
==== Front
World J Surg Oncol
World J Surg Oncol
World Journal of Surgical Oncology
1477-7819
BioMed Central London

39256833
3522
10.1186/s12957-024-03522-2
Research
Hypoalbuminemia and hypercalcemia are independently associated with poor treatment outcomes of anti-PD-1 immune checkpoint inhibitors in patients with recurrent or metastatic head and neck squamous cell carcinoma
Chiu Tai-Jan 1
Huang Tai-Lin 1
Chien Chih-Yen 2
Huang Wan-Ting 3
Li Shau-Hsuan lee.a0928@msa.hinet.net

1
1 grid.413804.a Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C.
2 grid.413804.a Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C.
3 grid.413804.a Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C.
11 9 2024
11 9 2024
2024
22 24226 5 2024
1 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Recent randomized phase III trials have demonstrated the efficacy of anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in treating patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC). However, a large proportion of such patients still have poor response. This study aimed to identify biomarkers for predicting anti-PD-1 ICI treatment outcomes .

Methods

We retrospectively analyzed 144 patients with RMHNSCC who received anti-PD-1 ICIs after progression to platinum-based chemotherapy between January 2017 and December 2022 at Kaohsiung Chang Gung Memorial Hospital. Data on clinicopathological parameters, albumin levels, calcium levels, and other pretreatment peripheral blood biomarkers, including total lymphocyte count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and prognostic nutritional index (PNI) were collected and correlated with the treatment outcome of anti-PD-1 ICIs.

Results

Low tumor proportion score (TPS), low combined positive score (CPS), NLR ≥ 5, PLR ≥ 300, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly correlated with poor response of ICIs. The overall response rates were 25% and 3% in patients with calcium < 10 mg/dL and calcium ≥ 10 mg/dL, respectively (P = 0.007). The overall response rates were 6% and 33% in patients with albumin < 4 g/dL and albumin ≥ 4 g/dL, respectively (P < 0.001). Univariate survival analysis showed that low TPS, low CPS, NLR ≥ 5,, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly associated with worse progression-free survival (PFS) and inferior overall survival (OS). Multivariate analysis revealed that calcium ≥ 10 mg/dL and albumin < 4 g/dL were independent poor prognosticators for worse PFS and inferior OS. The two-year OS rates were 26% and 9% in patients with calcium < 10 mg/dL and ≥ 10 mg/dL, respectively (P < 0.001). The two-year OS rates were 10% and 33% in patients with albumin < 4 g/dL and ≥ 4 g/dL, respectively (P < 0.001).

Conclusions

Hypercalcemia and hypoalbuminemia can potentially predict poor treatment outcomes of anti-PD-1 ICIs in patients with RMHNSCC. Blood calcium and albumin levels may be helpful in individualizing treatment strategies for patients with RMHNSCC.

Keywords

Head and neck cancer
Squamous cell carcinoma
Immune checkpoint inhibitors
Calcium
Albumin
Chang Gung Memorial HospitalCMRPG8N0802 and CORPG8M0461 CMRPG8N0802 and CORPG8M0461 National Science Council, TaiwanNSTC 112-2314-B-182A-029-MY3 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcBackground

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer-related death globally [1] and the fifth leading cause of cancer-related deaths in Taiwan, especially in men. Most patients present with stage III-IV disease with low surgical curability or inoperable status [2]. Although many patients with locally advanced HNSCC initially respond to multi-modality treatment with surgery, radiotherapy, and chemotherapy, they remain at high risk of post-treatment recurrence and/or distant metastasis [3]. Cytotoxic chemotherapy and target therapies, such as cetuximab or afatinib, have a short response duration for recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC), and patients with RMHNSCC have a median overall survival duration of less than one year [4].

