Cell Biochem Biophys DOI 10.1007/s12013-014-9845-3
ORIGINAL PAPER
Prognostic Significance of Pretreatment Laboratory Parameters in Combined Small-Cell Lung Cancer Xinyue Wang • Richeng Jiang • Kai Li
Ó Springer Science+Business Media New York 2014
Abstract Despite the increasing incidence of combined small-cell lung cancer (C-SCLC) in recent years, there have not been many data on clinical prognostic factors predicting prognosis of C-SCLC patients. In present study, we sought pretreatment features especially basic laboratory parameters predicting survival of C-SCLC. We analyzed 613 small-cell lung cancer (SCLC) patients at our institution between January 2005 and December 2010. We identified 114 patients with C-SCLC. The pathologic and clinical characteristics of these patients were reviewed. Data of laboratory parameters obtained during regular examinations at diagnosis of these patients were examined. The Kaplan–Meier method was used to calculate the survival rate and depict the survival curves. The Cox regression model was used to analyze the independent factors affecting the overall survival (OS). These data were compared with the results obtained from our 499 pure SCLC patients who presented during the same time period. Of the 613 SCLC patients analyzed, 18.6 % of the patients presented with C-SCLC. No difference in OS was observed in patients with C-SCLC and patients with pure SCLC (P = 0.995). The Kaplan–Meier survival curves
revealed that poor ECOG-PS (P \ 0.001), extensive disease (P \ 0.001), pathologic subtype of SC/LC (P \ 0.001), not receiving surgery (P = 0.001), elevated serum lactate dehydrogenase (LDH) (P = 0.005), elevated NSE (P = 0.043), and elevated neutrophile–lymphocyte ratio (NLR) (P = 0.018) were associated with adverse prognosis of patients with C-SCLC. By multivariate analysis, OS was affected by ECOG-PS (hazard ratio 2.001, P = 0.012), disease extent (hazard ratio 3.406, P \ 0.001), and NLR (hazard ratio 1.704, P = 0.030) in C-SCLC patients, while the risk factors that influenced the prognosis of the patients with pure SCLC were ECOG-PS (hazard ratio 2.132, P \ 0.001), disease extent (hazard ratio 1.482, P \ 0.001), and LDH (hazard ratio 1.811, P \ 0.001). Patients with C-SCLC carry a similar prognosis than those with pure small-cell variety. Easily accessible pretreatment parameters such as NLR should be considered in defining the prognosis of C-SCLC patients besides disease extent and performance status. Keywords Combined small-cell lung cancer Pure small-cell lung cancer Prognosis factors Neutrophile– lymphocyte ratio Surgery
Xinyue Wang and Richeng Jiang contributed equally to this study. X. Wang R. Jiang K. Li (&) National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China e-mail: [email protected] X. Wang R. Jiang K. Li Key Laboratory of Cancer Prevention and Therapy, Tianjin, China X. Wang R. Jiang K. Li Department of Thoracic Oncology, Cancer Institute and Hospital of Tianjin Medical University, Huanhuxi Road, Hexi District, Tianjin 300060, China
Introduction Small-cell lung cancer (SCLC) represents about 13 % of overall lung cancer cases worldwide. Unfortunately, despite trends toward modest improvement in survival of SCLC over the last 30 years, the outcome remains very poor [1]. Prognostic significance of various pretreatment parameters in patients with SCLC has been assessed in a number of retrospective studies. The factors recorded have differed between studies, but generally poor performance status,
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extensive stage, and an elevated serum lactate dehydrogenase (LDH) were the prognostic factors associated with poor survival in most studies [2–5]. Other factors positive in some studies are low serum sodium [2, 5–7], elevated alkaline phosphatase (ALP) [4, 6–8], male gender [2, 7–9], older age [2, 7], and low albumin [3, 6]. Neutrophile–lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) derived from blood routine counts known as systemic inflammatory markers were proved as prognostic factors in many types of cancer [10–16]. Prognostic importance of systemic inflammatory markers in NSCLC has been determined [10, 11, 16]. However, little is known whether systemic inflammatory factors are associated with the prognostic of SCLC. Combined small-cell lung carcinoma (C-SCLC) is defined by the world health organization (WHO) as smallcell carcinoma combined with an additional component that consists of any of the histologic types of non-small-cell carcinoma, usually adenocarcinoma, squamous-cell carcinoma, or large-cell carcinoma but less commonly spindle cell or giant cell carcinoma [17]. Some studies indicated that clinical characteristics in patients with C-SCLC do not differ significantly from those in patients with pure SCLC [18–21]. However, most of the research published from the 1970s to the 1990s, i.e., during when new methods of diagnosis such as PET-CT, immunohistochemistry was not routinely applied. Although in recent years, due to advances in the diagnosis of lung cancer, the incidence of C-SCLC has been increasing, and a recent study has shown that C-SCLC may have many of the features of NSCLC [22]; the WHO still considers C-SCLC to be a subset of SCLC. To our knowledge, only limited data with relative small numbers of patients are available with regard to clinical prognostic factors of cases with C-SCLC. In this study, we focus on the pretreatment basic laboratory parameters including systemic inflammatory factors which have been indicated to be important in predicting the prognosis of pure SCLC and/or NSCLC, to evaluate their prognostic significance in C-SCLC.
