Impact Factor 1.022
Volume 32, 12 Issues, 2022
  Original Article     October 2022  

Inflammatory Prognostic Index in Metastatic Renal Carcinoma Treated with Nivolumab

By Ferhat Ekinci1, Atike Pinar Erdogan1, Serkan Yildirim2, Gulcan Bulut3, Cengiz Yilmaz4, Sabri Barutca5

Affiliations

  1. Department of Medical Oncology, Manisa Celal Bayar University, Manisa, Turkey
  2. Department of Medical Oncology, Baskent University, Konya Application and Research Centre, Konya, Turkey
  3. Department of Medical Oncology, International Medicana Hospital, Izmir, Turkey
  4. Department of Medical Oncology, Bozyaka Training and Research Hospital, Izmir, Turkey
  5. Department of Medical Oncology, Aydın Adnan Menderes University, Aydın, Turkey
doi: 10.29271/jcpsp.2022.10.1288

ABSTRACT
Objective: To evaluate the utility of inflammatory prognostic index (IPI), albumin, c-reactive protein (CRP), and lactate dehydrogenase (LDH) as predictive biomarkers of oncologic outcome in metastatic renal cell cancer (mRCC) patients treated with nivolumab.
Study Design: Descriptive study.
Place and Duration of Study: Manisa Celal Bayar University, Aydın Adnan Menderes University, Bitlis Tatvan State Hospital and Private Hatay Defne Hospital Medical Oncology Clinics, Turkey, from January 2017 to June 2020.
Methodology: Seventy-five mRCC patients treated with nivolumab between January 2017 and June 2020 were enrolled. Several factors were retrospectively investigated, including IPI, CRP, LDH, and albumin level, for their association with progression-free survival (PFS) and overall survival (OS). The IPI was calculated as CRP × NLR/albumin. Univariate and multivariate analyses were performed to assess the prognostic value of relevant factors.
Results: When analysed according to the calculated IPI score, it is seen that the group with <2.153 has an OS duration of 96.3 months, while the group with ≥2.153 has a shorter time of 42.9 months (p=0.02). In the analysis performed according to albumin level, it was reported that those with low levels (22.8 months) had worse median OS than those with high levels (92.8 months) (p=0.004). According to the cox regression analysis results, it was determined that those with a high IPI score significantly increased the risk of death compared to those with a low score (HR:2.4, p=0.023). However, this significance could not be confirmed in the multivariate analysis. It was analysed that those with low albumin levels significantly increased the risk of death compared to both univariate analysis (HR:3.3, p=0.007) and multivariate analysis (HR:4.4, p=0.003).
Conclusion: Those with high IPI scores and low albumin levels were associated with worse median OS. However, only the multivariate analysis analysed albumin level as an independent prognostic variable. Prospective and more extensive research is needed to consolidate the potential prognostic power of these markers.

Key Words: Albumin, Immune checkpoint inhibitor, IPI score, Metastatic renal cell carcinoma, Nivolumab, overall survival, Progression-free survival.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes 3% of all malignancies.1 In comparison, 30% of them present with de-novo metastasis at the time of diagnosis and metastasis may develop in up to 40% of those who are diagnosed at an early stage and undergo curative surgery.1,2 Unfortunately, in the metastatic stage, the chance of cure cannot be provided with treatment options.

The fate of patients with metastatic RCC (mRCC), where conventional therapies such as chemotherapy and radiotherapy are ineffective, has begun to change significantly with the discovery of multikinase inhibitors. However, with immune checkpoint inhibitors (ICIs), more excellent response rates have been achieved.3,4 Nivolumab is a first-use programmed cell death protein-1 (PD-1) antibody for mRCC that blocks PD-1 and strengthens the anticancer.

T-cell-mediated immune response, after these successful results, nivolumab was placed at the centre of mRCC treatment combined with monotherapy and other tyrosine kinase inhibitors (TKIs) and ICIs agents.5-8 However, the main problem here is that not every patient responds to this treatment similarly and well. This leads to the need for markers that predict treatment response and survival. While the search for biomarkers that can predict response to treatment continues, no biomarker has yet entered daily clinical practice.9

Table I: Comparison of patient characteristics according to IPI cut-off value.
   

<2.153 (n-%) (n=47)

>=2.153 (n-%) (n=28)

Total (n-%) (n=75)

p-value

Age category

<65 years old

23 (48.90)

20 (71.40)

43 (57.30)

0.096

≥65 years old

24 (51.10)

8 (28.60)

32 (42.70)

Gender

Male

25 (53.20)

15 (53.60)

40 (53.30)

>0.99

Female

22 (46.80)

13 (46.40)

35 (46.70)

Presentation of metastasis

Recurrence

22 (46.80)

8 (28.60)

30 (40.00)

0.188

De novo

25 (53.20)

20 (71.40)

45 (60.00)

Lung metastasis

No

14 (29.80)

5 (17.90)

19 (25.30)

0.382

Yes

33 (70.20)

23 (82.10)

56 (74.70)

Liver metastasis

No

35 (74.50)

20 (71.40)

55 (73.30)

0.986

Yes

12 (25.50)

8 (28.60)

20 (26.70)

Brain metastasis

No

42 (89.40)

26 (92.90)

68 (90.70)

0.706

Yes

5 (10.60)

2 (7.10)

7 (9.30)

Bone metastasis

No

27 (57.40)

21 (75.00)

48 (64.00)

0.199

Yes

20 (42.60)

7 (25.00)

27 (36.00)

LN metastasis

No

18 (38.30)

8 (28.60)

26 (34.70)

0.545

Yes

29 (61.70)

20 (71.40)

49 (65.30)

Other metastasis

No

32 (68.10)

11 (39.30)

43 (57.30)

0.028*

Yes

15 (31.90)

17 (60.70)

32 (42.70)

Number of metastasis sites

<3

27 (57.40)

12 (42.90)

39 (52.00)

0.325

≥3

20 (42.60)

16 (57.10)

36 (48.00)

IMDC risk

Favourable

24 (51.10)

8 (28.60)

32 (42.70)

0.065

Intermediate

19 (40.40)

13 (46.40)

32 (42.70)

Poor

4 (8.50)

7 (25.00)

11 (14.70)

Initial therapy before nivolumab

IFN

7 (14.90)

3 (10.70)

10 (13.30)

0.64

Sunitinib

20 (42.60)

15 (53.60)

35 (46.70)

pazopanib

20 (42.60)

10 (35.70)

30 (40.00)

LDH level

Low

26 (55.30)

20 (71.40)

46 (61.30)

0.254

High

21 (44.70)

8 (28.60)

29 (38.70)

Albumin level

Low

4 (8.50)

7 (25.00)

11 (14.70)

0.088

High

43 (91.50)

21 (75.00)

64 (85.30)

Progression status under nivolumab

No

22 (46.80)

10 (35.70)

32 (42.70)

0.485

Yes

25 (53.20)

18 (64.30)

43 (57.30)

Best response to nivolumab

PR

20 (42.60)

10 (35.70)

30 (40.00)

0.507

CR

7 (14.90)

3 (10.70)

10 (13.30)

SD

12 (25.50)

6 (21.40)

18 (24.00)

PD

8 (17.00)

9 (32.10)

17 (22.70)

Number of lines taken for treatment

1

1 (2.10)

1 (3.60)

2 (2.70)

0.904

2

19 (40.40)

9 (32.10)

28 (37.30)

3

19 (40.40)

11 (39.30)

30 (40.00)

4

7 (14.90)

6 (21.40)

13 (17.30)

5

1 (2.10)

1 (3.60)

2 (2.70)

CRP level

Low

14 (29.80)

2 (7.10)

16 (21.30)

0.043*

High

33 (70.20)

26 (92.90)

59 (78.70)

irAEs due to nivolumab

No

32 (68.10)

23 (82.10)

55 (73.30)

0.288

Yes

15 (31.90)

5 (17.90)

20 (26.70)

Exitus status

No

32 (68.10)

15 (53.60)

47 (62.70)

0.312

Yes

15 (31.90)

13 (46.40)

28 (37.30)

The relationship between clinicopathological results and IPI score was evaluated with the chi-square test. IPI: Inflammatory prognostic index, LN: Lymph node, IMDC: International mRCC database consortium, IFN: Interferon, LDH: Lactate dehydrogenase, PR: Partial response, CR: Complete response, SD: Stable disease, PD: Progressive disease, irAEs: Immune-related adverse events, CRP: C-reactive protein.

Cancer-related inflammation is associated with poorer treatment response and poorer survival in many cancers, including RCC.8-10 Many parameters such as neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), systemic inflammation index (SII), albumin-alkaline phosphatase ratio (AAPR) and Glasgow Prognostic Score (GPS) (c-reactive protein and albumin), which reflect the inflammatory status and can be easily obtained, have also been investigated in many cancers including RCC.11 After obtaining statistically significant results with c-reactive protein (CRP), NLR and albumin-based inflammatory prognostic index (IPI), which were first investigated by Dirican et al. in non-small cell lung cancer, it was also studied in many different cancers.12-14 However, its efficacy in mRCC patients treated with nivolumab has not yet been studied. Therefore, the primary purpose of this study was to analyse the predictive and prognostic value of IPI in mRCC patients.