Recently, immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD-1) ICIs such as nivolumab or pembrolizumab, have been widely used in cancer treatments, including RMHNSCC. In the second-line setting of platinum-refractory RMHNSCC, nivolumab and pembrolizumab prolonged overall survival compared with the standard of care (standard single-agent systemic therapy such as methotrexate, docetaxel, or cetuximab) in the CheckMate 141 phase III and KEYNOTE-040 phase III trials, respectively [5, 6]. In 2019, the KEYNOTE-048 phase III study also showed that first-line monotherapy with pembrolizumab demonstrated significant improvement in overall survival compared to standard of care (EXTREME regimen: platinum/5-FU/cetuximab) in patients with PD-L1 combined positive score ≧ 1 RMHNSCC [7]. However, the response rates to single agent anti-PD-1 ICIs remains lower than 20%, and a large proportion of patients with RMHNSCC still has poor response [5–7]. Therefore, there is an urgent need to explore biomarkers that are rapidly and easily available for anti-PD-1 ICI response prediction and individualized therapeutic approaches. Recently, peripheral blood inflammatory markers which are recognized as potential markers of systemic inflammatory response such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have been studied to predict prognosis in different cancer treatments [8–10]. Peripheral blood nutritional markers such as albumin and prognostic nutritional index have also been examined for predicting the prognosis of different cancers [11, 12]. Furthermore, hypoalbuminemia and hypercalcemia are commonly observed in patients with RMHNSCC. However, their associations with the efficacy of anti-PD-1 ICIs remain largely unknown. Therefore, we conducted this study.

Methods

Patient and data collection

We retrospectively reviewed the medical records of patients with RMHNSCC who received ICI therapy at Kaohsiung Chang-Gung Memorial Hospital in Taiwan from January 2017 to December 2022. Patients with RMHNSCC who are unsuitable for further curative treatment with an adequate Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2 and received at least one cycle of ICI treatment after progression to platinum-based chemotherapy were enrolled. Patients were required to be ≧ 18 years old and have adequate bone marrow function (absolute neutrophil count ≧ 1.5 × 109/L, platelet count ≧ 75 × 109/L), hepatic function (serum total bilirubin ≦ 1.5 mg/dL and serum levels of aspartate aminotransferase and alanine aminotransferase ≦ 2.5 × upper limit of normal), and renal function (serum creatinine ≦ 1.5 mg/dL). Patients with nasopharynx cancer were excluded from the study. ICI treatment consisted of pembrolizumab and nivolumab. After ICI treatment, the patients underwent regular imaging studies (computed tomography, magnetic resonance imaging, or positron emission tomography ) to evaluate their response every 4 to 12 weeks. Patients with RMHNSCC continued to receive ICI treatment until the disease progressed, intolerable drug toxicities occurred, or the two years of Taiwan’s health insurance ended. The tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The objective response rate (ORR) was defined as the percentage of patients who achieved a complete response (CR) or a partial response (PR) as the best response. The overall survival (OS) was defined as the time from the start of ICI treatment to the date of death, regardless of the cause or cutoff time. Progression-free survival (PFS) was defined as the time from the beginning of ICI treatment to disease progression or death. The Institutional Review Board of Kaohsiung Chang-Gung Memorial Hospital (202200507B0 and 202201019B0) approved this study according to the principles of the Declaration of Helsinki. Furthermore, this study retrospectively analyzed existing clinical data, thus waiving the need for informed consent .

Definitions of prognostic factors

Serum albumin, calcium, and peripheral blood leukocyte counts, including neutrophils, lymphocytes, monocytes, and platelets, were analyzed before the first cycle of ICI treatment. Corrected calcium levels were used in this study and calculated using the following formula: (4 − albumin concentration in g/dL) × 0.8 + total serum calcium in mg/dL. Parameters including the ratio of platelet count to lymphocyte count (PLR), the ratio of neutrophil count to lymphocyte count (NLR), the ratio of lymphocyte count to monocyte count (LMR), PNI, 10 × serum albumin level + 0.005 × total lymphocyte count (PNI), were analyzed based on these results. Immunohistochemical staining for PD- L1 was performed on formalin-fixed paraffin-embedded HNSCC tissues using a Dako 22C3 pharmDx (Agilent Technologies/Dako, Carpinteria, California, USA) kit, following the manufacturer’s instructions. PD-L1 expression was measured using tumor proportion score (TPS) and combined positive score (CPS). TPS was categorized into three groups (< 50%, ≧50%, and < 80%, ≧80%). In addition, we also divided CPS into four groups(< 20, ≧20; <50, ≧50; and < 80, ≧80). Cancer cells with partial or complete membrane staining were counted as positive, whereas immune cells were counted if any staining was observed. The sample was validated by the evaluation of at least an estimated number of 100 cancer cells. Experienced pathologists independently evaluated all cases, considering their adequacy for analysis and PD-L1 expression by both TPS and CPS.

Statistical considerations

The association between response to ICIs and each factor was assessed using the Chi-square test or Fisher’s exact test. For OS and PFS, the Kaplan-Meier method and log-rank test were used for univariate analysis. Significant parameters at the univariate level were entered into a Cox regression model to analyze their relative prognostic importance. Patients without an OS or PFS event were censored at the date of their last visit if they were alive.

Results

Patient characteristics

Between January 2017 and December 2022, 144 patients with RMHNSCC and treated with ICI were enrolled in this study. The clinicopathological characteristics of the 144 patients with RMHNSCC are summarized in Table 1. There were 131 men and 13 women with a median age of 59 (28–91) years. The primary tumor sites included the oral cavity in 94 patients (65%), oropharynx in 28 patients (19%), larynx in 11 patients (11%), hypopharynx in 9 patients (6%), and unknown primary site in 2 patients (1%). One hundred and twenty-four patients (86%) had habits of smoking, 118 patients (82%) had alcohol drinking, and 127 patients (88%) chewed betel nuts. The pathological expression of positive p16 in 5 patients (3%), TPS < 49% in 77 patients (53%), 50–79% in 33 patients (23%), and ≧ 80% in 34 patients (24%); CPS < 20 in 38 patients (26%), 20–49 in 32 patients (22%), 50–79 in 35 patients (25%), and ≧ 80 in 39 patients (27%). ICIs were the second line of treatment in 105 patients (73%), the third in 34 patients (24%), and the ≧ 4th in 5 patients (3%). The type of ICIs was nivolumab in 44 patients and pembrolizumab in 100 patients.

Table 1 Characteristics of 144 patients with recurrent and metastatic head and neck squamous cell carcinoma receiving immune checkpoint inhibitors

Age	median (range)	59 (28 ~ 91)	
Sex			
	male	131 (91%)	
	female	13 (9%)	
TPS			
	0 ~ 49%	77 (53%)	
	50 ~ 79%	33 (23%)	
	≥ 80%	34 (24%)	
CPS			
	0 ~ 19	38 (26%)	
	20 ~ 49	32 (22%)	
	50–79	35 (25%)	
	≥ 80	39 (27%)	
Total lymphocyte count (/µL)	median (range)	870 (89 ~ 7371)	
NLR	median (range)	5.08 (0.02 ~ 93.00)	
PLR	median (range)	301 (26 ~ 2547)	
LMR	median (range)	1.79 (0.25 ~ 9.00)	
Calcium (mg/dl)	median (range)	9.4 (7.1 ~ 14.9)	
Albumin (g/dL)	median (range)	4.00 (2.35 ~ 5.14)	
PNI	median (range)	44.9 (29.1 ~ 75.9)	
Type of ICI			
	Pembrolizumab	100 (69%)	
	Nivolumab	44 (31%)	
Therapy line			
	2nd line	105 (73%)	
	3rd line	34 (24%)	
	≥ 4th line	5 (3%)	
Treatment regimen			
	ICI alone	107 (74%)	
	Combinationa	37 (26%)	
Primary tumor site			
	oral cavity	94(65%)	
	hypopharynx	9 (6%)	
	larynx	11 (8%)	
	oropharynx	28 (19%)	
	unknown	2 (1%)	
p16 expression			
	Negative	139 (97%)	
	Positive	5 (3%)	
Response to ICI			
	Complete response	9 (6%)	
	Partial response	20 (14%)	
	Stable disease	9 (6%)	
	Progression disease	106 (74%)	
Smoking			
	Absent	20 (14%)	
	Present	124 (86%)	
Alcohol			
	Absent	26 (18%)	
	Present	118 (82%)	
Betel-nut chewing			
	Absent	17 (12%)	
	Present	127 (88%)	
TPS, Tumor proportion score; CPS, Combined positive score; NLR, Neutrophil-to-lymphocyte ratio; PLR, Platelet-to-lymphocyte ratio; LMR, Lymphocyte-to-monocyte ratio; PNI, Prognostic nutritional index; ICI, immune checkpoint inhibitor

aICI combined with cetuximab in 14 patients, paclitaxel in 6 patients, docetaxel in 4 patients, afatinib in 5 patients, 5-FU in 4 patients, methotrexate in 2 patients, and lenvatinib in 2 patients

Treatment outcomes

Treatment response was evaluated according to RECIST version 1.1. (Table 1). Among the 144 patients evaluated, 9 patients (6%) had a complete response (CR), and 20 patients (14%) had a partial response (PR). A stable disease (SD) was in 9 patients (6%), and a progressive disease (PD) was in 106 patients (74%). The overall response rate (CR + PR) was 20%, and the disease control rate (CR + PR + SD) was 26%.

The Kaplan–Meier method was used to estimate the PFS and OS of 144 patients with RMHNSCC. At the time of analysis, the median periods of follow-up were 38.6 months (range, 21.7–52.2 months) for the 22 survivors. The median PFS was 2.7months ( range, 1-52.2 months), with a two-year PFS rate of 10%. The median OS was 7.5 months (range, 1-52.2 months), with a two-year OS rate of 22%.

Analysis of prognostic factors

The relationships between the response to ICIs and clinicopathological parameters are shown in Table 2. The overall response rate (CR + PR) was significantly correlated with high TPS expression, high CPS expression, NLR < 5, calcium < 10 mg/dL, albumin ≧ 4 g/dL, and PNI ≥ 45. The disease control rate ( CR + PR + SD) was significantly associated with high TPS expression, high CPS expression, NLR < 5, calcium < 10 mg/dL, albumin ≧ 4 g/dL, and PNI ≥ 45. The overall response rates were 25% and 3% in patients with calcium < 10 mg/dL and calcium ≥ 10 mg/dL (P = 0.007) respectively, and 6% and 33% in patients with albumin < 4 g/dL and albumin ≥ 4 g/dL (P < 0.001), respectively.

Table 2 Associations between the response of immune checkpoint inhibitors and clinical parameters in 144 patients with recurrent or metastatic head and neck squamous cell carcinoma

Parameters	Response of ICIs	Response of ICIs	
CR/PR	SD/PD	P value	CR/PR/SD	PD	P value	
Age							
 < 59	16	54	0.43	18	52	0.86	
 ≥ 59	13	61		20	54		
Sex							
 Male	27	104	0.65	35	96	0.78	
 Female	2	11		3	10		
TPS							
 < 50%	8	69	0.002*	15	62	0.044*	
 ≥ 50%	21	46		23	44		
TPS							
 < 80%	17	93	0.012*	24	86	0.025*	
 ≥ 80%	12	22		14	20		
CPS							
 < 20	3	35	0.028*	7	31	0.19	
 ≥ 20	26	80		31	75		
CPS							
 < 50	8	62	0.011*	15	55	0.19	
 ≥ 50	21	53		23	51		
CPS							
 < 80	15	90	0.004*	22	83	0.015*	
 ≥ 80	14	25		16	23		
Total lymphocyte count							
 < 1000/µL	16	66	0.83	19	63	0.31	
 ≥ 1000/µL	13	49		19	43		
NLR							
 < 5	19	50	0.034*	26	43	0.003*	
 ≥ 5	10	65		12	63		
PLR							
 < 300	15	57	0.84	24	48	0.059	
 ≥ 300	14	58		14	58		
LMR							
 < 1.8	13	59	0.53	14	58	0.059	
 ≥ 1.8	16	56		24	48		
Calcium							
 < 10 mg/dL	28	84	0.007*	37	75	0.001*	
 ≥ 10 mg/dL	1	31		1	31		
Albumin							
  < 4 g/dL	4	65	< 0.001*	7	62	< 0.001*	
 ≥ 4 g/dL	25	50		31	44		
PNI							
 < 45	8	66	0.004*	10	64	< 0.001*	
 ≥ 45	21	49		28	42		
Primary site							
 Oral cavity	15	77	0.13	20	72	0.092	
 Non-oral cavity	14	38		18	34		
Therapy line							
 2nd line	22	83	0.69	29	76	0.58	
 ≥ 3rd line	7	32		9	30		
Treatment regimen							
 ICI alone	21	86	0.79	26	81	0.33	
 Combination	8	29		12	25		
Smoking history							
 Absent	4	16	0.99	6	14	0.69	
 Present	25	99		32	92		
Alcohol history							
 Absent	3	23	0.23	4	22	0.16	
 Present	26	92		34	84		
Betel nut chewing history							
 Absent	1	16	0.12	3	14	0.38	
 Present	28	99		35	92		
ICI, immune checkpoint inhibitors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TPS, Tumor proportion score; CPS, Combined positive score; NLR, Neutrophil-to-lymphocyte ratio; PLR, Platelet-to-lymphocyte ratio; LMR, Lymphocyte-to-monocyte ratio; PNI, Prognostic nutritional index; *Statistically significant. Chi-Square test or Fisher’s exact test was used for statistically analyzed

Table 3 Results of univariate log-rank analysis of prognostic factors for progression-free survival and overall survival in 144 patients with recurrent or metastatic head and neck squamous cell carcinoma receiving immune checkpoint inhibitors

Factors	No. of patients	Progression-free survival (PFS)	Overall survival
(OS)	
2-year PFS rate (%)	P value	2-year OS rate (%)	P value	
Age						
 <59y/o	70	10%	0.98	21%	0.94	
 ≧ 59y/o	74	11%		23%		
Sex						
 Male	131	11%	0.91	22%	0.99	
 Female	13	8%		23%		
TPS						
 < 50%	77	4%	0.003*	16%	0.019*	
 ≥ 50%	67	18%		30%		
TPS						
 < 80%	110	6%	0.004*	17%	0.005*	
 ≥ 80%	34	24%		38%		
CPS						
 < 20	38	0%	0.09	25%	0.22	
 ≥ 20	106	14%		16%		
CPS						
 < 50	70	4%	0.017*	17%	0.07	
 ≥ 50	74	16%		27%		
CPS						
 < 80	105	6%	0.002*	16%	0.002*	
 ≥ 80	39	23%		39%		
Total lymphocyte count						
 < 1000/µL	82	10%	0.23	24%	1.00	
 ≥ 1000/µL	62	11%		19%		
NLR						
 < 5	69	13%	0.03*	29%	0.006*	
 ≥ 5	75	8%		16%		
PLR						
 < 300	72	13%	0.03*	26%	0.11	
 ≥ 300	72	8%		18%		
LMR						
 < 1.8	72	8%	0.21	18%	0.15	
 ≥ 1.8	72	13%		26%		
Calcium						
 < 10 mg/dL	112	12%	0.005*	26%	< 0.001*	
 ≥ 10 mg/dL	32	6%		9%		
Albumin						
 < 4 g/dL	69	4%	< 0.001*	10%	< 0.001*	
 ≥ 4 g/dL	75	16%		33%		
PNI						
 < 45	74	5%	< 0.001*	15%	< 0.001*	
 ≥ 45	70	16%		30%		
Primary site						
 Oral cavity	92	9%	0.08	20%	0.54	
 Non-oral cavity	52	14%		27%		
Therapy line						
 2nd line	105	11%	0.15	25%	0.17	
 ≥ 3rd line	39	8%		15%		
Treatment regimen						
 ICI alone	107	10%	0.58	22%	0.93	
 Combination	37	11%		22%		
Smoking history						
 Absent	20	10%	0.47	25%	0.86	
 Present	124	10%		22%		
Alcohol history						
 Absent	26	12%	0.73	19%	0.48	
 Present	118	10%		23%		
Betel-nut chewing history						
 Absent	17	12%	0.95	18%	0.90	
 Present	127	10%		23%		
TPS, Tumor proportion score; CPS, Combined positive score; NLR, Neutrophil-to-lymphocyte ratio; PLR, Platelet-to-lymphocyte ratio; LMR, Lymphocyte-to-monocyte ratio; PNI, Prognostic nutritional index; *Statistically significant

Table 3 shows univariate analyses of the log-rank analysis of prognostic factors for PFS and OS in 144 patients with RMHNSCC. Patients with TPS ≧ 80%, CPS ≧ 80, NLR < 5, PLR < 300, calcium < 10 mg/dL, albumin ≧ 4 g/dL, and PNI ≧ 45 had better PFS (Fig. 1), and TPS ≧ 80%, CPS ≧ 80, NLR < 5, calcium < 10 mg/dL, albumin ≧ 4 g/dL, and PNI ≧ 45 had superior OS (Fig. 2). Multivariate Cox regression analysis for PFS and OS in 144 patients found that calcium ≧ 10 mg/dL (PFS, P = 0.037, odds ratio: 1.575, 95% confidence interval: 1.028–2.411; OS, P = 0.002, odds ratio: 1.999, 95% confidence interval: 1.301–3.071), albumin < 4 g/dL (PFS, P0.015, odds ratio: 1.652, 95% confidence interval: 1.104–2.473; OS, P = 0.001, odds ratio: 1.862, 95% confidence interval: 1.277–2.715), and CPS < 80 (PFS, P = 0.003, odds ratio: 1.848, 95% confidence interval: 1.224–2.790; OS, P = 0.007, odds ratio: 1.845, 95% confidence interval: 1.185–2.872) were independent prognostic factors in poor PFS and OS of patients with RMHNSCC under ICI treatment. The two-year PFS and OS rates were 12% and 26% in patients with calcium < 10 mg/dL, and 6% and 9% in patients with calcium ≥ 10 mg/dL (P = 0.005 for PFS; P < 0.001 for OS). The two-year PFS and OS rates were 4% and 10% in patients with albumin < 4 g/dL, and 16% and 33% in patients with albumin ≥ 4 g/dL (P < 0.001 for PFS; P < 0.001 for OS).

Fig. 1 Progression-free survival in 144 patients with recurrent or metastatic head and neck squamous cell carcinoma receiving immune checkpoint inhibitors according to (A) Calcium < 10 mg/dL versus ≥ 10 mg/dL (B) Albumin < 4 g/dL versus ≥ 4 mg/dL (C) TPS (Tumor proportion score) < 80% versus ≥ 80% (D) CPS (Combined positive score < 80% versus ≥ 80% (E) Neutrophil-to-lymphocyte ratio < 5 versus ≥ 5 (F) Platelet-to-lymphocyte ratio < 300 versus ≥ 300 (G) Prognostic nutritional index < 45 versus ≥ 45

Fig. 2 Overall survival in 144 patients with recurrent or metastatic head and neck squamous cell carcinoma receiving immune checkpoint inhibitors according to (A) Calcium < 10 mg/dL versus ≥ 10 mg/dL (B) Albumin < 4 g/dL versus ≥ 4 mg/dL (C) TPS (Tumor proportion score) < 80% versus ≥ 80% (D) CPS (Combined positive score < 80% versus ≥ 80% (E) Neutrophil-to-lymphocyte ratio < 5 versus ≥ 5 (F) Platelet-to-lymphocyte ratio < 300 versus ≥ 300 (G) Prognostic nutritional index < 45 versus ≥ 45

Discussion

Although ICI treatments have generally been applied to RMHNSCC in recent years, the treatment results and prognostic factors have not been elucidated. Our study found that the ORR to ICI treatment after initial platinum-based treatment failure was 20%. The median OS was 7.5 months, with an estimated 24-month OS rate of 22%. The median PFS was 2.7 months, with an estimated 24-month PFS rate of 10%. These results are similar to those reported by CheckMate-141 [6] and KEYNOTE-040 [5]. Notably, in the present study, we found that low TPS, low CPS, NLR ≥ 5, hypercalcemia, hypoalbuminemia, and PNI < 45 were significantly correlated with poor response of ICIs, worse PFS and inferior OS. Multivariate analysis revealed that hypercalcemia and hypoalbuminemia were independent prognostic factors for worse PFS and inferior OS. The overall response rates were 25% and 3% in patients with calcium < 10 mg/dL and calcium ≥ 10 mg/dL, respectively (P = 0.007). The overall response rates were 6% and 33% in patients with albumin < 4 g/dL and albumin ≥ 4 g/dL (P < 0.001). The two-year OS rates were 26% and 9% in patients with calcium < 10 mg/dL and ≥ 10 mg/dL, respectively (P < 0.001). The two-year OS rates were 10% and 33% in patients with albumin < 4 g/dL and ≥ 4 g/dL, respectively (P < 0.001).

Albumin level is a common nutritional and predictive markers in patients with cancer. Several studies have demonstrated that low preoperative serum albumin levels affected postoperative survival and complications in different types of cancers [11, 13]. Serum albumin levels were also correlated with inflammatory status [14], and hypoalbuminemia often developed in patients with chronic inflammatory disease and advanced cancer patients with poor performance status [15, 16]. Therefore, serum albumin status has been used to evaluate the prognosis of patients with cancer receiving chemotherapy, radiotherapy, or target therapy, and some studies have demonstrated that hypoalbuminemia was associated with poor survival [17–19]. Recent studies also investigated the correlation between albumin levels and outcomes in patients treated with ICIs [20–22]. However, few studies explored the role of albumin levels in patients with RMHNSCC treated with ICIs [23, 24]. Our study demonstrated that the pretreatment albumin level is a useful biomarker for predicting ICI treatment response, PFS, and OS. Kenro et al. showed that the C‑reactive protein to albumin ratio (CAR) was a more independent and significant prognostic factor than the NLR in patients with RMHNSCC treated with nivolumab [23]. A high pretreatment CAR was significantly associated with poor OS and PFS. Our study also found that pretreatment high serum albumin levels could predict a better treatment response and superior PFS and OS. Matsuzaka et al. also showed that the modified Glasgow Prognostic Score (mGPS), a combination of albumin and CRP levels, was associated with cancer cachexia and prognosis in patients with unresectable locally advanced HNSCC [25]. Based on the above research, serum albumin level plays an important role in predicting the prognosis of patients with RMHNSCC receiving ICI treatments.

The regulation of calcium homeostasis is crucial for diverse cellular functions, such as energy metabolism, cell signaling, and cell motility. In addition, dysregulation of intracellular calcium levels is involved in tumor initiation and progression, and modulation of the calcium signaling pathway could affect the tumor microenvironment [26]. Hypercalcemia is commonly found in patients with squamous cell carcinoma; however, its prognostic association with ICIs efficacy has not been previously reported. The mechanism between serum calcium and inflammation may come from the interaction with the extracellular calcium-sensing receptor which has been reported to regulate inflammation via multiple downstream signaling pathways [27]. Calcium transport to the cytosol is crucial for immunoreceptor signaling, regulation of lymphocyte differentiation and activation, antibody and cytokine secretion, and cytotoxicity [28]. Immune checkpoints are also associated with calcium signaling. Calcium/calmodulin-dependent protein kinase ID (CaMK1D)-mediated treatment showed resistance to anti-PD-1/PD-L1 [29]. Although previous studies have shown that ICIs are associated with calcium signaling and calcium channel blockers [29], only a few studies have elucidated the correlation between calcium levels and the prognosis of cancer patients treated with ICIs. The unique finding of this study points out that serum calcium ≧ 10 mg/dL is a meaningful and independent prognostic factor in patients with RMHNSCC receiving ICI treatment. These results were partially supported by those of Zhuang et al. [30]. , which revealed that rectal cancer patients with high serum calcium and PLR status had worse disease-free survival and OS.

The third interesting finding of our study is that CPS ≧ 80 predicted significantly better PFS and OS in ICI treatments. While increasing the utility of ICI treatments in patients with RMHNSCC, additional specific biomarkers are required to improve the predictive prognosis. CPS is one of the most powerful biomarkers for ICI treatments and has demonstrated its predictive value in previous KEYNOTE-055 and KEYNOTE-048 studies [7, 31]. In KEYNOTE-055, 28% of pretreatment patients were CPS ≧ 50; ORR and DCR of all populations were 16% and 35%, respectively. In KEYNOTE-048, 40–45% of patients were CPS ≧ 20, with a median OS of 13 months in the pembrolizumab combined with chemotherapy group and 11.6 months in the pembrolizumab alone group. However, there was no difference in PFS between the pembrolizumab group and cetuximab with the chemotherapy group, even CPS ≧ 20. In our study, 74% of patients with RMHNSCC were under ICI treatment with CPS ≧ 20 and 27% with CPS ≧ 80; the median OS and PFS were 7.5 and 2.9 months in patients with CPS ≧ 20, and 10.1 and 3.7 months in patients with CPS ≧ 80, respectively. Many patients with RMHNSCC had high CPS expression in our study because of the reimbursement criteria for ICI treatments in Taiwan National Health Insurance. Emancipator et al. reported that a CPS > 50 indicated good ICI treatment efficacy in patients with RMHNSCC [32]. Our study also found that patients with RMHNSCC with ultra-high CPS expression, high serum albumin levels, and low serum calcium levels had better ICI treatment response and superior survival. This finding was in accordance with the results of the study by Saito et al. [33].

