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Impact of Radiotherapy on Kidney Function among Patients Who Received Adjuvant Treatment for Gastric Cancer: Logistic and Linear Regression Analyses

Cancers 2021, 13(1), 59; https://doi.org/10.3390/cancers13010059

by Jun Su Park¹

, Jeong Il Yu^2,*

, Do Hoon Lim², Heerim Nam³, Young Il Kim¹, Jeeyun Lee⁴, Won Ki Kang⁴, Se Hoon Park⁴, Seung Tae Kim⁴, Jung Yong Hong⁴, Tae Sung Sohn⁵, Jun Ho Lee⁵, Ji Yeong An⁵, Min Gew Choi⁵ and Jae Moon Bae⁵

Reviewer 1: Anonymous

Reviewer 2: Anonymous

Cancers 2021, 13(1), 59; https://doi.org/10.3390/cancers13010059

Submission received: 18 November 2020 / Revised: 14 December 2020 / Accepted: 24 December 2020 / Published: 28 December 2020

(This article belongs to the Special Issue Cancer Radiotherapy)

Round 1

Reviewer 1 Report

Authors showed that when kidney V20Gy was increased by 1%, the 5-year eGFR decreased by 0.209 mL/min/1.73 m2.

It could be interesting to obtain the same result for platinum, age and initial eGFR. Because of the number of the patient and the low number of variables, authors could propose a nomogram to give the % of risk of losing "x" % of the eGFR at 5 yr.

Furthermore authors could do an analysis by matching one or two patients without alteration of the renal function with patient with renal function impairment according to the factors retreived in the logistic analysis to confirm the significance of the renal function variation in both groups.

Author Response

POINT-BY-POINT RESPONSES TO REVIEWERS’ COMMENTS

Manuscript ID: cancers-1024573

Title of Paper: Incorporating sarcopenia and inflammation with radiation therapy in patients with hepatocellular carcinoma treated with nivolumab

RESPONSE: We are grateful for the valuable feedback from the editors and reviewers. After revising our manuscript according to the given comments, we herein provide our responses to the reviewers’ comments with explanations of the corrections/additions. All changes are highlighted in yellow. We welcome additional comments and suggestions. We hope that the revised manuscript and our responses will meet the journal’s requirements.

Reviewer # 1

This article reported the results of renal function impairment after treatment including platinum or platinum and radiations for stomach cancer. Authors showed a low incidence of complications and did not demonstrated any significant role of platinum or radiation in the impairment. Authors showed that when kidney V20Gy was increased by 1%, the 5-year eGFR decreased by 0.209 mL/min/1.73 m2. It could be interesting to obtain the same result for platinum, age and initial eGFR. Because of the number of the patient and the low number of variables, authors could propose a nomogram to give the % of risk of losing "x" % of the eGFR at 5 yr. Furthermore authors could do an analysis by matching one or two patients without alteration of the renal function with patient with renal function impairment according to the factors retreived in the logistic analysis to confirm the significance of the renal function variation in both groups.

→ We deeply appreciate your in-depth review. Following your important advice about the reduction of eGFR, we re-evaluated the distribution pattern of all patients according to the as follows. And, we created a new end-point, which is defined as an “≥ 10% decline in eGFR”. The “10%” was came from the first quartile “89.7%” in following histogram. The number of patients whose 5-year eGFR was decreased ≥ 10% was 172 (25.9%).

And, logistic regression analysis with this new end-point was performed and here is the results.

We inserted following results in Results section and supplementary materials.

Table. Logistic regression analyses to predict a decrease of 10% or more in estimated glomerular filtration rate

	Univariate			Multivariate
Variable	OR	95% CI	p	OR	95% CI	p
All patients (N = 663)
Age (continuous)	1.012	0.996-1.029	0.141	1.048	1.025-1.071	< 0.001
Sex (female)	0.886	0.617-1.271	0.511
Hypertension	1.345	0.829-2.184	0.230
Diabetes	1.031	0.584-1.821	0.917
Cisplatin	1.237	0.845-1.810	0.274
Radiotherapy	1.348	0.942-1.930	0.103	1.557	1.069-2.268	0.021
Baseline eGFR (continuous)	1.022	1.007-1.037	0.004	1.046	1.026-1.066	<0.001
Patients who received radiotherapy and whose DVH data was available (n = 287)
Age (continuous)	1.020	0.993-1.048	0.156
Sex (female)	1.733	1.026-2.928	0.040
Hypertension	1.782	0.795-3.993	0.161
Diabetes	2.259	0.898-5.678	0.083	2.723	1.055-7.026	0.038
Baseline eGFR (continuous)	1.020	0.999-1.042	0.066
Kidney V_5Gy (continuous)	1.023	0.997-1.051	0.082
Kidney V_20Gy (continuous)	1.071	1.027-1.118	0.002	1.077	1.031-1.124	0.001
Kidney D_mean (continuous)	1.002	1.001-1.003	0.004

