the acquisition of Simplicit90Y®). To the best of our knowledge, this is the first study that addressed the potential changes due to personalized predictive dosimetry in treatment administration in a retrospective cohort.
In our study, there was no significant statistical difference when comparing the two groups in terms of response rate per treated nodule (ORR), despite a trend in favor of personalized dosimetry (87.5% for personalized dosimetry versus 68.4% for standard dosimetry at 3 months, p= 0.24). These discordant results are probably due to the small size of our two groups population. By contrast, in the per patient analysis, there was a clear benefit of personalized dosimetry in terms of BOR at 3 months (80% versus 33.3%, p= 0.007) and 6 months post-treatment (77.8% versus 22.2%, p= 0.06).
The response rate we report is slightly higher than the results published recently in the randomized, multicenter DOSISPHERE-01 study23 using glass microspheres. In this study by Garin et al, a significant statistical difference was shown between objective response rates in favor of personalized predictive dosimetry compared to standard predictive dosimetry (71% versus 36%). However, we note that the diameter of tumors in our study was smaller, with a median of 65 mm, whilst in the DOSISPHERE-01, at least one nodule had minimum 70 mm. Large tumor size is well known to have a strong negative impact on response and overall survival after locoregional therapies24. This might partially explain the better results in our cohort.
Regarding toxicity, we observed a good safety profile in both groups with only one grade 3 biological toxicity. More importantly, due to the excellent tolerance and toxicity profile, almost all patients in our study were able to have sequential locoregional or systemic treatment. The preservation of the liver-function is more than essential ever since the development of multiple systemic treatments that improve the overall survival of HCC patients. The final results of the IMBRAVE 150 trial comparing the efficacy of the atezolizumab plus bevacizumab combination versus sorafenib for unresectable HCC showed a median overall survival (OS) of 19.2 vs. 13.4 months; stratified HR 0.66, 95% CI [0.52, 0.85]; p = 0.0009) with excellent tolerance25. Moreover, 48% of patients receiving the combination treatment and 52% of those in the Sorafenib arm had already underwent a local therapy before enrollment in the study, suggesting that a locoregional treatment does not prevent sequential treatment.
The DOSISPHERE-01 trial was a breakthrough for SIRT after 2 negative phase III trials (SARAH and SIRveNIB) and one phase II trial (SORAMIC) comparing or evaluating the addition of SIRT to Sorafenib. In terms of overall survival, personalized predictive dosimetry showed an important added value, with 26.6 months for the intention-to-treat population compared to 9.9 months in the SARAH trial and 11.3 months in the SIRveNIB trial. In the SORAMIC trial, the SIRT + sorafenib arm showed a median OS of 12.1 months, with no statistical difference from the Sorafenib arm of 11.4 months. Our study has shown an improvement of OS with personalized dosimetry, 33 months versus 17.2 months for patients treated after standard-dosimetry-based simulation. However, despite the advantage of personalized predictive dosimetry in terms of response, the survival was not impacted. This came as a surprise as a recent study evaluating the relationship between tumor absorbed dose, survival and tumor response in locally advanced inoperable HCC based on the SARAH study population showed that patients who received a higher dose (a threshold of 100 Gy for resin microshperes) had longer survival, 14.1 months [95% CI: 9.6 months, 18.6 months] vs 6.1 months [95% CI: 4.9 months, 6.8 months], respectively; p= 0.001)26. However, this might be also explained by our small population sample included in our study.
With the use of personalized predictive dosimetry, we obtain a better selection of patient that could benefit from SIRT, avoiding inefficient radiotherapies and thus unnecessary dose deposition, an obvious critical point in patient radioprotection. However, this leads to an increase of work-up failure. A higher number of patients were not suitable for SIRT after simulation with the use of Simplicit90Y®, 24.1% for group A versus 56.8% for group B. This point is often overlooked and yet, it is important to point out since patients might undergo an unnecessary hepatic angiography that represents an invasive procedure inducing stress. This drop-out in our study is illustrated in Table 1. In the standard predictive dosimetry group 75,86% of patients received treatment, compared to 43,24% in the personalized predictive dosimetry group, despite more than one work-up attempts. The principal explanation was shown to be poor tumor targeting in 50% of cases, resulting from the more precise multi-compartmental dosimetry approach available with Simplicit90Y®. As mentioned above, this can be interpreted as an advantage since it avoids a potentially toxic treatment in patients that have already an abnormal liver function. As a matter of fact, the toxicity profile ends up particularly favorable in our study. Of notice, high work-up failure is not observed when performing transarterial chemoembolization (TACE), particularly with the latest developments in drug eluting beads (DEB-TACE) and new catheters (e.g., balloon microcatheter). A recent prospective feasibility study of balloon-occluded chemoembolization using polyethylene glycol DEBs loaded with Doxorubicin, performed at our center, was recently published and has showed a 100% rate of technical success27. With adequate selection, median OS after TACE may reach 48 months as shown in a large retrospective study28.
In group A, the comparison between the administered activity and the recommended activity calculated using a personalized dosimetry software with multicompartmental (MIRD) approach showed that the patients who progressed received less activity than recommended (Figure 4) or that this activity was not adequately distributed (Figure 5). Our results indicate that reaching a minimal absorbed dose criteria increases the efficacy of SIRT. They support the use of a more personalized predictive dosimetry instead of the classical non-compartmental MIRD dosimetry for treatment planning. This is in line with the notion that a minimal absorbed dose of a minimum 205 Gy to the lesion is required to achieve an optimal response for SIRT with glass microspheres19,20.
Note that taking into account areas of necrosis in the tumor absorbed dose calculation does not provide an estimate of the dose to the viable tumor, as mentioned by Garin et al.
Dose-response link evaluations, in both groups, shows clearly that a total response cannot be reached if the perfused fraction of the total tumor volume is not enough and about 100%. Giving enough dose to a sufficient tumor volume fraction ensures at least a partial response.
Our study has several limitations, the most important being the small number of patients and its retrospective nature. Furthermore, a bias is to be taken into account due to the fact that some patients had already undergone previous treatments on the treated tumors. Moreover, the groups have been treated in two successive periods. Therefore, the benefit of the experience acquired may have influenced our results for the patients in group B. This effect is mitigated by the fact that the most sensitive part of the protocol that is subjected to a learning curve, that is the angiographic procedure has been performed by experienced radiologists (between 5-10 years’ experience of hepatic angiography practice).