Clinical prognosis of lung cancer in patients with moderate chronic kidney disease Running title: lung cancer in patients with chronic kidney disease

doi:10.21203/rs.3.rs-1660010/v1

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Clinical prognosis of lung cancer in patients with moderate chronic kidney disease Running title: lung cancer in patients with chronic kidney disease

https://doi.org/10.21203/rs.3.rs-1660010/v1

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Backgrounds: The clinical outcomes of patients with lung cancer coexisting chronic kidney disease (CKD) reported have been conflicting. In addition, there is insufficient evidence for treatment and prognosis of lung cancer according to renal function in patients with CKD. We evaluate clinical course and prognostic factors of lung cancer according to the renal function of moderate CKD patients.

Methods: A retrospective, multicenter study of lung cancer patients with moderate CKD was performed. Moderate CKD was defined as and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m². CKD was classified as stage 3 (eGFR of 30–60 mL/min/1.73 m²⁾, stage 4 (eGFR of 15–30 mL/min/1.73 m²⁾, and stage 5 (eGFR of <15 mL/min/1.73 m² or need of dialysis). The cumulative mortality was calculated by the Kaplan-Meier method, and the risk factors were explored by the Cox proportional hazards model.

Results: Among the lung cancer patients with moderate CKD (n = 181), the incidence of mortality was 83%. Median overall survival (OS) was 10.2 (3.3–28.3) months for all CKD patients, 11.1 (4.2–31.3) months for stage 3 CKD patients, 6.0 (1.8–16.3) months for stage 4 CKD patients, and 4.7 (2.1–40.1) months for stage 5 CKD patients (p = 0.060). Cox regression analysis revealed that age ≥75 years (adjusted hazard ratio [HR] 1.658; 95% confidence interval [CI] 1.148–2.394) and stage IV NSCLC (adjusted HR 3.198; 95% CI 2.136–4.788) were associated with increased mortality risk, whereas adenocarcinoma (adjusted HR 0.513; 95% CI 0.325–0.810) and stage 3 CKD (adjusted HR 0.566; 95% CI 0.383–0.837) were associated with decreased mortality risk.

Conclusions: Mortality risk of patients with lung cancer was lower in stage 3 CKD compared stage 4 or 5 CKD.

lung cancer

chronic kidney disease

mortality

Lung cancer is the leading cause of cancer-related mortality worldwide [1]. The comorbidities at the time of lung cancer diagnosis are one of the important factors that affect prognosis [2]. Lung cancer is associated with advanced age and smoking, both of which are also associated with comorbidities [3, 4]. Lung cancer is particularly common in the elderly, and the average age at diagnosis is 70 years [5]. Chronic kidney disease (CKD) is also common in the elderly due to an approximately 1% per year decrease in the average creatinine clearance (CrCl) [6]. CKD is associated with poor prognosis in various type of cancer [7]. However, the impact of CKD on the prognosis of lung cancer patients remains controversial. Patel et al. [8] and Na et al. [9] reported similar survival rates in lung cancer patients with and without CKD. By contrast, in a large population-based cohort study, Wei et al. [10] found an increased mortality rate in lung cancer patients with CKD compared to those without CKD. Therefore, the outcome of lung cancer patients with CKD remains unclear. Furthermore, there is insufficient evidence for lung cancer management according to the CKD stage (i.e., degree of renal impairment). The purpose of the present study was to analyze the clinical course and prognostic factors of lung cancer according to the renal function of moderate CKD patients, including pre-dialysis and hemodialysis patients.

Study design

The study enrolled 5,351 patients pathologically diagnosed with lung cancer between January 1, 2008 and December 31, 2019 at four university teaching hospitals. We retrospectively analyzed the medical records of 190 patients with stage 3 or higher CKD. Nine patients for whom treatment was discontinued due to transfer to another hospital were excluded.

Diagnosis of lung cancer

Lung cancer was pathologically confirmed on the basis of malignant cells in biopsy specimens, pleural fluid, or bronchial lavage fluid. Staging of lung cancer was assessed according to the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology 8th edition [11].

Definition of moderate chronic kidney disease

Renal function was evaluated as the estimated glomerular filtration rate (eGFR), calculated as: eGFR (mL/min/1.73 m²) = 194 × serum creatinine^− 1.094 (mg/dL) × age^− 0.278 (if female, 194 was replaced with 90.739). CKD was diagnosed at the time of lung cancer diagnosis, defined as an eGFR < 90 mL/min/1.73 m² in the presence of proteinuria/hematuria or abnormal kidney imaging [11]. CKD was classified as stage 3 based on an eGFR of 30–60 mL/min/1.73 m², stage 4 based on an eGFR of 15–30 mL/min/1.73 m², and stage 5 based on an eGFR of < 15 mL/min/1.73 m² or need of dialysis [12]. All stage 5 CKD patients enrolled in this study were on hemodialysis.