OR, odds ratio; CI, confidence interval; eGFR, estimated glomerular filtration rate; DVH, dose-volume histogram; V_5Gy, volume receiving 5 Gy or higher; V_20Gy, volume receiving 20 Gy or higher; D_mean, average radiation dose received by specific organ

Figure. Nomograms for predicting a decrease of 10% or more in eGFR 5 year after surgery

Unfortunately, however, because of the small number of patients with renal function impairment, the comparison after matching as you suggested could not be performed. In spite of several limitations of present study, it was revealed through multivariate analysis, so we are confident that the risk factors of the present study could be reliable. Of course, further prospective studies need to be confirmed.

Author Response File: Author Response.pdf

Reviewer 2 Report

This is an interesting study based on a large population of patients with gastric cancer, treated in the context of published phase III trials. Analysis of such data would provide important information regarding the renal toxicity expected by radiotherapy. There are however several major points that should be taken into account :

The study analyses two groups of patients. One that received postoperative Radiotherapy+chemo and a second that received chemo only. Two main questions are raised: i. did RT increase the risk of kidney function impairment - which demands an analysis in all 663 patients and, ii. what are the characteristics of RT (V5, V20, Dmean) that may have a causative relation to the kidney dysfunction. This latter question should focus on the group of 287 patients where DVH data are available.

I suggest that these two clearly distinct questions should dealt separately, as two distinct parts of the study, in the results.

Table 1 shows the patient characteristics. Table S2 is equally important and should be presented as a standard and not as a supplemental material.
In line 95, "...A total of 13 patients..." it should be clearly stated how many of them had received or not radiotherapy. RT is the main target of the paper.
DVH should be included in the second part of the study focusing on RT treated patients. A figure (similar to the Figure 2) should be provided showing the mean eGFR in two groups of irradiated patients, using chosen cut-off points for V5, V20 and Dmean. It is important for the study to propose cut-off points that define a higher risk of nephrotoxicity and this should be displayed in the results. Regression analysis taking into account the DVH data could be also performed.
2.3 Is it logistic regression analysis as stated in the title? Title of 2.4 is the same with the 2.3
The literature reveals several studies focusing on radiotherapy and kidney dysfunction in patients with gastric cancer and at least some of them should be discussed (for example:

1: Kaydıhan N,. Comparison of changes in renal function with dosimetric parameters in gastric cancer patients treated with adjuvant chemoradiotherapy. Jpn J Radiol. 2017 Dec;35(12):733-739.

2: Haneder S. Assessment of renal function after conformal radiotherapy and intensity-modulated radiotherapy by functional 1H-MRI and 23Na-MRI. Strahlenther Onkol. 2012 Dec;188(12):1146-54.

3: Yavas G. Basal renal function reserve and mean kidney dose predict future radiation-induced kidney injury in stomach cancer patients. Support Care Cancer. 2014 Feb;22(2):445-51.

4: Marcenaro M,. Kidney-sparing radiotherapy by multiple-field three-dimensional technique in the postoperative management of patients with gastric cancer: comparison with standard two-field conformal technique. Tumori. 2006 Jan-Feb;92(1):34-40.

5: Trip AK,. IMRT limits nephrotoxicity after chemoradiotherapy for gastric cancer. Radiother Oncol. 2014 Aug;112(2):289-94.

6: Haneder S,. Dose-dependent changes in renal (1)H-/(23)Na MRI after adjuvant radiochemotherapy for gastric cancer. Strahlenther Onkol. 2015 Apr;191(4):356-64.

7: Maor MH. Outcomes of high-dose unilateral kidney irradiation in patients with gastric lymphoma. Int JRadiat Oncol Biol Phys. 1998 Jun 1;41(3):647-50.

