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High impact of macroaggregated albumin‐based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90Y‐loaded glass microsphere radioembolization

Abstract Background & Aims Efficacy of radioembolization is derived from radioinduced damage, whereas tumour dosimetry is not considered as yet in prospective clinical trials. Objectives This study evaluates the impact of tumour dose (TD), based on 99mTc macroaggregated albumin (MAA) quantification, on response and overall survival (OS). Materials and Methods We consecutively included 85 patients with hepatocellular carcinoma treated with 90Y‐loaded glass microspheres. TD was calculated using a quantitative analysis of the MAA SPECT/CT. Responses were assessed after 3 months using the European Association for the Study of the Liver criteria. OS was assessed using Kaplan–Meier tests. Results Response rate was 80.3% on lesion‐based analysis (n=132), and 77.5% on patient‐based analysis. The response rate was only 9.1% for patients with TD <205 Gy against 89.7% for those with TD ≥205 Gy (P<10−7). Non‐portal vein thrombosis (PVT) patients exhibited a median OS of 11.75 m (95% CI: 3–30.7 m) for TD <205 Gy, and 25 m (95% CI: 15–34.7 m) for TD ≥205 Gy (P=.0391). PVT patients exhibited a 4.35 m median OS (95% CI: 2–8 m) for TD<205 Gy, and 15.7 m (95% CI: 9.5–25.5 m) for TD ≥205 Gy, (P=.0004), with HR of 6.99. PVT patients exhibited a median OS of 3.6 m (95% CI: 2–8 m) when PVT MAA targeting was poor or with TD <205 Gy (poor candidate), vs 17.5 m (95% CI: 11–26.5 m) for the others identified as good candidates (P<.0001), with HR of 12.85. Conclusion This study confirms the highly predictive value of MAA‐based TD evaluation for response and OS. TD evaluation and PVT MAA targeting should be further evaluated in ongoing trials, whereas personalized dosimetry should be implemented in new trial designs.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, with 500 000 new cases per year. 1 Radioembolization with 90 Y-loaded resin or glass microspheres is increasingly used in patients with unresectable tumours with promising clinical outcomes. [2][3][4][5] Also not yet recognized as a standard approach, radioembolization is currently recognized as a potential one by various scientific societies, such as the European Society of Medical Oncology. 6 90 Y-loaded microsphere radioembolization is preceded by a treatment simulation consisting of diagnostic angiography and hepatic perfusion scintigraphy with macroaggregated albumin (MAA), serving to identify lung and digestive shunts. The goal of radioembolization is to deliver a tumoricidal dose to the tumour while sparing healthy liver tissue. 7,8 Tumour-absorbed dose (TD) and that absorbed by healthy injected liver tissue (HILD) are two key parameters that should be defined when using radioembolization. However, these parameters are not currently used as yet in clinical trials.
When using glass microspheres in line with the product package insert, 9 the recommendation stipulates to deliver a radiation dose of 80-150 Gy to the injected liver volume (ILD), using a dose calculation based on the following accepted simplified formula: where "IA" represents the activity to be injected, "LSF" the lung shunt fraction (as measured by MAA liver perfusion scan) and "M" the mass of the liver volume to be treated.
Tumour dose and healthy injected liver dose (HILD) can be assessed either prior to therapy, using MAA quantification as a surrogate of microsphere distribution, 10,11 or after therapy using a direct quantification of 90 Y-loaded microspheres. 12 MAA dosimetry is the only one available prior to therapy and able to impact the patient treatment schedule. 13,14 When using local therapy as radioembolization, two of the most essential post-therapeutic parameters, besides toxicity, that must be evaluated are tumour response and overall survival. 5 It should be mentioned, however, that recurrence does not necessarily mean complete therapeutic failure, as this local therapy approach can often be repeated once more, yet with additional healthy liver exposure to radiation.
This study thus sought to evaluate the impact of predictive MAAbased dosimetry on response and survival in HCC patients treated with glass microspheres (TheraSphere ® ) using the product package insert's dosimetric recommendations, including a large sample of patients and tumours.

| Patient characteristics
Between December 2006 and December 2012, 108 HCC patients were treated in our centre; 23 were excluded from the analysis: 2 owing to having no MAA SPECT/CT evaluation, and 21 who were treated without using the product package insert's recommendations and received treatment intensification (i.e. a lobe dose >150 Gy).