Variables

We assessed the demographic and clinicopathological information of the patients, including their age; sex; body mass index (BMI); epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase, and programmed cell death protein-ligand 1 (PD-L1), treatment regimen; and progression-free survival (PFS), overall survival (OS), and 5-year survival rate. Chest computed tomography (CT) was performed after every 1–3 months to evaluate the treatment response. PFS was evaluated only in the first chemotherapy and was defined as the time from first chemotherapy commencement to either documented disease progression or death from any cause. OS was defined as the time from pathological diagnosis to death from any cause. Progression was evaluated on the basis of response using Response Evaluation Criteria in Solid Tumors (version 1.1) [13].

Statistical analysis

Frequencies are expressed as numbers (%) and descriptive data are expressed as medians with interquartile range (IQR). We compared the clinical features, pathological type of lung cancer, stage, treatment regimen, OS, PFS, and 5-year survival according to CKD groups. The Chi-square test or Fisher’s exact test was used to analyze categorical variables, and the Kruskal-Wallis test was used to analyze continuous variables. Cumulative survival curves were constructed for each lung cancer stage and CKD group using the Cox regression method. Univariate analysis was performed to identify prognostic factors related to OS by creating a categorical variable based on the median values of the clinical characteristics, pathological type, lung cancer stage, and CKD groups at the time of lung cancer diagnosis in CKD patients. Factors significantly associated with OS were further analyzed in a Cox proportional hazard model to adjust for the potential confounding effects of each factor. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. The seven variables included in the Cox regression analysis were sex and the factors with a p value < 0.05 in the univariate analysis. Cumulative survival curves were constructed using the Cox regression method with reference to age older than 75 years and adenocarcinoma status.

Clinical characteristics of patients with lung cancer in CKD

Table 1 presents the clinical characteristics of the enrolled patients. The patients had a median age of 75 (70–81) years, and 87% (157/181) of the patients were males. In patients with lung cancer in CKD, the median creatinine level was 1.68 (1.45–2.29) mg/dL and the CrCl was 35.9 (23.8–45.0) mL/min/1.73m². Comorbidities in lung cancer with CKD patients were hypertension, 68% (123/181); diabetes mellitus, 47% (85/181); chronic airway disease, 28% (50/181); heart disease, 18% (33/181); other cancer, 18% (33/181); old cerebral disease, 12% (22/181). The pathological type of lung cancer was non-small cell lung cancer (NSCLC) in 83% (150/181) and small cell lung cancer (SCLC) in 17% (31/181) of the patients. Among the NSCLC patients, adenocarcinoma was diagnosed in 41% (61/181), squamous cell carcinoma in 45% (68/181), and large cell carcinoma in 5% (8/181) of the patients. Thus, squamous cell carcinoma was the most common pathological type in enrolled patients. TNM stages of patients diagnosed with NSCLC, stage I–IV cancers were observed in 23% (35/150), 11% (16/150), 23% (34/150), and 43% (65/150), respectively. Among the SCLC patients, 26% (8/31) and 74% (23/31) had limited and extensive disease, respectively. The lung cancer patients with CKD were treated with surgery (25%; 45/181), radiotherapy (25%; 45/181), first-line chemotherapy (37%; 67/181), combined chemotherapy and radiotherapy (10%; 18/181), targeted therapy (12%; 21/181), or palliative supportive therapy (31%; 56/181).