The current study has some limitations. First, this was a single-center retrospective study. Furthermore, there was some heterogeneity in the cohorts. The enrolled patients with RMHNSCC that received ICI treatment consisted of 73% were the second line, 24% were the third line, and 3% were more than the fourth lines after initial platinum treatment, respectively. In this retrospective study, 69% and 31% of patients received pembrolizumab and nivolumab, respectively. The reason was largely due to Taiwan Healthy Insurance’s reimbursement of pembrolizumab or nivolumab to RMHNSCC patients as a second-line treatment since April 2019. In addition, some of these ICI treatments combined with chemotherapy or target therapies could also influence treatment results. Second, during this retrospective study, the pathological tissue samples for PD-L1 immunohistochemical staining varied among the patients with RMHNSCC. Several studies have addressed the spatiotemporal heterogeneity of PD-L1 expression in various solid carcinomas such as biopsy/resection and primary sites/metastases. Assessing the temporal heterogeneity of PD-L1 is a complex task. PD-L1 expression is considered a time-dependent biomarker that is prone to longitudinal fluctuations, and the timing of PD-L1 staining exhibits differing results. Third, patients with advanced head and neck cancer are usually in malnutrition state that causes hypoalbuminemia, and many previous studies have shown that malnutrition associated with poor cancer prognosis [34]. Therefore, malnutrition may have been a confounding factor in the present study.

Conclusions

Our study found that hypoalbuminemia and hypocalcemia were independently associated with poor treatment outcomes of anti-PD-1 immune checkpoint inhibitors in patients with RMHNSCC after platinum failure. Serum albumin and calcium are inexpensive, fast, and easily available examinations, and our findings suggest that they may help clinicians with further individualized therapeutic approaches in patients with RMHNSCC.

Acknowledgements

We thank Chang Gung Medical Foundation Kaohsiung Chang Gung Memorial Hospital Tissue Bank Core Laboratory for their excellent technical support.

Author contributions

Conceptualization, S-H Li; methodology, S-H Li; software, T-J Chiu; validation, C-Y Chien; formal analysis, T-J Chiu; investigation, C-Y Chien; resources, W-T Huang; data curation, T-J Chiu, T-L Huang, W-T Huang, and S-H Li; writing—original draft preparation, T-J Chiu; writing—review and editing, S-H Li; visualization, C-H Chien; supervision, S-H L; project administration, S-H Li; funding acquisition, T-J Chiu and S-H Li. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported in part by grants from the National Science Council, Taiwan (NSTC 112-2314-B-182 A-029-MY3), and Chang Gung Memorial Hospital (CMRPG8N0802, CORPG8P0491, and CORPG8M0461).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Ethical approval for this study was obtained from the Chang Gung Medical Foundation Institutional Review Board (202200507B0 and 202201019B0). All procedures used in studies involving human participants were performed in accordance with the ethical standards of the Institutional Research Committee and the World Medical Association Declaration of Helsinki. The requirement for written informed consent was waived by the Institutional Review Board of the Chang Gung Medical Foundation .

Consent for publication

Not applicable.

Conflict of interest

None.

Competing interests

The authors declare no competing interests.

Abbreviations

ICIs Immune checkpoint inhibitors

PD-1 Programmed cell death 1

HNSCC Head and neck squamous cell carcinoma

NLR Neutrophil-to-lymphocyte ratio

PLR Platelet-to-lymphocyte ratio

LMR Lymphocyte-to-monocyte ratio

PNI Prognostic nutritional index

TPS Tumor proportion score

CPS Combined positive score

PFS Progression-free survival

OS Overall survival

RMHNSCC Recurrent or metastatic head and neck squamous cell carcinoma

ECOG Eastern Cooperative Oncology Group

PS Performance status

RECIST Response Evaluation Criteria in Solid Tumors

ORR Objective response rate

CR Complete response

PR Partial response

SD Stable disease

PD Progressive disease

CAR C‑reactive protein to albumin ratio

mGPS Modified Glasgow Prognostic Score

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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