On-Demand Loco-Regional Treatment for Intrahepatic Lesions Improves Treatment Outcomes in Atezolizumab Plus Bevacizumab Therapy for Unresectable Hepatocellular Carcinoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is of interest but it needs some improvements.

1) The study design is retrospective and this aspect should be properly addressed in the Discussion

2) The sample size is limited and in particular it does not enable the subgroup analysis

3) Why DEB-TACE was used for bigger lesions (more than 5 cm)? What is the rationale? 

4) The authors should mention in the Discussion the sate of the art of TACE therapies in these patients (in this regard cite the relevant series PMID: 24870698)

5) Do the authors have also some data on other biomarkers, for example the monocyte/lymphocyte ratio? If not, they should at least mention it in the Discussion along with its important in several primary and secondary hepatic malignancies (in this regard cite the relevant series PMID: 27122671)

Author Response

Responses to the Comments by the reviewer 1:

• The study design is retrospective and this aspect should be properly addressed in the Discussion

>Thank you for your comment. I fully agree with your opinion. I have added the discussion about the limitation (page 9, lines 328-330).

2) The sample size is limited and in particular it does not enable the subgroup analysis.

>Thank you for your valuable comment. I agree with your comment. I have added the discussion about the limitation. Future studies with prospective and larger samples are desired (page 9, lines 328-330).

3) Why DEB-TACE was used for bigger lesions (more than 5 cm)? What is the rationale? 

>DEB-TACE has been reported to be superior to inhibit inflammatory responses and liver injury after TACE than conventional TACE. In present study, we prioritized to maintain hepatic reserve function after IHLRT so that Atez/Bev treatment could be continued. We have added the sentence with reference (page 3, lines 126-129).

4) The authors should mention in the Discussion the sate of the art of TACE therapies in these patients (in this regard cite the relevant series PMID: 24870698)

>Thank you for your valuable comments. We have added the discussion about TACE and its recent development with references you indicated (page 9, lines 302-305).

5) Do the authors have also some data on other biomarkers, for example the monocyte/lymphocyte ratio? If not, they should at least mention it in the Discussion along with its important in several primary and secondary hepatic malignancies (in this regard cite the relevant series PMID: 27122671)

>Thank you for your valuable and insightful comments. The data regarding monocyte/lymphocyte ratio was insufficient and immature in present cohort for publication. It should be investigated in future studies. Therefore, we have added the discussion about them with reference you indicated (page 9, lines 320-326).

Reviewer 2 Report

Comments and Suggestions for Authors

The authors investigate the effect of loco-regional treatment on outcome of patients with HCC under standard atezo/bev treatment. The authors describe a beneficial effect of additional locoregional treatment and investigate potential predictive factors. This is an important study as the standard atezo/bev treatment is still limited to approx 30% of patients only and improvements are urgently needed. The study is well conducted and the conclusions are justified. 

Since NLR is identified as a predictive biomarker, it is unusual to present the data only in the supplementary figure and not to include NLR in the uni/mulivariate analysis shown in Table 4.

As mALBI is a predictive factor, too, is there also a role for portal vein invasion?

AFP levels show a wide range in the patient population. Is there a subpopulation with distinct prognostic features?

 

Author Response

Responses to the Comments by the reviewer 2:

The authors investigate the effect of loco-regional treatment on outcome of patients with HCC under standard atezo/bev treatment. The authors describe a beneficial effect of additional locoregional treatment and investigate potential predictive factors. This is an important study as the standard atezo/bev treatment is still limited to approx 30% of patients only and improvements are urgently needed. The study is well conducted and the conclusions are justified. 

>Thank you for your warmful comments,

Since NLR is identified as a predictive biomarker, it is unusual to present the data only in the supplementary figure and not to include NLR in the uni/mulivariate analysis shown in Table 4.

>Thank you for your suggestions. We have added NLR to the uni/multivariate analysis (new Table 4). NLR was also an independent predictor for OS in present study.

As mALBI is a predictive factor, too, is there also a role for portal vein invasion?

>In present study, ALBI score was similar between MVI present or not. We have added the sentence (page 4, lines 167 and 168).

AFP levels show a wide range in the patient population. Is there a subpopulation with distinct prognostic features?

>Thank you for your insightful comments. AFP levels in patients with NASH, AL and HCV eradicated were relatively lower than those with HBV but not significant. In present study, the predictive value of AFP for objective response was limited in the result (page 7, line 246). Future studies with larger samples including each etiology are desired.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The revised manuscript is OK. Thank you!