Materials and Methods Patients Using electronic medical records, 652 SCLC patients presented at Cancer Institute and Hospital of Tianjin Medical University between January 2005 and December 2010 were identified. After excluding patients who were initially evaluated at other centers and cases with incomplete follow-up data, 499 pure SCLC and 114 C-SCLC patients were ultimately included in this study.
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Table 1 Main patient characteristics and laboratory parameters in combined SCLC cohort (n = 114) Variable
No. of patients
%
Gender Male
89
78.1
Female
25
21.9
Age 18–69
92
80.7
*70
22
19.3
Smoking Never
26
22.8
\400
7
6.1
C400
81
71.1
0
21
18.4
1
37
32.5
2
50
43.9
3
6
5.3
Limited disease
68
59.6
Extensive disease
46
40.4
SC/Sq
80
70.2
SC/LC
23
20.2
SC/A Othersa
6
5.3
5
4.4
None
83
72.8
Done
31
27.2
None
81
71.1
Done
33
28.9
CE
92
80.3
Non CE
22
19.7
Normal (C110 g/L)
108
94.7
Anemic (\110 g/L)
6
5.3
ECOG-PS
Disease extent
Pathology subtype
Surgery
Thoracic irradiation
Chemotherapy
Hemoglobin
ALT Normal (\40 U/L)
97
85.1
Elevated (C40 U/L) Albumin
17
14.9
Normal (C30 g/L)
107
93.9
7
6.1
110
96.5
4
3.5
Decreased (\30 g/L) ALP Normal (\132 U/L) Elevated (C132 U/L) LDH Normal (\240 U/L)
75
65.8
Elevated (C240 U/L)
39
34.2
Creatinine (n = 108)
Cell Biochem Biophys Table 1 continued Variable Normal (\80 lmol/L) Elevated (\80 lmol/L) Not assessed Urea (n = 108)
No. of patients
%
104
96.3
4
3.7
6
Normal (\7.2 mmol/L)
76
70.4
Elevated (C7.2 mmol/L)
32
29.6
Not assessed
Decreased (\135 mmol/L) Not assessed
73
91.3
7
8.8
34
NSE (n = 35) Normal (\15.2 lg/L)
9
25.7
Elevated (C15.2 lg/L)
26
74.3
Not assessed
79
Neutrophil-to-lymphocyte ratio Normal (\3) Elevated (C3) Platelet-to-lymphocyte ratio
Ethics Statement
6
Serum sodium (n = 80) Normal (C135 mmol/L)
of time were also collected and evaluated for the purposes of comparison. Follow-up information was collected directly from the outpatient clinic records or from family contact. The overall survival was calculated from the date of diagnosis to the date of death or last visit. Patients known to be alive at last contact were censored.
68
59.6
46
40.4
Normal (\150)
73
64.0
Elevated (C150)
41
36.0
SC/Sq combined small-cell and squamous-cell carcinoma, SC/LC combined small-cell and large-cell carcinoma, SC/A combined smallcell and adenocarcinoma, ALT alanine transaminase, ALP alkaline phosphatase, LDH lactate dehydrogenase, NSE neuronal specific enolase a
Others: 1 combined SCLC patient had small-cell carcinoma and carcinoid tumor, and 4 patients had a mix of more than one nonsmall-cell components
Demographic and clinical data of the 114 C-SCLC patients including age, gender, smoking history, ECOG performance status, disease extent, pathology subtype, as well as pretreatment basic laboratory parameters, therapeutic strategies, and the date of death were obtained in the present study. The two-stage system of the Veteran’s Administration Lung Group was used to classify the patients. Limited disease is defined as disease confined to the ipsilateral chest within a single radiation field, and extensive disease was defined as disease beyond the ipsilateral hemithorax including malignant pleural, pericardial effusion, or hematogenous metastasis. With regard to the combined pathology, combined small-cell and squamouscell carcinoma(SC/Sq) or combined small-cell and adenocarcinoma (SC/A) were defined as the presence of any amount of non-small-cell component, and for combined small-cell and large-cell carcinoma (SC/LC) diagnosis the presence of at least 10 % LCs were considered. In addition, the data of 499 pure SCLC patients seen in the same period
The study was approved by the Research Ethics Committee of Cancer Institute and Hospital of Tianjin Medical University, China. Informed consent was obtained either from the patients or the patient’s family before participating in the study. Statistical Analysis Seventeen pretreatment variables including 6 demographic and clinicopathological factors (age, gender, smoking history, ECOG performance status, disease extent, and pathology subtype), 8 factors measured in pretreatment basic laboratory examinations (hemoglobin, alanine transaminase (ALT), albumin, ALP, LDH, urea, creatinine, serum sodium), a serum tumor marker (neuronal specific enolase (NSE)), and 2 systemic inflammatory factors derived from blood routine counts (NLR and PLR derived from neutrophil, platelets, and lymphocyte) (Table 1) were chosen for analysis. Continuous variables were described using mean ± SD or median and range. Frequency counts and proportions were calculated for categorical data, and Chi square tests or the Fisher’s exact tests were adopted to compare between groups. The median of the overall survival was determined by the Kaplan–Meier method and compared among different groups using the log-rank test. Furthermore, we performed Cox proportional hazards regression analysis with stepwise variable selection to identify significant independent prognostic factors for the overall survival. Hazard ratios (HR) and 95 % confidence interval (CI) were generated. All P values were two sided, and P \ 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 20.
Results Patient Characteristics, Treatment and Laboratory Parameters Of the 613 SCLC patients analyzed, 114 (18.6 %) of the patients are presented with C-SCLC. C-SCLC patients characteristics including demographic, clinical, and
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Cell Biochem Biophys Table 2 Statistical description for laboratory parameters in combined SCLC cohort Variable
Mean ± SD/median (range)
Hemoglobin (g/L, n = 114) 9
137.69 ± 14.261
Neutrophil (10 /L, n = 114)
7.14 ± 3.487
Lymphocyte (109/L, n = 114)
2.07 ± 0.67
Platelets (109/L, n = 114)
260.52 ± 81.64
ALT (U/L, n = 114)
17 (4–546)
Albumin (g/L, n = 114)
43.76 ± 4.483
ALP (U/L, n = 114) LDH (U/L, n = 114)
74.35 ± 26.249 246.66 ± 139.190
Creatinine (lmol/L, n = 108)
70.19 ± 17.766
Urea (mmol/L, n = 108)
5.4 (2.0–94.0)
Serum sodium (mmol/L, n = 80)
141.15 ± 5.236
NSE (lg/L, n = 35)
19.50 (7.54–370.00)
ALT alanine transaminase, ALP alkaline phosphatase, LDH lactic dehydrogenase, NSE neuronal specific enolase