Table 1

Clinical characteristics and treatment of lung cancer patients with chronic kidney disease
characteristics	All patients (n = 181)	CKD 3 (n = 117)	CKD 4 (n = 42)	CKD5 (n = 22)	p-value
Age, year	75 (70–81)	75 (71–81)	79 (71–82)	73 (64–78)	0.040
Male	157 (87%)	104 (89%)	35 (83%)	18 (82%)	0.507
Body mass index, kg/m²	23.0 (21.4–25.1)	23.4 (22.0-25.7)	22.0 (19.8–24.9)	22.0 (20.0–24.0)	0.007
BUN, mg/dL	24.6 (19.1–31.8)	22.0 (17.5–25.6)	32.0 (28.0-45.4)	44.6 (25.9–54.1)	< 0.001
Creatine, mg/dL	1.68 (01.45–2.29)	1.5 (1.4–1.68)	2.4 (1.8–3.2)	6.3 (5.0-8.3)	< 0.001
Creatine clearance, mL/minute/1.73 m²	35.9 (23.8–45.0)	40.9 (36–48)	23.0 (17.3–26.4)	8.9 (6.8–8.3)	< 0.001
Comorbidity Hypertension Diabetes Chronic airway disease Heart disease Other cancer Old cerebral disease	123 (68%) 85 (47%) 50 (28%) 33 (18%) 33 (18%) 22 (12%)	82 (70%) 50 (43%) 33 (28%) 17 (15%) 22 (19%) 12 (12%)	29 (69%) 22 (52%) 13 (31%) 9 (21%) 8 (19%) 5 (12%)	12 (55%) 13 (59%) 4 (18%) 7(32%) 3 (14%) 3 (14%)	0.353 0.268 0.540 0.130 0.837 0.975
Pathologic type NSCLC Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Sarcoma Undifferentiated NSCLC SCLC	150 (83%) 61 (41%) 68 (45%) 8 (5%) 2 (1%) 11 (7%) 31 (17%)	99 (85%) 38 (38%) 50 (51%) 5 (5.1%) 1 (1.0%) 5 (5.1%) 18 (15%)	33 (79%) 12 (36%) 13 (39%) 3 (10%) 1 (3.0%) 4 (12%) 9 (21%)	18 (82%) 11 (61%) 5 (28%) 0 0 2 (11%) 4 (18%)	0.665 0.203 0.124 0.415 0.625 0.388 0.665
EGFR (n = 107) ALK (n = 54) PD-1 (n = 49)	18 (17%) 1 (2%) 26 (53%)	10 (9%) 0 20(41%)	4 (4%) 0 3 (6%)	4 (4%) 1 (1.9%) 3 (6%)	0.387 < 0.001 0.017
NSCLC stage Stage I Stage II Stage III Stage IV	35 (23%) 16 (11%) 34 (23%) 65 (43%)	21 (21%) 10 (10%) 23 (23%) 45 (46%)	7 (21%) 6 (18%) 6 (18%) 14 (42%)	7 (39%) 0 5 (28%) 6 (33%)	0.251 0.126 0.717 0.630
SCLC stage Limited stage Extensive stage	8 (26%) 23 (74%)	4 (22%) 14 (78%)	1 (11%) 8 (89%)	3 (75%) 1 (25%)	0.045 0.045
Palliative supportive therapy	56 (31%)	35 (30%)	14 (33%)	6 (27%)	0.867
Surgery Pneumonectomy Lobectomy Wedge resection	45 (25%) 1 (2.3%) 41 (91%) 3 (6.7%)	31 (27%) 1 (3.2%) 28 (90%) 2 (6.6%)	8 (19%) 0 8 (100%) 0	6 (27%) 0 5 (83%) 1 (17%)	0.608 0.760 0.810 0.399
Radiotherapy Lung Other	46 (25%) 37 (80%) 11 (24%)	30 (26%) 24 (80%) 7 (23%)	8 (19%) 8 (100%) 1 (13%)	8 (36%) 5 (62%) 3 (38%)	0.318 0.941 0.201
Chemotherapy 1st chemotherapy AP GP GC TP TC EC EP 2nd chemotherapy 3rd chemotherapy Adjuvant chemotherapy Chemo-combined radiotherapy	67 (37%) 9 (13%) 9 (13%) 6 (9%) 6 (9%) 5 (7%) 11 (16%) 7 (11%) 25 (14%) 11 (6%) 13 (7%) 18 (10%)	45 (81%) 9 (20%) 7 (15%) 4 (9%) 5 (11%) 4 (9%) 8 (17%) 3 (7%) 17 (15%) 8 (7%) 11 (9%) 13 (11%)	13 (31%) 0 0 2 (15%) 1 (8%) 1 (8%) 3(23%) 2 (15%) 4 (10%) 1 (2%) 2 (5%) 2 (5%)	9 (100%) 0 2 (25%) 0 0 0 0 2 (25%) 4 (18%) 2 (9%) 0 3 (14%)	0.628 0.750 0.597 0.196 0.659 0.548 0.915 0.326 0.591 0.479 0.230 0.412
Targeted therapy Gefitinib Erlotinib afatinib	21 (12%) 8 (38%) 8 (38%) 3 (14%)	12 (10%) 4 (33%) 6 (50%) 2 (17%)	4 (10%) 1 (25%) 1 (25%) 1 (25%)	5 (23%) 3 (75%) 1 (25%) 0	0.219 0.078 0.758 0.776
Death	151 (83%)	93 (80%)	38 (90%)	20 (90%)	0.156
Overall survival, months	10.2 (3.3–28.3)	11.1 (4.2–31.3))	6.0 (1.8–16.3)	4.7 (2.1–40.1)	0.060
Progression free survival, months	4.9 (2.7–106)	4.7 (2.9–7.8)	4.9 (0.8–10.6)	7.2 (2.7–18.2)	0.456
Survival ≥ 5 years	17 (9%)	12 (10%)	2 (5%)	3 (14%)	0.443
Data are presented as the median value (interquartile range) or number. CKD, chronic kidney disease; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma receptor tyrosine kinase; PD-1, programmed cell death protein-1; AP, pemetrexed with cisplatin; GP, gemcitabine with cisplatin; GC, gemcitabine with carboplatin; TP, paclitaxel with cisplatin; TC, paclitaxel with carboplatin; EC, etoposide with carboplatin; EP, etoposide with cisplatin

