Nonsurgical hepatocellular carcinoma treated with selective internal radiation therapy and personalized dosimetry: real-life data from French centers

Introduction

The unique features of hepatocellular carcinoma (HCC), the leading cause of primary liver cancer, which is commonly associated with cirrhosis (1) and portal hypertension (2) in Europe, require a collaborative management strategy and appropriate treatment modalities. Some definite therapeutic and strategic innovations have been noted in recent years with the advent of immune checkpoint inhibitors (ICIs) (3-5), a flexible management strategy (6) recommended by many experts for more than a decade (7,8) and the combination of intra-arterial therapy and systemic treatments (9,10). Transarterial chemoembolization (TACE) has long been the only recommended treatment option for intermediate stages (11) and was often used beyond the recommended guidelines given the limited number of therapeutic options (12). Moreover, selective internal radiation therapy (SIRT) or radioembolization based on the intra-arterial injection of yttrium-90 (Y90)-labeled resin or glass microspheres is experiencing renewed interest with the use of personalized dosimetry. Recognized as an effective therapeutic alternative for early HCC (6,13), SIRT with personalized dosimetry has shown an overall survival (OS) benefit for advanced HCC patients with vascular invasion (14) and may constitute an alternative to TACE with better long-term local control (15,16). However, its place is currently not well defined beyond early-stage HCC owing to negative phase 3 trials compared with treatment with tyrosine kinase inhibitors (TKIs) using standard dosimetry (17-19). We therefore felt that measuring the impact of this treatment, which has been available and used in our centers since 2019, was essential.

The objectives of our study were to determine the characteristics of patients with HCC receiving SIRT in the era of personalized dosimetry in real life; to evaluate the efficacy of this treatment modality on OS for intermediate- and advanced-stage HCC; and to define the prognostic variables associated with OS in patients treated with SIRT and the adverse effects observed in this population. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-72/rc).

Methods

In three French centers in the southern region (Hôpital Saint-Joseph in Marseille, Hôpital Universitaire de la Timone in Marseille, and Hôpital Universitaire de l’Archet in Nice), we retrospectively analyzed all consecutive patients with HCC who received SIRT with Y90 (glass microspheres) guided by personalized dosimetry, either as first-line or a subsequent line of therapy, administered as a standalone treatment or in combination with other therapies, from January 2019 to December 2023. The SIRT treatment decision was made during a multidisciplinary team discussion in accordance with local practices at each center. HCC diagnosis was based on the European Association for the Study of the Liver (EASL) guidelines (11), which use imaging or histological criteria. The selected patients had stage A or B HCC according to the Barcelona Clinic Liver Cancer (BCLC) system that was not amenable to curative treatment (surgical resection or ablation) or were considered poor candidates for TACE alone. The selected patients also included those with stage C HCC with unilateral intrahepatic vascular invasion classified according to the extent of tumor thrombus (20) (type I: tumor thrombus in segmental branches of the portal vein or above; type II: tumor thrombus in the right or left portal vein), together with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a Child-Pugh (CP) grade of A or higher (according to each institution). The exclusion criteria included a contraindication during the first planning phase, a hepatic-pulmonary shunt >20%, an estimated dose to the lungs >30 Gy, extrahepatic fixation or insufficient targeting, and additional liver transplantation. A total of seventy-three patients (Timone n=35, Saint-Joseph n=18, and Archet n=20) were included out of a total of ninety selected patients, as twelve patients did not satisfy the criteria after the initial simulation phase, and five patients underwent additional transplantation (Figure 1). To better interpret our results, this multicenter SIRT cohort was compared with a large single-center cohort of patients (n=1,049) from Hôpital Saint-Joseph treated with other therapeutic modalities between January 2007 and December 2023 (Table S1 and Figure 1) whose data were collected from an internal database (21), and patients with BCLC stage A or D HCC were excluded from the comparative analysis. The data from the SIRT treatment cohort were collected from each center’s internal database and analyzed retrospectively. Baseline data prior to SIRT and follow-up demographic, clinical, and biological characteristics, including complete blood count, blood chemistry [particularly alpha-fetoprotein (AFP) and C-reactive protein (CRP) levels], and pre- and posttreatment radiological characteristics, were collected. Only patients for whom essential data were available were included.

Figure 1 First treatment modalities in the single-center cohort and flowchart of the SIRT cohort. Anti-PD-L1 + anti-VEGFA, anti-programmed death receptor ligand 1 + anti-vascular epidermal growth factor A; BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; SC, supportive care; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; TKI, tyrosine kinase inhibitor.

The protocol for this study was approved by the Hôpital Saint-Joseph Ethics Committee (No. 18050614) and complied with the requirements of the Declaration of Helsinki and its subsequent amendments. Owing to the retrospective nature of the analysis, the obligation to obtain written informed consent from patients was waived. Hôpital Universitaire de la Timone and Hôpital Universitaire de l’Archet were informed and agreed with this study.

SIRT treatment protocol

The injection of glass microspheres (TheraSpheres^®, BTG UK Limited, London, UK) containing 90Y was performed via femoral access and catheterization of one or more branches of the hepatic artery according to a two-step plan if the patient met the eligibility criteria in terms of liver function and performance indices. During the first planning phase, an arteriography was performed to determine the best injection strategy (lobar, segmental, or targeted), to identify any extrahepatic flow, and to perform prophylactic embolization if necessary. This was followed by an injection of technetium-99m (99mTc-MAA)-labeled albumin macroaggregates, which simulate microsphere fixation, and a single-photon emission computed tomography/computed tomography (SPECT/CT) scan to analyze their distribution with the objectives of studying tumor lesion targeting, eliminating any arteriovenous fistulas or extrahepatic fixations, and assessing pulmonary fixation. If there were no contraindications, we calculated the activity to be injected using the personalized dosimetry method, considering lung fixation (<30 Gy to the lungs and <50 Gy as a cumulative dose if multiple treatments were given) or using the following formula considering the estimated absorbed doses delivered to different parts of the liver: Activity (expressed in GBq) = [D Liver × m Liver/50 × (1 − pulmonary shunt)] (D Liver or mean dose delivered to the liver expressed in Gy corresponding to the estimated dose delivered to the perfused region; shunt or pulmonary fixation fraction expressed as a percentage; m Liver or liver mass in kg). The dose limits for the different areas varied depending on whether cirrhosis was present. The second phase of treatment, performed seven to fourteen days later, consisted of injecting 90Y-loaded microspheres into the patient under the same conditions as the 99mTc-MAA injected during the planning stage. A positron emission tomography/CT (PET/CT) scan was used to assess the total dose delivered to the tumor, healthy liver, entire liver, and lungs.

Personalized dosimetry method

Simplicit90Y™, MIRADA, a dosimetry software (Mirada Medical Ltd., Oxford, UK) based on a local deposition model, was used to coregister all the images and to estimate the absorbed dose according to the SPECT and PET microsphere distributions. To determine the dose, the functional images were coregistered on anatomical volumes [CT/magnetic resonance imaging (MRI)] to determine the absorbed dose by the tumor, the liver lobe and the whole liver. The image registration functionality of Simplicit90Y™ was used to superimpose anatomical and functional images: “rigid or deformable (elastic) option”. The absorbed dose was automatically determined using the software and considering the “number of counts” of the functional images contained in the anatomical volume. Only rigid, automatic and manual coregistrations were used for further purposes, as the deformable coregistration was considered excessive deformation for the SPECT and PET data. Simplicit90Y™ was used to estimate the tumoral, lobar (perfused volume) and whole-liver absorbed dose as well as the overlap of the biodistribution of microspheres from SPECT and PET imaging.

Follow-up

Patient follow-up included radiological evaluation by contrast-enhanced CT scan and clinical and biological assessment (including liver function parameters, complete blood count, creatinine, CRP, and AFP levels) 6 weeks after SIRT treatment, at twelve weeks after SIRT treatment (CT scan and/or MRI), every twelve weeks during the first year, and then every 6 months until death or the end of follow-up. Tumor response was assessed according to the modified response evaluation criteria in solid tumors (mRECIST). The overall response rate (ORR) was defined as the percentage of patients who achieved a complete response (CR) or partial response (PR). The disease control rate (DCR) was defined as the percentage of patients who achieved CR, PR, or stable disease (SD). Side effects were recorded from the date of radioembolization and, in particular, at the first assessment at six weeks. Side effect severity was classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0.

Other treatment modalities (single-center cohort)

Patients with BCLC stage B HCC were treated primarily with TACE and, less frequently, with surgical resection in the absence of portal hypertension in patients with unilobar oligodominant HCC. Conversely, systemic treatment was used in cases of diffuse or infiltrating HCC or in cases where TACE was contraindicated.

Patients with BCLC stage C HCC received systemic treatment consisting of a combination of anti-programmed death-ligand 1 (PD-L1) with anti-vascular epidermal growth factor (VEGF)-A antibodies as first-line treatment beginning in August 2020 or TKIs in cases of contraindication or TKIs as first-line treatment during an earlier period [2008–2020]. These patients were treated less frequently with surgical resection in the absence of portal hypertension in cases of HCC with unilateral limited portal vein invasion (20) if the patient met the eligibility criteria for liver function and performance status or by TACE in cases of sectoral tumor portal vein thrombosis in accordance with expert recommendations at the time (22). Similarly, a small number of patients with intra-extrahepatic tumor portal vein thrombosis were treated with an intraarterial injection of ¹³¹I-labeled iodized oil (23) before 2010.

Each treatment modality was followed using contrast-enhanced CT and/or magnetic resonance (MR) imaging at eight weeks and then every 3 months during the first year before moving to 6-month examinations.

Statistical analysis

Quantitative data are presented as the means and standard deviations or medians and interquartile ranges (Q1–Q3); qualitative data are reported as frequencies and percentages. Quantitative data distributed according to a normal distribution were compared between groups using Student’s t-test or the nonparametric Wilcoxon test; otherwise, the Chi-squared test or Fisher’s test was used to compare qualitative data. The Mantel-Haenszel Chi-squared test was performed to compare data on an ordinal scale. The assumption of normality of distributions was assessed using the Shapiro-Wilk test. OS was defined as the time interval between the start of treatment and death or the date of the last follow-up for patients still alive. OS was compared between groups using the log-rank test. OS results are reported as medians and interquartile ranges (Q1–Q3). Prognostic factors associated with survival were analyzed using a Cox proportional hazards regression model. Factors identified as significant in the univariate analysis were included in the multivariate model analysis. The multivariate results are reported as hazard ratios (HRs) and 95% confidence intervals (CIs). A comparative analysis with a cohort of patients with HCC was performed. The SIRT groups and the single-center cohort were matched using propensity scores on the basis of age, ECOG PS, CP grade (A, B, C), Albumin-Bilirubin (ALBI) grade [1, 2, 3], BCLC stage (B, C), vascular invasion (presence vs. absence), and metastases (presence vs. absence) (24). HCC patients with no known treatment were removed from the matching. All P values were considered significant at an α level of 0.05. All calculations were performed using SAS V9.4 statistical software (SAS Institute Inc., Cary, NC, USA).

Results

Baseline characteristics

Patients treated with SIRT mostly had cirrhosis classified as CP A, with a favorable performance status (Table 1). Esophageal varices were reported in 45% of cases. HCCs were predominantly multifocal and preferentially unilobar, with a mean tumor diameter of 59.6 mm. HCCs were classified mainly as BCLC stage B (37%) or C (50.7%), with vascular invasion in 49% of the patients and metastases in 5.5% of the patients. SIRT guided by personalized dosimetry was the first-line treatment in nearly 51% of the patients and was combined with another therapy in approximately one-quarter of the patients. Dosimetry was evaluated in sixty-four patients, and 94% of them received a tumor dose of 205 Gy or higher.

Efficacy

SIRT: intermediate- and advanced-stage HCC

After a median follow-up of 11.9 (6.2–21.1) months, 53% of patients treated with SIRT died. Patients with BCLC stage B and C HCC had median OS times of 35.2 (6.5–infinite) months and 12.8 (6.8–infinite) months, respectively (Figure 2), and progression-free survival times of 6.2 (2.9–infinite) and 8.0 (3.8–15.9) months, respectively. A post-SIRT radiological response was observed in 44 out of 58 evaluable patients (90% of the population; n=64) at 6 weeks, resulting in an RR of 76% (including 20% CR) according to the mRECIST criteria and a DCR of 88%, with disease progression observed in 12% of patients (n=7). A post-SIRT radiological response was observed in 24 out of 40 evaluable patients (63% of the study population) at 3 months, resulting in an RR of 60% (including 42% CR) and a DCR of 72%, with disease progression observed in 28% of patients (n=11).

Figure 2 Kaplan-Meier curves describing the overall survival of HCC patients treated with SIRT according to BCLC stage. Data are presented as medians and interquartile ranges (Q1–Q3). BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; SIRT, selective internal radiation therapy.

Among patients with BCLC stage B/C HCC, 44 patients (69%) received subsequent treatment after SIRT therapy: 22 patients received systemic treatment (16 received anti-PDL1 plus anti-VEGFA, whereas 6 received TKI); eleven patients received local-regional treatment, such as ablation or TACE; four patients received surgical resection; and seven patients received a new SIRT session.

Single-center cohort

After a median follow-up of 17.0 (5.6–40.0) months, 81% of patients in the single-center cohort died; the median OS was significantly different according to the BCLC system (P<0.001) (Figure 3).

Figure 3 Kaplan-Meier curves describing the overall survival of the population with HCC from the single-center cohort according to BCLC stage. Overall survival was not measurable in nine patients: 4 patients from BCLC stage A, 4 from BCLC stage B, and 1 from BCLC stage C. HCC patients with BCLC stage AB were those with a single tumor ≥5 cm in diameter. Data are presented as medians and interquartile ranges (Q1–Q3). BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma.

Comparative study of OS in patients with intermediate/advanced HCC from the SIRT and monocentric cohorts before matching

BCLC stage C HCC with unilateral portal tumor vein thrombosis

A comparative study of the two cohorts revealed that compared with other treatment modalities, SIRT was superior in terms of OS for patients with BCLC stage C HCC with type I and type II portal vein tumor thrombosis [16.0 (8.0–infinite) vs. 10. 0 (6.4–16.6) months, respectively; P=0.02] (Table 2). SIRT was a second-line treatment in more than 50% of the patients. Patients in the SIRT cohort were significantly older but had a more favorable PS, better liver function, fewer infiltrating tumors, and fewer nodules (Table 3). The median OS of patients with stage C HCC with intrahepatic portal vein invasion treated with SIRT was significantly greater than that of patients treated with TKI or TACE (Table S2).

BCLC stage B HCC

A comparative study of the two cohorts revealed no significant difference in median OS for patients with intermediate-stage HCC treated with SIRT or other therapeutic modalities (Table 4). SIRT was a second-line treatment in more than 50% of the patients. The SIRT cohort included more patients with CP grade A cirrhosis, and their mean bilirubin level was significantly lower. Fewer nodules were observed in the SIRT group, but the tumor diameter was greater (Table 5).

Comparative study of OS in patients with intermediate/advanced HCC from the SIRT and monocentric cohorts after matching

Finally, there were 51 patients in each group, and approximately 50% of the patients had advanced HCC and vascular invasion (Table 6). Patients from the single-center cohort underwent primarily intra-arterial treatment. In addition, more than one-third received systemic treatment, and nearly 15% received curative treatment. The analysis revealed no significant difference in median OS between the two groups after matching [SIRT: 16.0 (7.6–infinite) vs. 17.4 (9.9–27.7) months, HR 1.13 (0.70–1.83), P=0.63) (Figure 4), respectively], following a comparable median follow-up duration [SIRT: 12.6 (6.8–21.3) vs. 14.0 (7.3–27.3) months, P=0.17].

Figure 4 Kaplan-Meier curves describing the overall survival of patients with intermediate/advanced HCC treated with SIRT or another therapeutic modality after matching. Data are presented as medians and interquartile ranges (Q1–Q3). HCC, hepatocellular carcinoma; MC, monocentric cohort; SIRT, selective internal radiation therapy.