METHODOLOGY

The data of patients diagnosed with mRCC, who were treated at Manisa Celal Bayar University, Aydın Adnan Menderes University, Bitlis Tatvan State Hospital and Private Hatay Defne Hospital Medical Oncology Clinics, Turkey, between January 2017 and June 2020 were retrospectively analyzed. Those with a history of secondary malignancy or any ICI treatment prior to nivolumab or with insufficient laboratory data were excluded from the study. Also, those who had used the given nivolumab therapy for at least three months were included.

Table II: Comparison of the patient characteristics with OS and PFS results.
   

Median OS

(95% CI Min-Max)

p-value

Median PFS

(95% CI Min- Max)

p-value

Age category

<65 years old

92.8 (61.6-124.0)

0.565

8.0 (3.5-12.4)

0.742

≥65 years old

82.9 (78.4-87.5)

13.7 (7.9-19.6)

Gender

Male

82.4 (79.4-85.5)

0.931

8.0 (4.4-11.5)

0.696

Female

92.8 (55.5-130.0)

13.5 (7.7-19.3)

Presentation of metastasis

Recurrence

112.0

0.001

9.9 (0.6-19.2)

0.739

De novo

47.5 (21.4-73.5)

10.7 (5.4-16.0)

Lung metastasis

No

92.8 (81.7-103.8)

0.067

13.5 (0.9-26.1)

0.788

Yes

82.4 (28.9-136.0)

9.4 (5.9-13.0)

Liver metastasis

No

82.9 (69.5-96.4)

0.688

8.9 (5.1-12.7)

0.707

Yes

96.3 (30.7-161.9)

11.7 (6.0-17.3)

Brain metastasis

No

82.4 (60.7-104.2)

0.591

10.7 (5.2-16.3)

0.434

Yes

96.3 (68.9-123.7)

4.7 (2.2-7.2)

Bone metastasis

No

112.0

0.022

13.5 (7.1-19.8)

0.008

Yes

81.1 (28.1-134.0)

5.4 (3.7-7.2)

LN metastasis

No

82.9 (63.6-102.3)

0.6

7.3 (5.2-9.4)

0.142

Yes

82.4 (55.2-109.7)

13.9 (7.2-20.7)

Other metastasis

No

96.3 (74.1-118.5)

0.916

8.0 (5.2-10.7)

0.495

Yes

82.4 (29.0-135.9)

11.7 (6.9-16.5)

Number of metastasis sites

<3

92.8 (75.2-110.3)

0.24

8.9 (5.8-12.0)

0.743

≥3

82.4 (33.1-131.8)

10.7 (4.5-16.9)

IMDC risk

Favourable

81.1 (10.6-151.5)

0.097

14.5 (6.9-22.1)

0.842

Intermediate

96.3 (80.1-112.5)

9.9 (5.4-14.5)

Poor

47.5 (10.8-84.1)

6.6 (2.7-10.4)

Initial therapy before nivolumab

IFN

71.7 (20.5-112.9)

0.641

14.8 (12.0-17.7)

0.503

Sunitinib

82.9 (80.1-85.8)

9.9 (2.1-17.7)

pazopanib

92.8 (17.2-168.3)

9.4 (3.5-15.4)

Progression status under nivolumab

No

 

<0.001

 

 

Yes

47.5 (6.3-88.6)

 

Reason for discontinuation of nivolumab

Progression

71.5 (21.9-121.5)

<0.001

 

 

Hyperprogression

10.4 (5.0-15.7)

 

irAEs

 

 

irAEs due to nivolumab

No

82.4 (41.0-123.9)

0.152

9.9 (5.8-14.0)

0.421

Yes

 

14.5 (0-30.7)

Retreatment after irAEs

No

 

 

4.0 (1.7-6.3)

0.012

Yes

 

14.8 (2.2-27.4)

IPI score

<2.153

96.3 (69.9-122.8)

0.02

11.7(5.9-17.4)

0.286

≥2.153

42.9 (42.6-43.1)

7.6(2.6-12.6)

CRP level

Low

92.8 (0-194.9)

0.323

8.0 (3.9-12.1)

0.277

High

82.9 (56.0-109.9)