8: Boda-Heggemann J. Combined adjuvant radiochemotherapy with IMRT/XELOX improves outcome with low renal toxicity in gastric cancer. Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1187-95.

9: Dewit L. Compensatory renal response after unilateral partial and whole volume high-dose irradiation of the human kidney. Eur J Cancer. 1993;29A(16):2239-43.

Author Response

POINT-BY-POINT RESPONSES TO REVIEWERS’ COMMENTS

Manuscript ID: cancers-1024573

Title of Paper: Incorporating sarcopenia and inflammation with radiation therapy in patients with hepatocellular carcinoma treated with nivolumab

Reviewer # 2

Comments and Suggestions for Authors

The study analyses two groups of patients. One that received postoperative Radiotherapy+chemo and a second that received chemo only. Two main questions are raised: i. did RT increase the risk of kidney function impairment - which demands an analysis in all 663 patients and, ii. what are the characteristics of RT (V5, V20, Dmean) that may have a causative relation to the kidney dysfunction. This latter question should focus on the group of 287 patients where DVH data are available.

I suggest that these two clearly distinct questions should dealt separately, as two distinct parts of the study, in the results.

→ Thank you for your insightful comments. We revised “Introduction” and divided the main results into 2.2 and 2.3.

Table 1 shows the patient characteristics. Table S2 is equally important and should be presented as a standard and not as a supplemental material.

→ Thank you for your good comment. We changed the “Table S2” into “Table 2” following your suggestion.

In line 95, "...A total of 13 patients..." it should be clearly stated how many of them had received or not radiotherapy. RT is the main target of the paper.

→ We added the description about the number of patients who received RT. Among 13 patients, the number of patients received radiotherapy was 8.

DVH should be included in the second part of the study focusing on RT treated patients. A figure (similar to the Figure 2) should be provided showing the mean eGFR in two groups of irradiated patients, using chosen cut-off points for V5, V20 and Dmean. It is important for the study to propose cut-off points that define a higher risk of nephrotoxicity and this should be displayed in the results. Regression analysis taking into account the DVH data could be also performed.

→ Unfortunately, we could not provide clear cut-off point in V5, V20, and Dmean for defining a higher risk of nephrotoxicity. The number of patients developed renal function impairment was 13, and 8 of them received radiotherapy. Among these 8 patients, only 4 patients were available for DVH data.

In terms of mean eGFR figure, we divided patients into 3 groups using V5, V20, and Dmean, and compared the 5-year eGFR using ANOVA. There was no difference in mean eGFR according to V5, V20, Dmean group. We think that radiation-induced eGFR decline in present study was minimal, while age and baseline eGFR had a greater influence over 5-year eGFR. Radiation-induced nephrotoxicity occurs at much higher dose range. QUANTEC suggested dose-volume constraints for estimated risk of <5% as follows: V20Gy < 32% and Mean dose < 15-18Gy (doi: 10.1016/j.ijrobp.2009.07.1754).

Kidney V_5Gy	No. of patients	5-year eGFR (ml/min/1.73m²)		ANOVA p-value
Kidney V_5Gy	No. of patients	Mean	SD	ANOVA p-value
< 20%	12	89.2	12.4	0.945
20-40%	196	88.8	12.4
≥ 40%	79	88.3	15.2

Kidney V_20Gy	No. of patients	5-year eGFR (ml/min/1.73m²)		ANOVA p-value
Kidney V_20Gy	No. of patients	Mean	SD	ANOVA p-value
< 10%	53	87.9	13.1	0.631
10-20%	182	88.5	13.2
≥ 20%	52	90.2	13.6

Kidney D_mean	No. of patients	5-year eGFR (ml/min/1.73m²)		ANOVA p-value
Kidney D_mean	No. of patients	Mean	SD	ANOVA p-value
< 500 cGy	20	85.9	14.7	0.409
500-1000 cGy	211	88.5	13.0
≥ 1000 cGy	56	90.3	13.6

2.3 Is it logistic regression analysis as stated in the title? Title of 2.4 is the same with the 2.3

→ Thank you for your good comment. It was a typo and was corrected as follows, “Linear Regression Analysis to Predict 5-year eGFR”.

The literature reveals several studies focusing on radiotherapy and kidney dysfunction in patients with gastric cancer and at least some of them should be discussed (for example: