Optimization of the Clinical Effectiveness of Radioembolization in Hepatocellular Carcinoma with Dosimetry and Patient-Selection Criteria

Round 1

Reviewer 1 Report

The author in this manuscript reviews the main clinical results of Selective internal radiation therapy in hepatocellular carcinoma. The performance of the treatment was based on liver function, tumour characteristics and tumour targeting etc. In their, review the authors highlighted some features that contributed to the performance of the treatment and draw their conclusion that SIRT is an effective therapy in HCC. They found dosimetry as a key role for predicting treatments effectiveness. The introduction is well written, explaining the phases of SIRT planning and discussing treatment options planning of HCC depending on the BCLC. This review provides a comprehensive overview of the treatment methods and an understanding of the factors responsible for treatment ineffectiveness in HCC.

The sections are structured nicely and the reference for the studies included in this review is also correct.

However, the review would benefit from giving some more information on the statistical method that was incorporated in this metadata analysis. For example, in Table 1, I see significant at P < 0.05 there are some stars marks but the explanation is missing. What was compared and which statistical method was used for this. Similar in Table2, 3 and 4. Additionally, it would be useful for a reader if the manuscript provides an overview of all the studies in one supplementary table.

More information on differences statistically significant would be helpful to understand what the difference means. 

Author Response

Dear reviewer,

We thank you very much for your interesting comments.

 

Comments reviewer 1:

“the review would benefit from giving some more information on the statistical method that was incorporated in this metadata analysis. For example, in Table 1, I see significant at P < 0.05 there are some stars marks but the explanation is missing. What was compared and which statistical method was used for this. Similar in Table2, 3 and 4. Additionally, it would be useful for a reader if the manuscript provides an overview of all the studies in one supplementary table.

More information on differences statistically significant would be helpful to understand what the difference means.”

 

Response to reviewer 1:

Dear reviewer,

We thank you very much for your interesting comments.

Indeed, the statistical methods were not explained in tables. This revised version describes the methods in footnotes.

Based on your recommendations we added also a new table (new table 2), reporting the main characteristics of these dosimetric studies.

Reviewer 2 Report

This is an interesting review, describing the importance of patients’ selection for SIRT in HCC.

For selection good HCC candidates for SIRT, authors could:

• add that ALBI score is correlated with OS and toxicity (Lescure and al, Cancers 2021).
• discuss the role of tumor size.

Authors could discuss if the new systemic treatment for HCC patients, immunotherapy with atezolizumab-bevacizumab, could change the place of SIRT; and how future clinical trials had to be designed to place SIRT in this new era of immunotherapy in HCC patients.

Author Response

Dear reviewer,

We thank you very much for your review and your very interesting comments.

 

• add that ALBI score is correlated with OS and toxicity (Lescure and al, Cancers 2021).

Response to reviewer:

Indeed, this study was added in the table reporting the factors of poor prognosis after SIRT (new table 6). The higher risk of REILD for patients ALBI grades 2 or 3 was also discussed (line 366, page 10).

 

• discuss the role of tumor size.

Response to reviewer: This is a very interesting point highlighting the interest of tumor dosimetry.  The following paragraph was added to the manuscript (section 4. Personalized dosimetry in SIRT, line 255, page 8):

 

“Moreover, a large HCC tumor size (³ 5 cm) was a factor of poor prognosis in some studies (Abouchaleh et al. 2018, Zu et al. 2020, Salem et al. 2010.) These studies included patients treated by glass microspheres, using the recommended method of activity planning (80-150 Gy to the targeted liver). Besides, Garin et al. (2017) demonstrated a significant lower response rate in large HCC tumors (size ≥ 5cm) using this same method of activity planning, probably because of tumor underdosing. More interestingly, using an optimized method of activity planning increasing the tumor absorbed dose, Garin et al. (2015) demonstrated a high response rate in large HCC tumors and no correlation between the tumor size (³ 5 cm) and the patient survival. “

 

 

• Authors could discuss if the new systemic treatment for HCC patients, immunotherapy with atezolizumab-bevacizumab, could change the place of SIRT; and how future clinical trials had to be designed to place SIRT in this new era of immunotherapy in HCC patients.

Response to reviewer: Indeed, the novel immunotherapies recently changed the treatment algorithm of advanced HCC.

The following paragraph was added in the manuscript (section 2- clinical results of SIRT in HCC, line 93, page 3):

 

“Patients treated with atezolizumab plus bevacizumab demonstrated a superior survival and progression-free survival compared to patients treated with sorafenib (Finn et al. 2020). However, randomized controlled trials comparing SIRT to sorafenib have failed to demonstrate a superior outcome with SIRT (Vilgrain et al. 2017, Chow et al. 2017, Ricke et al. 2019). Consequently, the place of SIRT in advanced HCC is an alternative and possibilities for therapy optimization should be investigated. “

Moreover, the place of SIRT can be in combination with immunotherapy. The following paragraph was added in section 2 (line 116, page 4):

“Controlled trials currently investigate the combination of SIRT plus immunotherapy in patients with intermediate and advanced HCC. Preliminary results of the combination of nivolumab three weeks after SIRT demonstrated a favorable tolerability and encouraging response rates (NASIR HCC-trial, International Liver Cancer Association 2020 virtual conference, Tai et al. 2021). A randomized trial (NCT04541173) is also investigating the safety and effectiveness of SIRT followed by the combination of atezolizumab plus bevacizumab. In theory, the combination of immunotherapy after SIRT may give a synergistic clinical effect and improve tumor control and patient survival. Ionizing radiation may induce the release of tumor-associated antigens, targeted by antigen presenting cells and result in a stimulation of the immune response, boosting the effects of immunotherapy (Lee, 2020). SIRT must be performed before the initiation of immunotherapy, when the biological effects of the ionizing radiations are effective.

Reviewer 3 Report

Radioembolization (RE) is one of the therapeutic approaches to hepatocarcinoma (HCC). In this review the authors address the possibility to optimize the treatment administering an activity calculated individually based on optimal tumor average absorbed dose values (I wonder if in the future EUD should be a better dose index to consider, due to the 3-D distribution of the activity in the tumor/liver).

The authors present a metanalysis (based on previously published literature) where the optimal tumor average dose values for both the resin and glass types of Y-90 microspheres are shown, addressing the importance of the individual dosimetry (and appropriate selection of patients, based on BCLC staging system) in Y-90 microspheres RE treatments.

The conclusion is that the optimization of the treatment needs internal dosimetry evaluations and an accurate selection of the patients: it is a relevant contribution to the improvement of the outcome of RE procedures.

Bibliography is complete and accurate.

The paper is interesting, well written, concise but significant, and deserves publication, in my opinion.

Two minor revisions:

Table 1: in the firs row of the table is reported "TRR". The acronym is not explained in the legend (probably TRR must be replaced by RR: Response rate);

Table 2: the third citation of Garin et al. is not complete (year and citation number is missed)

Author Response

Dear reviewer,

We thank you very much for your review and your comments.

 

• Table 1: in the first row of the table is reported "TRR". The acronym is not explained in the legend (probably TRR must be replaced by RR: Response rate);

Response to reviewer: Indeed, thank you, a footnote with RR was added.

 

• Table 2: the third citation of Garin et al. is not complete (year and citation number is missed)

Response to reviewer: The new table 3 is correct in this version.