Incidence Of Mortality In Patients With Lung Cancer According To Ckd Stage

During the follow-up period, there were 151 (83%) deaths in patients with lung cancer in CKD. According to the CKD stage, 80% (93/117) of patients with stage 3 CKD, 90% (38/42) with stage 4 CKD, and 90% (20/22) with stage 5 CKD (p = 0.156). Figure 1 shows the Cox survival curves for PFS (Fig. 1A) and OS (Fig. 1B) in patients with lung cancer patients by CKD stage. The median PFS was 4.9 (2.7–106) months for all CKD patients, 4.7 (2.9–7.8) months for stage 3 CKD patients, 4.9 (0.8–10.6) months for stage 4 CKD patients, and 7.2 (2.7–18.2) months for stage 5 CKD patients (p = 0.456). The median OS was 10.2 (3.3–28.3) months for all CKD patients, 11.1 (4.2–31.3) months for stage 3 CKD patients, 6.0 (1.8–16.3) months for stage 4 CKD patients, and 4.7 (2.1–40.1) months for stage 5 CKD patients (p = 0.060).

Clinical Outcomes Of Patients With Lung Cancer In Ckd

Tables 2 present the clinical outcomes of lung cancer patients with CKD. Among all CKD patients with lung cancer, the 5-year survival rate was 17% for patients aged less than 75 years and 3% for those aged more than 75 years. The 5-year survival rate was 11% for NSCLC patients (21% for adenocarcinoma and 6% for squamous cell carcinoma) and 0% for SCLC patients. In the survival outcome of NSCLC by TNM stage, 5-year survival rate was 34% for stage I, 0% for stage II, 3% for stage III, 3% for stage IV. The OS was 51.9 (20.0–71.5) months in stage I, 14.5 (5.0–40.0) months in stage II, 11.1 (4.4–31.3) months in stage III, and 6.6 (30.1–14.4) months in stage IV. Among SCLC patients, the OS was 4.1 (1.5–21.4) months with limited disease and 2.1 (0.9–8.2) months with extensive disease.

Table 2

clinical outcome of lung cancer patients with chronic kidney disease
	All patients (n = 181)		CKD 3 (n = 117)		CKD 4 (n = 42)		CKD 5 (n = 22)		P-value
	Overall survival	5year survival	Overall survival	5year survival	Overall survival	5year survival	Overall survival	5year survival	P-value
Age ≥ 75 < 75	6.1 (2.1–18.5) 13.8 (4.7–40.8)	3 (3%) 14 (17%)	6.5 (2.4–18.6) 22.6 (8.5–50.0)	2 (3.7%) 12 (19%)	4.1 (1.8–14.2) 10.0 (1.6–22.8)	0 2 (13%)	4.5 (2.1–57.4) 4.8 (1.8–39.7)	1 (14%) 2 (13%)	0.694 0.044
Pathologic type NSCLC Adenocarcinoma Squamous cell carcinoma SCLC	11.1 (4.0–35.0) 21.7 (8.1–50.8) 8.8 (3.3–26.2) 3.4 (1.0-8.4)	17 (11%) 13 (21%) 4 (6%) 0	15.6 (5.7–39.5) 17.7 (9.8–53.5) 12.6 (4.2–28.8) 4.4 (1.1–8.5)	12 (12%) 8 (21%) 4 (8%) 0	9.5 (3.6–25.6) 31.4 (8.6–57.9) 4.0 (1.6–9.5) 1.7 (0.9–3.6)	2 (6%) 2 (17%) 0 0	4.7 (2.7–45.2) 11.5 (4.5–60.9) 3.7 (0.2–22.7) 3.0 (1.5–33.1)	3 (16%) 3 (27%) 0 0	0.122 0.686 0.001 0.194
NSCLC stage Stage I Stage II Stage III Stage IV	51.9 (20.0-71.5) 14.5 (5.0–40.0) 11.1 (4.4–31.3) 6.6 (30.1–14.4)	12 (34%) 0 3 (9%) 2 (3%)	53.5 (29.2–98.5) 22.3 (6.6–46.3) 20.6 (9.1–50.0) 8.2 (3.3–15.1)	9 (43%) 0 3 (13%) 0	34.5 (10.4–58.9) 10.0 (3.3–29.4) 6.1 (1.8–10.6) 5.9 (2.1–16.7)	1 (14%) 0 0 1 (7%)	41.2(5.3–62.2) - 3.7 (0.7–18.9) 3.8 (1.5–18.8)	2 (29%) - 0 1 (17%)	0.186 0.151 0.002 0.875
SCLC stage Limited stage Extensive stage	4.1 (1.5–21.4) 2.1 (0.9–8.2)	0 0	4.1 (1.2–5.5) 4.4 (1.1–9.3)	0 0	3.23 1.4 (0.9–3.5)	0 0	25.6 (0.9–39.7) 2.13	0 0	0.295 0.421
Palliative therapy	3.2 (1.0-8.2)	0	3.5(1.0-8.4)	0	3.5 (1.1–8.2)	0	1.1 (0.3–3.2)	0	0.049
Surgery	45.9 (24.3–69.2)	14 (8%)	48.3 (27.9–71.6)	11 (9%)	33.0 (10.8–57.9)	1 (2%)	22.5 (5.0-63.6))	2 (9%)	0.130
Adjuvant therapy	40.4 (29.3–50.0)	1 (1%)	45.9 (30.6–50.0)	1 (1%)	25.4 (10.4–40.3)	0	-	-	-
Radiotherapy of lung	20.0 (6.9–40.4)	3 (2%)	20.3 (7.9–49.2)	2 (2%)	6.03 (1.6–21.3)	0	41.2 (25.6–59.1)	1 (5%)	0.027
Chemo combined radiotherapy	16.1 (7.4–29.9)	1 (1%)	11.1 (6.2–19.7)	0	12.4 (1.0-23.8)	0	39.7 (11.5–60.9)	1 (5%)	0.030
Chemotherapy	10.5 (4.5–22.3)	2 (3%)	10.7 (6.3–21.0))	0	4.0 (1.3–24.6)	1 (2%)	11.5 (4.5–36.5)	1 (5%)	0.637
2nd chemotherapy	18.8 (12.0-27.6)	2 (3%)	15.1 (10.4–19.7)	0	32.1 (15.1-101.6)	1 (2%)	30.0 (10.0–54.0)	1 (5%)	0.028
3rd chemotherapy	18.2 (9.4–30.1)	0	17.4 (10.9–21.8)	0	40.3	0	30.0 (26.6–33.4)	0	0.054
Targeted therapy	18.2 (9.5–30.8)	2 (3%)	8.0 (1.8–16.6)	0	26.9 (12.8–98.6)	1 (2%)	4.8 (4.5–47.1)	1 (5%)	0.575
Data are presented as the median value (interquartile range) or number. P values were obtained using Cox survival analysis, CKD, chronic kidney disease; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer

Prognostic Factors Of Patients With Lung Cancer In Ckd

Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors for lung cancer patients with CKD (Table 3). From the univariate analysis, old age (≥ 75 years), a low BMI (≤ 23 kg/m²), comorbid chronic airway disease, SCLC, and stage IV NSCLC were associated with poor prognosis in terms of reduced OS (all p < 0.05). From the multivariate analysis, age ≥ 75 years (adjusted HR = 1.658; 95% CI = 1.148–2.394, p = 0.007) and stage IV NSCLC (adjusted HR = 3.198; 95% CI = 2.136–4.788, p < 0.001) were independent prognostic factors. By contrast, the pathological type of adenocarcinoma (adjusted HR = 0.513; 95% CI = 0.325–0.810, p = 0.004) and stage 3 CKD (adjusted HR = 0.566; 95% CI = 0.383–0.837, p = 0.004) were associated with reduced mortality risk. Figure 2 shows the Cox survival curves for age ≥ 75 years (Fig. 2A) and patients with adenocarcinoma (Fig. 2B).

Table 3

Prognostic factors of lung cancer patients with chronic kidney disease
	Univariate analysis			Multivariate analysis
Characteristics	HR	CI	p-value	HR	CI	p-value
Age ≥ 75 years	1.688	1.220–2.336	0.002	1.658	1.148–2.394	0.007
Male	1.151	0.725–1.825	0.551	1.515	0.813–2.824	0.191
Body mass index ≤ 23 kg/m²	1.532	1.111–2.113	0.009	1.188	0.822–1.716	0.359
Co-morbidity Diabetes Chronic airway disease Heart disease Other cancer	0.999 1.485 1.358 0.784	0.725–1.377 1.030–2.145 0.904–2.041 0.519–1.182	0.997 0.034 0.141 0.245	0.770	0.507–1.171	0.222
NSCLC Adenocarcinoma Squamous cell carcinoma	0.505 1.115	0.355–0.718 0.802–1.551	< 0.001 0.518	0.513	0.325–0.810	0.004
SCLC	2.561	1.694–3.870	< 0.001
NSCLC stage Stage 4	3.044	2.091–4.432	< 0.001	3.198	2.136–4.788	< 0.001
SCLC stage Extensive stage	1.280	0.558–2.936	0.560
CKD 3	0.684	0.493–0.951	0.024	0.566	0.383–0.837	0.004
HR, hazard ration; CI, confidence interval; CKD, chronic kidney disease; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer

In the present study, moderate CKD was present in 3.6% of newly diagnosed lung cancer patients. A previous cohort study conducted in Taiwan reported an incidence of 1.7% for lung cancer coexisting with CKD [10]. However, the previous study defined CKD on the basis of International Classification of Disease codes from health insurance data; thus, the incidence of moderate CKD was higher than that in our study, which defined CKD on the basis of the eGFR.

Lung cancer is histopathologically classified as NSCLC or SCLC. NSCLC accounts for more than 80–85% of lung cancers, of which almost 40% are adenocarcinomas and 25–30% are squamous cell carcinomas [14–16]. In the present study, the histological type of lung cancer was SCLC in 17% and NSCLC in 83% of the patients, similar to the general proportions based on lung cancer histology. Among the NSCLC patients, squamous cell carcinoma was the most common type (45%), followed by adenocarcinoma (41%). In a retrospective study of 671 patients who underwent pulmonary resection for NSCLC, Yamamoto et al. [17] reported that squamous cell carcinoma was more frequently diagnosed in CKD patients than in non-CKD patients (34.5% vs. 15.4%, respectively; p < 0.01). Cigarette smoking is a stronger risk factor for squamous cell carcinoma than for adenocarcinoma, and the proportion of smoking was higher in CKD patients than in non-CKD patients in the previous study.

In the present study, we analyzed the clinical course of lung cancer in moderate CKD patients and found that old age (≥ 75 years) and stage IV NSCLC were poor prognostic factors, whereas adenocarcinoma and stage 3 CKD were good prognostic factors. The older patients (≥ 75 years) had a 1.66-fold higher mortality rate than the younger patients. Mortality due to lung cancer generally peaks at 85 years, consistent with our results [20]. As a result of subgroup analysis, although there was no difference in the stage of lung cancer, surgery (38.8%) was the most frequently preferred treatment option for patients aged < 75 years, whereas only supportive treatment (44.8%) was preferred for patients aged ≥ 75 years (p < 0.001).

In addition, stage IV NSCLC was an independent poor prognostic factor for lung cancer patients with coexistent CKD. In the present study, the 5-year survival rates for NSCLC were 34% for stage I patients, 0% for stage II patients, 9% for stage III patients, and 3% for stage IV patients. The 5-year survival rates were lower in the present study than in a previous study that reported 5-year survival rates of 68–92% for stage I NSCLC, 53–60% for stage II NSCLC, 13–36% for stage III NSCLC, and 0–10% for stage IV NSCLC [21]. The subgroup analysis showed that 36% (65/181) of the patients had stage IV NSCLC at diagnosis and received palliative chemotherapy (49.2%) or supportive treatment (38.5%). In a large retrospective study of medical cost according to the treatment modality and disease stage, Cipriano et al. [22] reported that 13.9% of stage IV NSCLC patients did not receive anti-cancer treatment. Similarly, in the present study, anti-cancer treatment was not administered to a large proportion of stage IV NSCLC patients with CKD, which may explain the poor prognosis of these patients.

By contrast, adenocarcinoma pathology and stage 3 CKD were favorable prognostic factors in this study. EGFR mutations are the most common target driver mutations found in lung adenocarcinoma and are detected in 62% of the Asian population [23, 24]. In lung adenocarcinoma, the median OS was 14 months when treated with pemetrexed-platinum doublet chemotherapy, but the value increased to 39 months upon treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI) [25–27]. In the present study, 61 patients were diagnosed with lung adenocarcinoma, of whom 16 had EGFR mutations and 15 were treated with EGFR-TKIs. The survival analysis, although not reached statistically significant, revealed a longer median OS in the EGFR-TKI treatment group compared to the non-EGFR-TKI treatment group (21.7 vs. 15.8 months; p = 0.593).

In addition, the mortality risk of patients with lung cancer was reduced by 43% in CKD stage 3 compared CKD 4 or 5 stages in this study. The rate of early diagnosis (i.e., at cancer stages I–IIIA) was highest in stage 5 CKD patients (40.9%) compared to stage 3 and 4 patients (37.6% and 40.5%, respectively), which may be explained by the frequent chest X-rays being performed on stage 5 CKD patients who are receiving hemodialysis. The proportions of patients who underwent surgical treatment in patients with resectable lung cancer stage I–IIIA were 63.6%, 47.1%, and 66.7% for stage 3–5 CKD, respectively (Supplementary Table 1). However, in stage I–IIIA lung cancer patients, the 5-year survival rates were 25.0% for stage 3 CKD, 5.9% for stage 4 CKD, and 22.2% for stage 5 CKD. Previous studies have reported 5-year survival rates of 28–43% after lung resection in hemodialysis patients with lung cancer, which was non-inferior to those among patients not receiving hemodialysis [28, 29]. In this study, the survival rate was highest among patients with stage 3 CKD, probably because they frequently received adjuvant chemotherapy after lung resection. Almost 84.6%, 15.4%, and 0.0% of patients with stage 3–5 CKD received adjuvant chemotherapy, respectively. In other words, the early diagnosis rate was higher in stage 5 CKD patients compared to stage 3 CKD patients, whereas the rate of surgery was similar. Nevertheless, the poor survival rate for stage 5 CKD patients was likely due to the low adjuvant chemotherapy rate. Although the study results are limited by the retrospective study design and relatively small sample size (n = 181), the clinical outcomes of lung cancer in patients with CKD were significantly influenced by factors related to renal function as well as lung cancer characteristics (old age, cancer stage, and pathological type). Additionally, despite patients with stage 3 CKD having a better lung cancer prognosis than stage 4 or 5 CKD patients, the former received more aggressive lung cancer treatment than patients with impending or definitive end-stage renal disease (i.e., stage 4 or 5 CKD, respectively).

We evaluated the survival outcomes and prognostic factors for lung cancer according to the renal function. Mortality risk of patients with lung cancer was lower in stage 3 CKD compared stage 4 or 5 CKD. In addition, stage 3 CKD patients received more aggressive anti-cancer treatment than stage 4 or 5 CKD patients. Although the treatment of lung cancer should be individualized according to renal function, limited information is available. Therefore, further large-scale studies are required to determine the optimal treatment for lung cancer in patients with renal dysfunction.

CKD

Chronic kidney disease

CrCl

creatinine clearance

eGFR

estimated glomerular filtration rate

BMI

body mass index

EGFR

epidermal growth factor receptor

PD-L1

programmed cell death protein-ligand 1

PFS

progression-free survival

overall survival

computed tomography

IQR

interquartile range

Hazard ratio, CI:confidence intervals

NSCLC

non-small cell lung cancer

SCLC

small cell lung cancer

TKI

tyrosine kinase inhibitor

Acknowledgments

None

Author’s contributions

Conception and design: YSS, TK. Acquisition of data: YSS, TK, SHK, HC, TRS, HIK, SHJ, JYH, MGL, SC, IGH. Analysis and interpretation of data: YSS, SHK, HC, TRS. Writing, review, and/or revision of the manuscript: YSS, TK, SHJ. Study supervision: YSS, TK, MGL, IGH. TK prepared the first draft, which all authors revised for critical content. All authors reviewed and approved the final version of the manuscript.

Funding

No funding was obtained for this study.

Availability of data and materials

The dataset used and analysed during the present study is available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

This study was conducted in accordance with the amended Declaration of Helsinki. The Institutional Review Board of Hallym University Sacred Heart Hospital approved the study protocol, and informed consent was waived due to the retrospective nature of the study (HKS 2022-02-020).

Consent for publication

Not applicable.

Competing interests

The authors have declared that no competing interests exist.

Siegel RL, Miller KD, Fuchs HE, Jemal A: Cancer statistics, 2022. CA: a cancer journal for clinicians 2022.
Tammemagi CM, Neslund-Dudas C, Simoff M, Kvale P: Impact of comorbidity on lung cancer survival. International journal of cancer 2003, 103(6):792–802.
Yancik R: Cancer burden in the aged: an epidemiologic and demographic overview. Cancer: Interdisciplinary International Journal of the American Cancer Society 1997, 80(7):1273–1283.
Doll R, Peto R, Wheatley K, Gray R, Sutherland I: Mortality in relation to smoking: 40 years' observations on male British doctors. Bmj 1994, 309(6959):901–911.
Bade BC, Dela Cruz CS: Lung Cancer 2020: Epidemiology, Etiology, and Prevention. Clin Chest Med 2020, 41(1):1–24.
Lindeman RD: Changes in renal function with aging. Implications for treatment. Drugs Aging 1992, 2(5):423–431.
Weng PH, Hung KY, Huang HL, Chen JH, Sung PK, Huang KC: Cancer-specific mortality in chronic kidney disease: longitudinal follow-up of a large cohort. Clin J Am Soc Nephrol 2011, 6(5):1121–1128.
Patel P, Henry LL, Ganti AK, Potti A: Clinical course of lung cancer in patients with chronic kidney disease. Lung cancer 2004, 43(3):297–300.
Na SY, Sung JY, Chang JH, Kim S, Lee HH, Park YH, Chung W, Oh KH, Jung JY: Chronic kidney disease in cancer patients: an independent predictor of cancer-specific mortality. Am J Nephrol 2011, 33(2):121–130.
Wei Y-F, Chen J-Y, Lee H-S, Wu J-T, Hsu C-K, Hsu Y-C: Association of chronic kidney disease with mortality risk in patients with lung cancer: a nationwide Taiwan population-based cohort study. BMJ open 2018, 8(1):e019661.
Detterbeck FC: The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg 2018, 155(1):356–359.
Japanese Society of N: Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018. Clin Exp Nephrol 2019, 23(1):1–15.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009, 45(2):228–247.
Rami-Porta R, Bolejack V, Giroux DJ, Chansky K, Crowley J, Asamura H, Goldstraw P: The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer. Journal of Thoracic Oncology 2014, 9(11):1618–1624.
Chansky K, Detterbeck FC, Nicholson AG, Rusch VW, Vallières E, Groome P, Kennedy C, Krasnik M, Peake M, Shemanski L: The IASLC lung cancer staging project: external validation of the revision of the TNM stage groupings in the eighth edition of the TNM classification of lung cancer. Journal of Thoracic Oncology 2017, 12(7):1109–1121.
Wahbah M, Boroumand N, Castro C, El-Zeky F, Eltorky M: Changing trends in the distribution of the histologic types of lung cancer: a review of 4,439 cases. Annals of diagnostic pathology 2007, 11(2):89–96.
Egawa H, Furukawa K, Preston D, Funamoto S, Yonehara S, Matsuo T, Tokuoka S, Suyama A, Ozasa K, Kodama K: Radiation and smoking effects on lung cancer incidence by histological types among atomic bomb survivors. Radiation research 2012, 178(3):191–201.
Kim H, Yoo T-H, Choi KH, Oh K-H, Lee J, Kim SW, Kim TH, Sung S, Han SH: Baseline cardiovascular characteristics of adult patients with chronic kidney disease from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Journal of Korean medical science 2017, 32(2):231–239.
Lu MS, Lu HI, Chen TP, Chen MF, Lin CC, Tseng YH, Tsai YH: Lung cancer outcome in the setting of chronic kidney disease: Does the glomerular filtration estimation formula matter? Thoracic Cancer 2019, 10(2):268–276.
Hashim D, Carioli G, Malvezzi M, Bertuccio P, Waxman S, Negri E, La Vecchia C, Boffetta P: Cancer mortality in the oldest old: a global overview. Aging (Albany NY) 2020, 12(17):16744–16758.
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V: The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. Journal of Thoracic Oncology 2016, 11(1):39–51.
Cipriano LE, Romanus D, Earle CC, Neville BA, Halpern EF, Gazelle GS, McMahon PM: Lung cancer treatment costs, including patient responsibility, by disease stage and treatment modality, 1992 to 2003. Value in Health 2011, 14(1):41–52.
Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang PC: A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014, 9(2):154–162.
Midha A, Dearden S, McCormack R: EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015, 5(9):2892–2911.
Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355(24):2542–2550.
Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T et al: Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018, 378(2):113–125.
Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B et al: Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020, 382(1):41–50.
Obuchi T, Hamanaka W, Yoshida Y, Yanagisawa J, Hamatake D, Shiraishi T, Iwasaki A: Clinical outcome after pulmonary resection for lung cancer patients on hemodialysis. The Annals of thoracic surgery 2009, 88(6):1745–1748.
Takahama M, Yamamoto R, Nakajima R, Tsukioka T, Tada H: Pulmonary resection for lung cancer patients on chronic hemodialysis: clinical outcome and long-term results after operation☆. Interactive CardioVascular and Thoracic Surgery 2010, 11(2):150–153.

No competing interests reported.

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Clinical prognosis of lung cancer in patients with moderate chronic kidney disease Running title: lung cancer in patients with chronic kidney disease

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Abstract

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Background

Methods

Study design

Variables

Statistical analysis

Results

Clinical characteristics of patients with lung cancer in CKD

Incidence Of Mortality In Patients With Lung Cancer According To Ckd Stage

Clinical Outcomes Of Patients With Lung Cancer In Ckd

Prognostic Factors Of Patients With Lung Cancer In Ckd

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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