Proton Beam Therapy for Treatment-Naïve Hepatocellular Carcinoma and Prognostic Significance of Albumin-Bilirubin (ALBI) Grade

Round 1

Reviewer 1 Report

The authors describe “Proton Beam Therapy for Treatment-Naïve Hepatocellular Carcinoma and Prognostic Significance of Albumin-Bilirubin (ALBI) Grade”. The title is impressive, and this study results have potential usefulness in future medicine. However, some concerns should be addressed.

 

Major Points

1.    In this study, 31 patients still survived, and 15 died of progressive disease.

Did any patients die from the progression of liver dysfunction after treatment?

Illustrate changes in mALBI every 3 to 6 months during the follow-up period after proton beam therapy.

In addition, it is necessary to specify the occupied site of the irradiated tumor in the table.

Were there any differences in mALBI changes by irradiation area (e.g., liver hilum and liver surface)?

 

2.    The author should describe the definition of local progression.

 

In this study, does local progression mean intra-irradiated area recurrence? Please add the figure of local progression after proton beam therapy.

Author Response

Reviewer 1’s comments

The authors describe “Proton Beam Therapy for Treatment-Naïve Hepatocellular Carcinoma and Prognostic Significance of Albumin-Bilirubin (ALBI) Grade”. The title is impressive, and this study results have potential usefulness in future medicine. However, some concerns should be addressed.

 Major Points

1. In this study, 31 patients still survived, and 15 died of progressive disease.

Did any patients die from the progression of liver dysfunction after treatment?

 

à Response: We appreciate you for your kind considerations and comments on our paper. As described in results section (Page 5 line 45 – 46 and Page 9 line 34- 35), no patients died from the progression of liver dysfunctions after treatment without disease progression. At last follow up time, two patients died from unknown cause had no evidence of disease progression and liver dysfunction.

In Page 5 line 45 - 46,

“Of the 46 patients, 31 patients are still alive, and 15 patients died from disease progression (n=11), underlying chronic renal failure (n=2), and unknown causes (n=2).”

In Page 9 line 34 – 35,

“PBT-related ≥grade 3 AEs, hepatic failure, and death were not observed.”

 

Illustrate changes in mALBI every 3 to 6 months during the follow-up period after proton beam therapy.

In addition, it is necessary to specify the occupied site of the irradiated tumor in the table.

Were there any differences in mALBI changes by irradiation area (e.g., liver hilum and liver surface)?

 

à Response: According to reviewer’s comments, we revised the manuscript as follow,

In Page 4 line 37 – 38 (Table 1),

Characteristics		n (%)
…	…	…
Tumor location	Hilar	19 (41.3)
	Non-hilar	27 (58.7)

 

In Page 6 line 39 - 40 (Table 2)

			FFLP		PFS		OS
Characteristics		N	5 year (95% CI), %	p value*	5 year (95% CI), %	p value*	5 year (95% CI), %	p value*
….	…	…	…		…		…
Tumor location	Hilar	19	87.4 (70.9 – 103.9)	0.261	36.1 (14.1 – 58.1)	0.333	57.4 (34.9 – 79.9)	0.155
	Non-hilar	27	96.0 (88.4 – 103.6)		48.3 (28.1 – 68.5)		76.7 (57.9 – 95.5)

                    

In Page 9 line 37 – 43,

“The change of Child-Pugh score was not significantly related ALBI grade and tumor location (p>0.05 each) (Supplementary Table 2). The change of ALBI score was 0.13 ± 0.11 (5.0 ± 4.0 %) and increased ALBI grade was observed in 4 (8.7%) patients. Tumor location was not significantly related with change of ALBI grade (p>0.05 each) (Supplementary Table 2). The change of ALBI grade (0 vs. +1) was not significantly related with OS (5-year, 65.8% [95% CI, 49.9 – 81.7] vs. 100% [95% CI, NA], respectively) (p=0.101).”

 

Supplementary Table2 was added,

Supplementary Table S2. Change of Child-Pugh score and albumin-bilirubin (ALBI) grade after proton beam therapy

Change of Child‒Pugh score	-1, n (%)	0, n (%)	+1, n (%)	+2, n (5)	p value*
All patients	3 (6.5)	42 (91.3)	1 (2.2)	0 (0.0)
ALBI grade
1	0 (0.0)	11 (100)	0 (0.0)	0 (0.0)	0.669
2/3	3 (6.5)	31 (88.6)	1 (2.9)	0 (0.0)
Tumor location
Hilar	1 (5.3)	18 (94.7)	0 (0.0)	0 (0.0)	1.000
Non-hilar	2 (7.4)	24 (88.9)	1 (3.7)	0 (0.0)
Change of ALBI grade	-1, n (%)	0, n (%)	+1, n (%)	+2, n (5)	p value*
All patients	0 (0.0)	42 (91.3)	4 (8.7)	0 (0.0)
Tumor location
Hilar	0 (0.0)	17 (89.5)	2 (10.5)	0 (0.0)	1.000
Non-hilar	0 (0.0)	25 (92.6)	2 (7.4)	0 (0.0)

^*Fisher’s exact test, two-tail.