| Planning and administration of 90 Y-loaded glass microspheres
For the simulation, diagnostic angiography was carried out for arterial mapping and catheter positioning to optimize tumour targeting while avoiding digestive shunts. Coil embolization was not performed systematically. A liver perfusion scan was conducted following injection of 185 MBq of MAA into the hepatic artery, with planar and SPECT/ CT acquisition.
A quantitative uptake analysis of tumour and non-tumour liver tissue was performed as previously described. 11 The activity to be injected was calculated conventionally to achieve the dosimetric end points described in the package insert, 9 i.e. 80-150 Gy to the treated liver (without exceeding 30 Gy to the lungs for one treatment and 50 Gy as cumulative dose).
Tumour dose was evaluated solely for lesions >2 cm to avoid error of quantification related to partial volume effect, as suggested by several authors. 10 PVT dose was not technically achievable (size often lower than 2 cm or delineation of PVT and main tumour not possible with MAA). However, MAA PVT targeting was evaluated visually and

Key points
• Largest study with MAA dosimetry on HCC.
• High impact of tumour dose on response and OS.
• The higher the dose above the threshold, the greater the effect.
• Tumour dose evaluation should be used in the treatment schedule.
classified as poor in the event of PVT uptake lower or equal than to the healthy liver; or as high in the event of PVT uptake higher than to the healthy liver ( Fig. 1).
Portal vein thrombosis patients were classified as good candidates for radioembolization if TD was ≥205 Gy and in the presence of good PVT targeting. They were classified as poor candidates if either TD was <205 Gy or PVT targeting was poor.
In the case of multiple treatments, the dosimetric analysis was performed for the first treatment only as previously described, 11 except for the only one patient who received two injections in the same lobe within 2 months where cumulative doses were calculated.
Twenty-four patients received two treatments. In case of bilateral disease (n=10), two lobar treatments were administered separately at an interval of 6-8 weeks. In case of incomplete response after a first injection, a second treatment was performed at least 6 months after the first one (n=8). For one patient with technical difficulty with incomplete tumour coverage a second injection in the same lobe was performed at 2 months and five patients received a second injection as a result of recurrence.
For the therapeutic phase, glass microspheres were usually injected on Day 3 after calibration, each time using a lobar approach.
Injections were performed 1 week after the simulation in 93% of cases, and 2-3 weeks after the simulation in only 7%.

| Response evaluation
Response evaluation was performed using both lesion-based and patient-based analyses, yet only for the delineable treated lesions. As radioembolization is a local therapy, the analysis of a potential dose/ response relationship requires a response analysis only of the treated lesions.

Response of treated tumours was assessed using European
Association for the Study of the Liver (EASL) criteria. Accordingly, progression was defined as new lesion occurrence or increased enhancing tissue size of at least 25% in the target lesions on the arterial phase; partial response was defined as decreased enhancing tissue size of at least 50% in the target lesions; a complete response was defined as disappearance of hypervasularization and stable disease by the others situations. An objective response was defined by a partial or complete response, whereas no response was defined by stable disease or progression. The PVT extension variations during follow-up were not considered in tumour response evaluation, excepting complete disappearance (complete revascularization of the portal vein), as previously described. 5 Triphasic CT scans were performed 3 months after treatment, then every 3 months until disease progression or death.
The mean follow-up duration was 22.2±16.3 months.
Potential variables associated with response in univariate analysis were as follows: TD as continuous and dichotomized variable <205 vs ≥205 Gy, as well as tumour size as continuous or dichotomized variable <5 vs ≥5 cm and <10 vs ≥10 cm. Multivariate analysis was performed for variables that were significant in univariate analysis.
The threshold TD of 205 Gy, described in a preliminary study, 11 was used to calculate the diagnostic performances of MAA dosimetry to predict the response status. A "true positive" (TP) was defined as an objective response obtained with a TD ≥205 Gy; a "true negative" (TN) was defined as no objective response with a TD <205 Gy; a "false negative" (FN) was defined as an objective response with a TD <205 Gy; a "false positive" (FP) corresponded to no objective response with a TD ≥205.

| Toxicity analysis
Toxicities were scored using the common terminology criteria for adverse events (CTCAE) (V4). Only permanent and clinically rele- or >120 Gy) and HR <30%. Multivariate analysis was performed for variables that were significant in univariate analysis.

| Survival
Overall survival was defined as the time between treatment and last follow-up or death. Several variables were tested (see Tables 2   and 3).

| Statistics
Quantitative values were expressed as mean±standard deviation (SD), compared between responders and non-responders using both lesion-

P=.0430.
On multivariate analysis using continuous variables, only TD remained significantly associated with response (P<.00001).
Using the threshold tumoral dose of 205 Gy, TD was predictive of response with a sensitivity of 99.1%, a positive predictive value of 91.5% (10 false-positive results) and an accuracy of 91.6%.
In the event of false-positive results, visual comparison of MAA and 90 Y microsphere distribution revealed a clear mismatch in only four cases (one partial arterial dissection during the therapeutic angiography, two cases with slightly different catheter repositioning and one case without specific angiographic abnormality).

Response
Response evaluation was available for 80 patients, as 5 patients had diffuse and non-evaluable lesions according to EASL criteria.
In total, 18 patients did not respond to treatment, whereas 62 did.  All causes taken into account, the mortality rate was 0% at 1 month, and 5.8% at 3 months.
The median OS values stratified using tested parameters are displayed in Table 2. TD was significantly associated with OS for the overall cohort as for both BLCC B and BLCC C patients (Fig. 3A-C). Other parameters associated with OS were CLIP classification (overall population only), tumour size <10 or ≥10 cm, tumour type (overall population only), PVT involvement, MAA PVT targeting as well as good or poor candidate for PVT patients (Table 2).
On multivariate analysis for the global cohort, TD was the only variable remaining significantly associated with OS (Table 3).
Regarding the 31 PVT patients, 25 were good candidates to radioembolization (i.e. 80.6%) and 6 poor candidates (i.e. 19.4%). One On multivariate analysis involving the PVT cohort, only PVT targeting remained significantly associated with OS (Table 3).

Toxicity
Severe permanent liver toxicity was found in nine patients (10.5%), For the overall population, three multivariate analyses were performed including successively one of the three linked variables proven significant in univariate analysis (+ the others significant variables): HILD as continuous variable (no significant variable found), HILD ≥100 Gy (only biliary disease was significant, P=.0352) and HILD ≥120 Gy with an HR <30% (only HILD ≥120 Gy with an HR <30% was significant, P=.0473).
For the PVT patients, only poor MAA PVT targeting was highly predictive of liver toxicity at multivariate analysis, P<10 −3 .

| DISCUSSION
The first significant finding derived from this study is the clear and highly significant correlation between TD and response, with a and 98.3% in tumour-and patient-based analyses respectively (only one lesion with a TD <205 Gy responded to radioembolization). We also demonstrated that the false-positive rate was high, 33.3% for TDs ≥205 Gy and <260 Gy, and very low, −3.2% only for TD ≥260 Gy (P=.0012), in accordance with a fundamental radiobiology law: "The higher the dose above the threshold dose, the more severe the damage (till the maximal achievable damage is obtained)". Thus, our results suggest that we should target a TD of at least 205 Gy, yet with an even better response achieved if we are able to target TD higher to this threshold (with the limitation that we also have to take into account the dose delivered to the healthy injected liver). This result, obtained on over 130 evaluated lesions, confirms preliminary published data obtained on smaller numbers of lesions treated with both glass or resin microspheres, even if the threshold doses applied were different. 10,11,16,17 A broad evidence demonstrating the accuracy of MAA as a surrogate for microsphere distribution and quantification has thus now become available. This point is of great relevance given that it is still a controversial concept with several studies performed with resin microspheres claiming the contrary. 18,19 It must nevertheless be underlined that numerous confounding factors may cause bias in MAA dosimetric evaluation, including two angiographic parameters with a major potential impact: rigorous catheter repositioning and spasm occurrence. 19 It must be stressed that neither the precise position of the catheter nor the occurrence of vasospasm was analysed in the two cited negative studies. 18,19 In spite of a recently published example pertaining to a dramatic vasospasm with huge impact on tumour uptake quantification, 20 this parameter has almost never been discussed, and it has recently been proposed to employ an as minimally invasive as possible angiographic procedure when using MAA as dosimetric tool. 20,21 The high accuracy of MAA dosimetry in response prediction is of major interest, as MAA dosimetry is available prior to therapy it can be used for treatment personalization. 8,13,14,16 It has to be highlighted that the target TD of 120 Gy recommended by a panel of expert for resin microspheres 8 is different than the threshold doses observed for glass microsphere, i.e. between 205 and 217 Gy depending on the studies. 11,16 The great difference in the specific activity of microspheres (50 Bq per sphere for resin; 2500 Bq per sphere for glass) results in a high difference in the number of spheres to be injected for the same activity, with then a high difference regarding dose distribution heterogeneity, as recently demonstrated in a simulation study. 22 As the radiobiological effect depends not only on the absorbed dose but also highly on dose distribution heterogeneity, 16

| CONCLUSION
This study highlights the impact of MAA-based tumour dose evaluation on both response and OS for HCC patients treated with glass microspheres. Those results suggest that TD should be analysed in the large phase III ongoing trials (at least retrospectively), to avoid missing the group of patient best candidate to radioembolization. While further prospective studies are now warranted to evaluate MAA dosimetry, these results open up the possibility of using a personalized dosimetric approach that could potentially strongly improve radioembolization effectiveness.

ACKNOWLEDGEMENT
Authors thank the Labex IRON for its financial support.

FINANCIAL SUPPORT
None.

CONFLICT OF INTEREST
Etienne Garin is a consultant for BTG.