Prognostic factors of survival in the SIRT cohort

The prognostic variables with an unfavorable impact on OS according to univariate analysis were CP grade C, the presence of metastases, tumor size, and CRP level (Table 7). Only hemoglobin had a beneficial effect on OS. Multivariate analysis confirmed these findings for the CP grade, tumor size, and hemoglobin level. The risk of early death was lower for patients with CP grades A and B cirrhosis than for those with CP grade C cirrhosis. Similarly, the risk of early death increased with increasing tumor size. Conversely, the risk of early death decreased with increasing hemoglobin concentration.

Adverse events

Overall, 44 patients (60%) reported one or more adverse events following SIRT, which were mostly moderate in severity (Table 8). Severe side effects reported in a minority of patients (18%) included gastrointestinal bleeding in two patients, postprocedural ascites in two patients, and liver failure in two patients. We report no deaths related to the procedure and no cases of radiation-induced liver disease.

Discussion

Although the role of yttrium-90 in HCC treatment strategies remains controversial, this study revealed that SIRT following personalized dosimetry is used as a therapeutic solution in our centers, preferably for advanced and intermediate-stage HCCs, similar to a large multicenter series (25). Moreover, we observed that SIRT is commonly used in combination and after first-line treatment as a rescue therapy. Interestingly, in our study, BCLC stage, treatment line, and the combination of SIRT plus another treatment modality were not unfavorable prognostic variables. Our patient characteristics were similar to those in published studies, with a greater number of unilobar tumors (15,26-29), with respect to baseline liver function. Most patients were classified as CP grade A, but a few patients were classified as CP grade B (27,30) or C (29,30) or ALBI grade 3 (15,31). Portal hypertension (25,31) was also found in approximately half of our patients, whereas a minority had extrahepatic disease (25).

The median OS of patients with intermediate-stage HCC treated with SIRT was more than 35 months in our study. The difference observed is not significant compared with that of other treatment modalities after a median follow-up of 12 months. These results should be interpreted with caution because this is a retrospective study. However, these results are not unexpected. SIRT following personalized dosimetry is a treatment option for intermediate-stage HCC because, compared with TACE, it allows for better local control (15,16), especially for sustainably treating large HCCs greater than 5 cm in size (32). In our study, the median OS of patients treated with TACE was comparable to that reported in a literature review of more than 10,000 patients (33). To date, the concept of ‘effective TACE’ has gained acceptance (6). Indeed, TACE has a risk of failure because of the lack of a safety margin related to the procedure or even locoregional tumor progression (34-37). The future of TACE treatment likely lies in a multimodal approach (9,10). Thus, SIRT with personalized dosimetry is more suitable for treating macronodular HCC, infiltrative lesions, or those with peripheral emboli. These two intra-arterial treatments are therefore complementary.

Our study revealed that SIRT is an effective therapeutic solution for BCLC stage C HCC with intrahepatic portal vein invasion, with a median OS rate superior to that of other therapeutic modalities, particularly TKIs, as previously shown (14,38). The standard treatment for advanced HCC is based on systemic therapies (6) and now consists primarily of combinations of antibodies targeting the immune checkpoint proteins CTLA-4 (human cytotoxic T-lymphocyte antigen-4), PD-1 and its ligand PD-L1 or a combination of ICIs and antiangiogenic agents (39). A response is achieved in approximately one-third of patients receiving these combined systemic therapies, and no effective predictive biomarkers are available. Furthermore, phase III trials have focused mainly on advanced HCC patients with metastases and, less frequently, those with vascular invasion (5,40-42). The median OS was 14.2 months for patients with vascular invasion in the IMbrave150 study (3). Advanced-stage HCCs constitute a heterogeneous group with a wide spectrum of tumors (20,43,44). Thus, unilateral intrahepatic portal vein invasion should be differentiated from extrahepatic portal vein invasion and from cases involving both intrahepatic portal branches. Surgery may be a treatment option (45); however, cirrhosis and portal hypertension, which are frequently associated with HCC, as well as comorbidities, are all factors limiting surgical resection in this context. SIRT overcomes these difficulties. Unlike the phase III SARAH, SIRveNIB, and SORAMIC trials (17-19), personalized dosimetry prior to the procedure allows for effective treatment in this setting of intrahepatic vascular invasion. The DOSISPHERE-01 study (14) reported a response rate of 71%, with a significant impact on OS. In our study, 94% of patients received a tumor dose of 205 Gy or higher, whereas in standard dosimetry, a dose of approximately 120 Gy was administered (27,28). The median OS after matching did not significantly differ between the intermediate and advanced HCC population treated with SIRT and that treated with other modalities in our study after a median follow-up of nearly 12 months. However, the Kaplan-Meier curves diverge significantly 24 months after treatment, in favor of patients treated with SIRT. These findings suggest that SIRT provided an additional benefit in our population, in which 50% of the HCC patients experienced vascular invasion.

We identified several prognostic factors for survival previously described in patients treated with SIRT, such as tumor size (28,46), liver function (47), and inflammatory markers (48) such as CRP. Notably, CRP and the presence of metastases demonstrated prognostic value only in univariate analysis. Furthermore, in our study, a decrease in hemoglobin was associated with poor prognosis. This finding is unusual but not surprising. Indeed, different factors, such as renal failure, inflammatory syndrome, malnutrition, and/or portal hypertension associated with liver disease or cancer, can contribute to hemoglobin deficiency.

In our study, there were no deaths following SIRT, and the adverse effects observed were mostly moderate. However, as noted in other studies (13,28,49), we observed severe side effects, including two cases of gastrointestinal bleeding, one following an esophageal rupture and the second following a radiation-induced gastric ulcer in a patient with a history of right hepatectomy and multinodular recurrence in the left liver treated with SIRT. The same patient developed ascites during the follow-up period after SIRT. Two cases of severe liver failure involved patients with impaired liver function at baseline.

The limitations of our study are related to its retrospective design, with the risk of incomplete data collection and missing data. The absence of double radiological readings is also a limitation, along with the lack of precision regarding the type of progression or the variety of treatments in the control group. Furthermore, the insufficient follow-up period compared with that in other studies (13-15) likely affects the survival results.

Conclusions

This multicenter French study shows that SIRT following personalized dosimetry is used in current practice as a treatment solution for intermediate and advanced HCC in combination with and beyond first-line therapy. Our results show that SIRT may be an effective alternative treatment for intermediate-stage HCC and an effective therapeutic solution for advanced HCC patients with intrahepatic vascular invasion, with a good safety profile, which is supported by its pretreatment planning phase. Thus, this treatment fully fits into the therapeutic arsenal of HCC.

Acknowledgments

We would like to thank Rahamia Ahamada for the help in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-72/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-72/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-72/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-72/coif). Patrick Chevallier reports grant and honoraria for lectures, presentations, and support for attending meetings from Roche, Boston. O.P. reports grant, honoraria for lectures, presentations and support for attending meetings from Gilead. F.S. reports grant, honoraria for lectures, presentations and support for attending meetings from Gilead. Paul Castellani reports grant and honoraria for lectures, presentations from Gilead, Abbvie, Cook, AstraZeneca. A.T. reports grant from Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen, and honoraria for lectures, presentations from Gilead, Bayer, Eisai, Intercept, and support for attending meetings from Gilead, Bayer, Eisai, Intercept. M.B. reports grant and honoraria for lectures, presentations from Merck-Schering Plow, Gilead, Janssen, Vertex, Boehringer-Ingelheim, BMS, Roche, Abbvie, GSK, and support for attending meetings from Gilead, BMS, Roche, Abbvie, GSK. R.G. reports grant and honoraria for lectures, presentations, and support for attending meetings from Gilead, AstraZeneca. M.C. reports grant and support for attending meetings from Roche. R.A. reports grant and honoraria for lectures, presentations from Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen, and support for attending meetings from Gilead, Abbvie, Ipsen. X.A. reports grant from Servier, Gilead, Roche, Boston, and honoraria for lectures, presentations from Servier, Roche, Boston, and support for attending meetings from Gilead. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The protocol for this study was approved by the Hôpital Saint-Joseph Ethics Committee (No. 18050614) and complied with the requirements of the Declaration of Helsinki and its subsequent amendments. Owing to the retrospective nature of the analysis, the obligation to obtain written informed consent from patients was waived. Hôpital Universitaire de la Timone and Hôpital Universitaire de l’Archet were informed and agreed with this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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