 

2. The author should describe the definition of local progression.

In this study, does local progression mean intra-irradiated area recurrence? Please add the figure of local progression after proton beam therapy.

 

 à Response: According to reviewer’s comments, we revised the manuscript and added the figure of local progression (supplementary Fig. 1) as follow,

Page 3 line 42 – 47,

“Disease progression was classified according to its sites, as follows: local progression was defined as the presence of a growth or new tumor within 1 cm from the margin of the PTV; intrahepatic progression was defined as the presence of growth or a new tumor within the liver, except for local progression; and extrahepatic progression was defined as growth or a new tumor outside of the liver, such as regional or non-regional lymph nodes and distant organs (Supplementary Fig. 1).”

In Page 3 line 1,

“…was considered the ITV without additional margins [13,15,20,21] (Supplementary Fig. 1).”

 

 

Author Response File: Author Response.docx

Reviewer 2 Report

There have been many reports supporting the efficacy of proton beam therapy for hepatocellular carcinoma.  However, few reports have analyzed the clinical outcomes of PBT for treatment-naïve patients. The authors evaluate the outcomes of PBT as initial therapy for treatment-naïve HCC patients. It is informative manuscript and well written but has some problems for the publication. I would like to ask the authors following issue.

 

1.     In Table 4, the authors report the change in Child-Pugh score before and after PBT, but not the change in ALBI grade.  Please describe the change in ALBI grade as well. 

On the other hand, the authors compare the incidences of AEs above CECAE grade 1 by ALBI grade before PBT. Is it appropriate to compare AEs of about grade 1? Please make a comment on this.

 

2.     The authors describe in detail the pattern of recurrence after PBT and even the treatment for recurrent lesions. Can you infer from these why the ALBI grade affected OS?  Were patients with ALBI grade 2/3 not adequately treated for recurrent tumors? Please make a comment on this, if possible.  

 

3.      Table 1.  Sixth line from the bottom.

I think _RRL V_27GyE is a misspelling of _RNLV_27GyE, because I can find _RNLV_27GyE in the footnote. 

 

4.      Line 203 to 206

In univariate analysis, patients with no vascular invasion, vascular invasion 

into the segmental branches and AJCC stage III/IV disease had significantly lower FFLP 

rates than those with vascular invasion into the main and first branches and AJCC stage 

I/II disease (p<0.05 each)

 

It must be 

“ In univariate analysis, patients with vascular invasion into the main and first branches 

and AJCC stage III/IV disease had significantly lower FFLP rates than those with no vascular invasion, vascular invasion into the segmental branches and AJCC stage I/II disease (p<0.05 each)”

 

5.      Line 239

I think “( Fig. 2A and B) must be “(Fig. 2C and D)”.

Author Response

Reviewer 2’s comments

There have been many reports supporting the efficacy of proton beam therapy for hepatocellular carcinoma.  However, few reports have analyzed the clinical outcomes of PBT for treatment-naïve patients. The authors evaluate the outcomes of PBT as initial therapy for treatment-naïve HCC patients. It is informative manuscript and well written but has some problems for the publication. I would like to ask the authors following issue.

1. In Table 4, the authors report the change in Child-Pugh score before and after PBT, but not the change in ALBI grade.  Please describe the change in ALBI grade as well. 

On the other hand, the authors compare the incidences of AEs above CECAE grade 1 by ALBI grade before PBT. Is it appropriate to compare AEs of about grade 1? Please make a comment on this.

 

à Response: We appreciate you for your kind considerations and comments on our paper. According to reviewer’s comments, we revised the manuscript and added the supplementary Table 2.

In Page 9 line 37 – 43,

“The change of Child-Pugh score was not significantly related ALBI grade and tumor location (p>0.05 each) (Supplementary Table 2). The change of ALBI score was 0.13 ± 0.11 (5.0 ± 4.0 %) and increased ALBI grade was observed in 4 (8.7%) patients. Tumor location was not significantly related with change of ALBI grade (p>0.05 each) (Supplementary Table 2). The change of ALBI grade (0 vs. +1) was not significantly related with OS (5-year, 65.8% [95% CI, 49.9 – 81.7] vs. 100% [95% CI, NA], respectively) (p=0.101).”

Supplementary Table2 was added,

Supplementary Table S2. Change of Child-Pugh score and albumin-bilirubin (ALBI) grade after proton beam therapy

Change of Child‒Pugh score	-1, n (%)	0, n (%)	+1, n (%)	+2, n (5)	p value*
All patients	3 (6.5)	42 (91.3)	1 (2.2)	0 (0.0)
ALBI grade
1	0 (0.0)	11 (100)	0 (0.0)	0 (0.0)	0.669
2/3	3 (6.5)	31 (88.6)	1 (2.9)	0 (0.0)
Tumor location
Hilar	1 (5.3)	18 (94.7)	0 (0.0)	0 (0.0)	1.000
Non-hilar	2 (7.4)	24 (88.9)	1 (3.7)	0 (0.0)
Change of ALBI grade	-1, n (%)	0, n (%)	+1, n (%)	+2, n (5)	p value*
All patients	0 (0.0)	42 (91.3)	4 (8.7)	0 (0.0)
Tumor location
Hilar	0 (0.0)	17 (89.5)	2 (10.5)	0 (0.0)	1.000
Non-hilar	0 (0.0)	25 (92.6)	2 (7.4)	0 (0.0)

^*Fisher’s exact test, two-tail.

 

 

2. The authors describe in detail the pattern of recurrence after PBT and even the treatment for recurrent lesions. Can you infer from these why the ALBI grade affected OS?  Were patients with ALBI grade 2/3 not adequately treated for recurrent tumors? Please make a comment on this, if possible.  

 

 à Response. As like reviewer’s comments, the ALBI grade and change of ALBI grade may influence the adequateness of subsequent treatments, types of subsequent treatments (i.e., curative or palliative), patterns of failure after subsequent treatments can affect OS. As described in manuscript (Page 6 line 7 – 10) and supplementary Table 1, after confirmation of disease progressions, all patients received the various subsequent treatments. Due to relative small number of study populations and heterogeneity of subsequent treatment, present study did not thoroughly evaluate the impact of ALBI grade and change of ALBI grade, subsequent treatments for recurrent tumors and patterns of recurrence after PBT and/or subsequent treatments on OS. It should be one of limitations of present study, and thus we make a comment on this in manuscript (in discussion section) as follow,

Page 10 line 50 – Page 11 line 3,

“…in the present study, the predictive ability of ALBI grade and change of ALBI grade for PBT-related toxicity was not thoroughly evaluated because of the low incidence of PBT-related AEs and the relatively small number of study population (n=46). In addition, impacts of ALBI grade and changes of ALBI grade on treatment selection for progressive diseases and OS and probable prognostic factors including the patterns of failures after PBT and/or subsequent treatment after disease progressions were also not thoroughly assessed. Thus, further large-scale studies…”

,

3. Table 1.  Sixth line from the bottom.

I think _RRL V_27GyE is a misspelling of _RNLV_27GyE, because I can find _RNLV_27GyE in the footnote. 

 à Response: According to reviewer’s comments, we revised the manuscript as follow,

In Page 5 line 27 – 28 (in Foot note of Table 1),

“_RRLV_27GyE, relative volume of the remaining residual liver receiving ≥27 GyE; _TLV_27GyE, relative volume of …”

 

4. Line 203 to 206

In univariate analysis, patients with no vascular invasion, vascular invasion 

into the segmental branches and AJCC stage III/IV disease had significantly lower FFLP 

rates than those with vascular invasion into the main and first branches and AJCC stage 

I/II disease (p<0.05 each)

 It must be 

“ In univariate analysis, patients with vascular invasion into the main and first branches 

and AJCC stage III/IV disease had significantly lower FFLP rates than those with no vascular invasion, vascular invasion into the segmental branches and AJCC stage I/II disease (p<0.05 each)”

 à Response: According to reviewer’s comments, we revised the manuscript as follow,

In Page 6 line 13 – 18,

“In univariate analysis, patients with vascular invasion into the main and first branches and AJCC stage III/IV disease had significantly lower FFLP rates than those with no vascular invasion, vascular invasion into the segmental branches and AJCC stage I/II disease (p<0.05 each) (Table 2) (Supplementary Fig. 2A and B).”

5. Line 239

I think “( Fig. 2A and B) must be “(Fig. 2C and D)”.

 à Response: According to reviewer’s comments, we revised the manuscript as follow,

In Page 7 line 50,

“… analysis (p<0.05 each) (Table 2) (Fig. 2C and D).”

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors answered all of the concerns raised by the reviewer. I have no comment.

Reviewer 2 Report

The author answered our questions point by point very well. 

We believe that this paper contains new findings and will provide useful information to our readers.