11.7 (5.9-17.4)

LDH level

Low

82.4 (65.8-99.1)

0.948

9.9 (3.5-16.3)

0.946

High

92.8 (67.3-118.2)

9.4 (0-19.1)

Albumin level

Low

22.8 (2.5-43.1)

0.004

13.9 (0-35.5)

0.511

High

92.8 (76.4-109.1)

9.9 (5.7-14.1)

Total

 

82.9 (68.5-97.4)

 

9.9 (4.4-15.4)

 

The relationship between IPI score and OS-PFS was analysed using the Kaplan-Meier method with log-rank statistics. OS: Overall survival, PFS: Progression-free survival, Min: Minimum, Max: Maximum, IPI: Inflammatory prognostic index, LN: Lymph node, IMDC: International mRCC database consortium, IFN: Interferon, LDH: Lactate dehydrogenase, PR: Partial response, CR: Complete response, SD: Stable disease, PD: Progressive disease, irAEs: Immune-related adverse events CRP: C-reactive protein.

The study was designed as a multicenter retrospective cohort. Age, gender, presentation of metastasis (recurrence or de novo), metastasis sites (lung, liver, bone, brain, lymph node and other sites), number of metastasis sites, international metastatic RCC Database Consortium (IMDC) risk situations, initial therapy before nivolumab, the reason for discontinuation of nivolumab, progression status under nivolumab, the best response to nivolumab, immune-related adverse events (irAEs) due to nivolumab, and retreatment status after irAEs were recorded. Albumin, CRP, lactate dehydrogenase (LDH), lymphocyte and neutrophil values measured at the time of metastasis were noted.

The statistical analysis of the data obtained in this study was performed with the SPSS (Statistical Package for the Social Sciences) 16.0 package program. The IPI was calculated by the formula CRP×NLR/albumin. The Youden Index method was used to find the cut-off value for the IPI variable according to the ROC curve, and this value was obtained as 2.153. The threshold value for each biological baseline parameter was defined as albumin= 3.5 g/dL, CRP=0.5 mg/dL, and lactate dehydrogenase level=248 U/L. They were analysed to see whether they were higher or lower than these threshold values. The endpoints of this study included Progression-free survival (PFS) and overall survival (OS). PFS was obtained by calculating the difference, in months, between the start of nivolumab therapy and the time to progression. OS was obtained by calculating the time (in months) between the date of diagnosis and the date of exitus (data cut-off for non-exitus patients). Tumour response was analyzed according to the Immune Response Evaluation Criteria in Solid Tumours (irRECIST).

Table III: Univariate and multivariate COX regression analysis results of OS and PFS.
 

Univariate

OS HR (95% CI)

(Min-max)

p-value

Multivariate

OS HR (95% CI)

(Min-max)

p-value

Univariate

PFS HR (95% CI)

(Min-max)

p-value

Age category

<65 years old vs. ≥65 years old

1.2 (0.5-2.6)

0.565

 

 

0.9 (0.4-1.6)

0.742

Gender

Male vs. Female

1.0 (0.4-2.2)

0.931

 

 

1.1 (0.6-2.0)

0.696

Presentation of metastasis

De novo vs. Recurrence

4.4 (1.7-11.4)

0.002

3.0 (1.1-7.9)

0.025

1.1 (0.5-2.0)

0.739

Lung metastasis

Yes vs. No

2.6 (0.9-7.5)

0.077

 

 

1.0 (0.5-2.1)

0.788

Liver metastasis

Yes vs. No

1.1 (0.5-2.7)

0.688

 

 

0.8 (0.4-1.6)

0.708

Brain metastasis

Yes vs. No

0.7 (0.2-2.1)

0.592

 

 

1.4 (0.5-3.7)

0.437

Bone metastasis

Yes vs. No

2.3 (1.1-5.1)

0.026

2.4 (1.0-5.5)

0.033

2.2 (1.2-4.2)

0.01

LN metastasis

Yes vs. No

1.2 (0.5-2.7)

0.6

 

 

0.6 (0.3-1.1)

0.145

Other metastasis

Yes vs. No

1.0 (0.4-2.1)

0.916

 

 

0.8 (0.4-1.4)

0.496

Number of metastasis sites

≥3 vs. <3

1.5 (0.7-3.3)

0.244

 

 

0.9 (0.4-1.6)

0.743

IMDC risk

Intermediate vs. Favorable

Poor vs. Favorable

0.7 (0.3-1.6)

2.1 (0.8-5.7)

0.453

0.126

 

 

1.2 (0.6-2.3)

1.1 (0.4-2.9)

0.564

0.763

Initial therapy before nivolumab

Sunitinib vs. IFN

Pazopanib vs. IFN

1.3 (0.3-4.7)

1.7 (0.4-6.2)

0.647

0.394

 

 

1.8 (0.6-5.3)

1.7 (0.5-5.3)

0.254

0.299

Progression status under nivolumab

Yes vs. No

9.5 (2.2-40.2)

0.002

7.2 (1.6-32.1)

0.009

 

 

Reason for discontinuation of nivolumab

Hyperprogression vs. Progression

irAEs vs. Progression

1.0 (0.1-8.0)

11.8 (1.1-121.0)

0.953

0.036

 

 

 

 

irAEs due to nivolumab

Yes vs. No

0.4 (0.1-1.3)

0.162

 

 

0.7 (0.3-1.5)

0.423

Retreatment after irAEs

No vs. Yes

0.6 (0.06-7.7)

0.763

 

 

5.7 (1.2-26.8)

0.025

Number of lines taken for treatment

Increase per unit

 

 

 

 

1.6 (1.1-2.2)

0.003

IPI score

≥2.153 vs. <2.153

2.4 (1.1-5.3)

0.023

1.6 (0.6-4.0)

0.271

1.3 (0.7-2.5)

0.288

CRP level

High vs. Low

0.6 (0.2-1.5)

0.3

 

 

0.6 (0.3-1.3)

0.28

LDH level

High vs. Low

1.0 (0.4-2.1)

0.948

 

 

1.0 (0.5-1.8)

0.946

Albumin level

Low vs. High

3.3 (1.3-7.9)

0.007

4.4 (1.6-12.0)

0.003

1.3 (0.5-2.9)

0.513

The relationship between IPI score and OS-PFS was analyzed using the Kaplan-Meier method with log-rank statistics. OS: Overall survival, PFS: Progression-free survival, Min: Minimum, Max: Maximum, IPI: Inflammatory prognostic index, LN: Lymph node, IMDC: International mRCC database consortium, IFN: Interferon, LDH: Lactate dehydrogenase, PR: Partial response, CR: Complete response, SD: Stable disease, PD: Progressive disease, irAEs: Immune-related adverse events CRP: C-reactive protein. All variables were insignificant (p-value >0.05) in the cox regression multivariate analysis for PFS.

The cut-off value of the IPI score based on OS and PFS was determined by analysing the sensitivity and specificity values and calculating the area under the ROC curve. The IPI value was categorised by determining the cut-off value with the ROC curve, and then the chi-square test was applied. The relationship between IPI score and OS-PFS was evaluated using the Kaplan-Meier method with log-rank statistics.

Univariate and multivariate Cox Regression Analysis methods were used to calculate the respective hazard ratios (HRs) and 95% confidence intervals (CIs). These results were presented as median (minimum-maximum), mean and standard deviation and the categorical variables were expressed as counts and percentages. While examining the normality distribution of quantitative data according to categorical variables, the Shapiro-Wilk test was used in those with n <30 group numbers, while the Kolmogorov-Smirnov test was used in those with n >30. For all statistical results, a p-value of <0.05 was considered statistically significant.

RESULTS

A total of 75 mRCC patients treated with nivolumab were evaluated. When the patients are categorised according to age and gender, it is seen that <65 years old (57.3%, n=43) and male (53.3%, n=40) gender predominate. The most common site of metastasis was the lung (74.7%, n=56). When the IMDC risk groups are examined, it is seen that the favourable (42.7%, n=32) and intermediate (42.7%, n=32) groups are equally distributed, while the poor (14.7%, n=11) group is in the minority. When pre-nivolumab treatments are examined, it is seen that there is a balanced distribution between pazopanib (40.0%, n=30) and sunitinib (46.7%, n=35). IrAEs were observed in 26.7% (n=20) of the patients. At the end of the data analysis, 37.3% (n=28) of the patients were exitus (Table I).

At the data cut-off date (June 2020), the median follow-up was 52.8 (95% CI, 32.4-73.2) months. The median PFS of all patients was calculated as 9.9 (95% CI, 4.4-15.4) months and OS as 82.9 (95% CI, 68.5-97.4) months. When median OS is examined in terms of metastasis presentation, it is seen that those with recurrence were 112 months, and those who presented de-novo were 47.5 (95% CI, 21.4-73.5) months (p<0.001). However, this difference is not significant in PFS (p=0.739). When metastasis sites are examined, it is seen that those with bone metastases have statistically significantly shorter PFS (5.4 months, 95% CI, 3.7-7.2, p=0.008) and OS (81.1 months, 95% CI, 28.1-134.0, p=0.022). When the reasons for discontinuation of nivolumab treatment are examined, it is seen that OS is significantly lower in patients with hyper-progression (10.4 months, 95% CI, 5.0-15.7, p<0.001). Although, there are no significant survival results in terms of OS and PFS in those who develop irAEs, it is observed that those who retreatment after irAEs have longer PFS (14.8 months, 95% CI, 2.2-27.4, p=0.012). When analysed according to the calculated IPI score, it is seen that the group with <2.153 has an OS duration of 96.3 months (95% CI, 69.9-122.8), while the group with ≥2.153 has a shorter time of 42.9 (95% CI, 42.6-43.1) months (p=0.02). However, a similar difference in PFS could not reach statistical significance (p=0.286). In the analysis performed according to albumin level, it was reported that those with low levels (22.8 months, 95% CI, 2.5-43.1) had worse median OS than those with high levels (92.8 months, 95% CI, 76.4-109.1, p=0.004, Table II).

According to the cox regression analysis results, it was determined that those with a high IPI score significantly increased the risk of death compared to those with a low score (HR:2.4, 95% CI, 1.1-5.3, p=0.023). However, this significance could not be confirmed in the multivariate analysis. It was analysed that those with low albumin levels significantly increased the risk of death compared to both univariate analysis (HR:3.3, 95% CI,1.3-7.9 p=0.007) and multivariate analysis (HR:4.4, 95% CI,1.6-12.0, p=0.003). The power of these parameters to predict OS was not comparable in PFS (Table III).

DISCUSSION

Inflammation is a multifactorial process that prepares the ground for cancer development by taking part in all stages of tumour formation, and data are showing that it is clinically associated with disease recurrence, metastasis and poor prognosis.3,15 Inflammation mediators are an essential component of the tumour microenvironment and are suggested to be the precursor of oncogenic change in some cancers and cause angiogenesis and metastasis development.15 This situation causes genomic instability and DNA damage, leading to the settlement of the protumourigenic structure. The most common inflammatory response indicators are a set of biochemical or haematological markers in cancer patients. The most commonly used ones are the increase in CRP, leukocyte, neutrophil and thrombocyte counts, and low albumin and lymphocyte levels.13,15 Here, it should be emphasised that albumin acts as both an indicator of nutritional status and a negative acute phase reactant, and its relationship with poor prognosis in many cancers, including RCC, has been proven9,11,16 The IPI score, which incorporates CRP, neutrophil, lymphocyte, and albumin levels, was used for the first time in mRCC patients treated with nivolumab.

NLR is the most common parameter used to indicate treatment response and prognosis in mRCC patients treated with nivolumab. In a study conducted by Jeyakumar et al. involving 42 patients, it was observed that patients using other ICIs agents were included, although nivolumab was predominant.17 Statistically, significantly shorter OS and PFS values were reported above the cut-off value determined for NLR (p=0.025, p=0.003). Another study of 142 patients conducted by Lalani et al. reported that NLR calculated at week 6 of nivolumab treatment predicted OS and PFS more strongly than baseline (p = 0.004, p<0.001). Similarly, high basal or post-treatment NLR levels have been associated with poor prognosis.18 In a study conducted on the Japanese population in 2020, the prognostic role of NLR, TLR, lymphocyte/monocyte ratio (LMR) and LDH, which were examined before and six weeks after treatment, was investigated in 65 mRCC patients treated with nivolumab. In univariate analysis, LDH (p=0.026), TLR (p=0.001), and LMR affected disease-specific survival significantly. However, in multivariate analysis, LDH (p=0.0123, HR=3.92, 95% CI, 1.37-10.80) and TLR (p=0.0008, HR=7.95, 95% CI, 2.16-51.64) were reported to be analysed as independent prognostic markers. In this study, as a result of a separate analysis with the combination of LDH and PLR, it was concluded that this combination was the most important prognostic marker (p<0.0001).19

In a recent study of 45 patients by Fujiwara et al., the effect of modified GPS (mGPS) developed using serum albumin and CRP levels on prognosis in mRCC patients treated with nivolumab was investigated. In this scoring system, low albumin (≤3.5 g/dL) and high CRP (≤1.0 mg/dL) levels were arranged as score 2, none as score 0, and only low albumin or high CRP levels as score 1. In the multivariate analysis, it was reported that an increase in the score from 0 to 2 (p=0.004 (1 vs. 0), p=0.002 (2 vs. 0) has an independent prognostic value for survival.20 In this scoring, CRP and albumin levels were used with a logic similar to the IPI score in this study. However, unlike the IPI score, NLR is also included. This study concluded that only albumin (p=0.003) was an independent prognostic variable in the regression analysis of CRP and albumin levels separately.

In a recent study conducted by Yoshino et al. the prognostic power of albumin and alkaline phosphatase (ALP) ratio (AAPR) was evaluated in the same patient group.11 The ALP level was included in the scoring in this study because it can regulate tumour development through its release from kidney cells and many other tissues and organs and suppression of inflammatory signals.21 In this study, in which a total of 60 patients were evaluated, the median OS (p<0.0001) and PFS (p=0.0006) were found to be significantly shorter in the low AAPR group compared to the high group. In the multivariate analysis, although the AAPR score was reported as an independent prognostic variable for OS (p=0.015), this significant relationship could not be achieved for PFS (p=0.174).

The most extensive patient population study examining the relationship between mRCC-diagnosed inflammatory markers and survival treated with nivolumab included 303 cases. In the study conducted by De Giorgi et al., NLR, PLR, SII and body mass index (BMI) were used.22 However, only a high SII (p <0.0001) score and low BMI (p=0.01) were reported as independent prognostic variables.

The significant limitations of this study are that it was designed retrospectively, and the IPI score does not have the ideal cut-off value that prevents routine use. The relatively small number of patients may also have prevented some factors from reaching statistical significance. In addition, this situation led to heterogeneity as the patients received nivolumab treatment at any stage after the first-line treatment.

CONCLUSION

In this study, involving mRCC patients treated with nivolumab, those with high IPI scores and low albumin levels were associated with worse median OS. However, only the multivariate analysis analysed the albumin level as an independent prognostic variable. Prospective and more extensive studies are required to corroborate the potential prognostic power of these markers.

ETHICAL APPROVAL:
The Health Sciences Ethics Committee approved this study of Manisa Celal Bayar University Faculty of Medicine with the decision dated 23.12.2020 and No. E-20478486.

PATIENTS’ CONSENT:
Written consent was obtained from the participants.

COMPETING INTEREST:
The authors declared no competing interest.

AUTHORS’ CONTRIBUTION:
FE: Concept, design, and drafting.
APE, GB, SB: Materials.
FE, GB, SY, CY: Data collection and processing.
GB, FE: Analysis and interpretation.
FE, APE, SY: Literature search.
FE, APE, SB, GB: Critical review.
All the authors have approved the final version of the manuscript to be published.

REFERENCES

  1. Massari F, Mollica V, Rizzo A, Cosmai L, Rizzo M, Porta C. Safety evaluation of immune-based combinations in patients with advanced renal cell carcinoma: A systematic review and meta-analysis. Expert Opin Drug Saf 2020; 19(10):1329-38. doi: 10.1080/14740338.2020.1811226.
  2. Capitanio U, Montorsi F. Renal cancer. The Lancet 2016; 387(10021):894-906. doi: 10.1016/S0140-6736(15) 00046-X.
  3. Peinemann F, Unverzagt S, Hadjinicolaou AV, Moldenhauer I. Immunotherapy for metastatic renal cell carcinoma: A systematic review. J Evid Based Med 2019; 12(4):253-62. doi: 10.1111/jebm.12362.
  4. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373(19):1803-13. doi: 10.1056/NEJMoa1510665.
  5. Nishiyama N, Hirobe M, Kikushima T, Matsuki M, Takahashi A, Yanase M, et al. The neutrophil-lymphocyte ratio has a role in predicting the effectiveness of nivolumab in Japanese patients with metastatic renal cell carcinoma: A multi-institutional retrospective study. BMC Urol 2020; 20(1):110. doi: 10.1186/s12894-020-00679-2.
  6. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378(14):1277-90. doi: 10.1056/NEJMoa17 12126.
  7. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021; 384(9):829-41. doi: 10.1056/NEJMoa2026982.
  8. Monteiro FSM, Soares A, Debiasi M, Schutz FA, Maluf FC, Bastos DA, et al. First-line treatment of metastatic renal cell carcinoma in the immuno-oncology Era: Systematic review and network meta-analysis. Clin. Genitourin Cancer 2020; 18(4):244-51.e4. doi: 10.1016/j.clgc.2020.02.012.
  9. Rebuzzi SE, Signori A, Banna GL, Maruzzo M, De Giorgi U, Pedrazzoli P, et al. Inflammatory indices and clinical factors in metastatic renal cell carcinoma patients treated with nivolumab: The development of a novel prognostic score (Meet-URO 15 study). Ther Adv Med Oncol 2021; 13: 17588359211019642. doi: 10.1177/17588359211019642.
  10. Bersanelli M, Cortellini A, Buti S. The interplay between cholesterol (and other metabolic conditions) and immune-checkpoint immunotherapy: Shifting the concept from the "inflamed tumour" to the "inflamed patient". Hum Vaccin Immunother 2021; 17(7):1930-4. doi: 10.1080/21645515. 2020.1852872.
  11. Yoshino M, Ishihara H, Ishiyama Y, Tachibana H, Toki D, Yamashita K, et al. Albumin-to-alkaline phosphatase ratio as a novel prognostic marker of nivolumab monotherapy for previously treated metastatic renal cell carcinoma. In Vivo 2021; 35(5):2855-62. doi: 10.21873/invivo.12573.
  12. Dirican N, Dirican A, Anar C, Atalay S, Ozturk O, Bircan A, et al. A new inflammatory prognostic index, based on c-reactive protein, the neutrophil to lymphocyte ratio and serum albumin is useful for predicting prognosis in non-small cell lung cancer case. Asian Pac J Cancer Prev 2016; 17(12):5101-6. doi: 10.22034/APJCP.2016.17.12.5101.
  13. Dirican A, Ekinci F, Erdogan AP, Goksel G. Inflammatory prognostic index score as a new parameter predicting overall survival in renal cell carcinoma. J Surg Medicine 2021; 5(2):163-7. doi: 10.28982/josam.850739.
  14. Erdoğan AP, Ekinci F, Karabaş A, Balcik OY, Barutça S, Dirican A. Could the inflammatory prognostic index predict the efficacy of regorafenib in patients with metastatic colorectal cancer. J Gastrointest Cancer 2022; 53(1):45-51. doi: 10.1007/s12029-021-00642-w.
  15. Greten FR, Grivennikov SI. Inflammation and cancer: Triggers, mechanisms, and consequences. Immunity 2019; 51(1):27-41. doi: 10.1016/j.immuni.2019.06.025.
  16. Ekinci F, Balcik OY, Oktay E, Erdogan AP. HALP score as a new prognostic index in metastatic renal cell cancer. J Coll Physicians Surg Pak 2022; 32(3):313-8. doi: 10.29271/ jcpsp.2022.03.313.
  17. Jeyakumar G, Kim S, Bumma N, Landry C, Silski C, Suisham S, et al. Neutrophil lymphocyte ratio and duration of prior anti-angiogenic therapy as biomarkers in metastatic RCC receiving immune checkpoint inhibitor therapy. J Immunother Cancer 2017; 5(1):82. doi: 10.1186/s40425- 017-0287-5.
  18. Lalani AA, Xie W, Martini DJ, Steinharter JA, Norton CK, Krajewski KM, et al. Change in neutrophil-to-lymphocyte ratio (NLR) in response to immune checkpoint blockade for metastatic renal cell carcinoma. J Immunotherapy Cancer 2018; 6(1):1-9. doi: 10.1186/s40425-018-0315-0.
  19. Yamamoto Y, Matsuyama H, Matsumoto H, Sakano S, Fuji N, Oba K, et al. Prognostic value of risk stratification using blood parameters for nivolumab in Japanese patients with metastatic renal-cell carcinoma. Japanese Clin Oncol 2020; 50(2):214-20. doi: 10.1093/jjco/hyz168.
  20. Fujiwara R, Takemura K, Fujiwara M, Yuasa T, Yasuoka S, Komai Y, et al. Modified glasgow prognostic score as a predictor of prognosis in metastatic renal cell carcinoma treated with nivolumab. Clin Genitourinary Cancer 2021; 19(2):e78-e83. doi: 10.1016/j.clgc.2020.10.007.
  21. Rao SR, Snaith AE, Marino D, Cheng X, Lwin ST, Orriss IR, et al. Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer. Br J Cancer 2017; 116(2): 227-36. doi: 10.1038/bjc.2016.402.
  22. De Giorgi U, Procopio G, Giannarelli D, Sabbatini R, Bearz A, Buti S, et al. Association of systemic inflammation index and body mass index with survival in patients with renal cell cancer treated with nivolumab. Clin Cancer Res 2019; 25(13):3839-46. doi: 10.1158/1078-0432.CCR-18-3661.