pathologic data as well as data of laboratory parameters are shown in Table 1. The mean age of the patients was 59.31 years. Of the 114 patients, including 89 males and 25 females, 68 (59.6 %) patients suffered limited disease, 46 (40.4 %) suffered extensive disease. Histologically, 80 patients (73.7 %) had SC/Sq, 23 patients (20.2 %) had SC/ LC, 6 patients (5.3 %) had SC/A, 1 (0.9 %) C-SCLC patient had small-cell carcinoma and carcinoid tumor, and other 4 patients had a mix of more than one non-small-cell components. Eleven of the SC/Sq cases had basaloid/ spindle components. The ECOG performances status score of 21 patients (18.4 %) was 0, score of 37 patients (32.5 %) was 1, score of 50 patients (43.9 %) was 2, and score of other 4 patients (5.3 %) was 3. Among all the C-SCLC patients, 31 (27.2 %) underwent surgical resection with lobectomy or pneumonectomy as the initial treatment, 27 surgery cases received adjuvant chemotherapy with EP regimen (platinum and etoposide). The 83 non-surgical patients received routine SCLC treatment. All patients in our cohort underwent at least 4 cycles of platinum-based chemotherapy with routine regimen for SCLC (adjuvant chemotherapy also included), and 33 patient received thoracic irradiation (postoperative radiotherapy also included). Refer to the normal range of the laboratory parameter values in our institute or previous studies, pretreatment laboratory parameters were categorized into normal and abnormal values (Table 1). Statistical description for laboratory parameters in C-SCLC cohort is shown in Table 2. Survival Analysis The median OS was 14 months (Fig. 1). The 1, 2, and 5-year survival rates were 51.2, 30.3, and 15.9 %, respectively. The
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Fig. 1 Overall survival in patients with combined SCLC and patients with pure SCLC (n = 613)
Kaplan–Meier estimation of OS stratified by levels of different factors is shown in Table 3. The following factors were identified as adverse prognostic features by the logrank test: a poor ECOG-PS (v2 = 23.816, P \ 0.001), extensive disease (v2 = 42.449, P \ 0.001), SC/LC (v2 = 67.271, P \ 0.001), not receiving surgery (v2 = 10.294, P = 0.001), elevated LDH (v2 = 7.806, P = 0.005), elevated NSE (v2 = 4.112, P = 0.043), and elevated NLR (v2 = 5.641, P = 0.018). After selection of these parameters for multivariate analysis using Cox’s proportional hazards model, ECOG-PS (hazard ratio 2.001, P = 0.012), disease extent (hazard ratio 3.406, P \ 0.001), and NLR (hazard ratio 1.704, P = 0.030) were independent prognostic factors for poor overall survival. NSE was not taken into account because they were determined only in 35 cases, respectively, which would limit the number of patients considered for distribution into prognostic groups. Comparison with Pure SCLC With regard to the 499 patients with SCLC (375 male and 124 female patients) presented during the same time period, the mean age was 58.53 years. In this pure SCLC group, 265 (53.1 %) patients suffered limited disease and 234 (46.9 %) suffered extensive disease. There was no statistical difference between pure SCLC and C-SCLC patients in terms of gender (v2 = 0.43, P = 0.512), age (v2 = 2.998, P = 0.083), smoking history (v2 = 2.226, P = 0.329), ECOG performance status (v2 = 0.025, P = 0.873), or disease extent (v2 = 1.601, P = 0.206).
Cell Biochem Biophys Table 3 Univariate survival analysis in combined SCLC patients, showing significant values (P \ 0.05) Variable
Median OS (months)
Chi-square value
P value
0
31
23.816
\0.001
1 2
14 11
3
6 42.449
\0.001
67.271
\0.001
ECOG-PS
Disease extent Limited disease Extensive disease
24 9
Pathology subtype SC/Sq
variables, ECOG-PS (hazard ratio 2.132, P \ 0.001), disease extent (hazard ratio 1.482, P \ 0.001), as well as LDH (hazard ratio 1.811, P \ 0.001) remained independent predictors of overall survival, which was partly different with that of C-SCLC group (Table 4). With regard to the patients who received surgery (n = 74), no significant difference in survival between two subtypes of SCLC was found (v2 = 0.096, P = 0.757). However, among patients with extensive disease who were not given surgery (n = 280), C-SCLC cases had a poorer OS (v2 = 16.466, P \ 0.0001) (Fig. 3).
Discussion 18
SC/LC
6
SC/A
14
Surgery None
11
Done
25
10.294
0.001
7.806
0.005
4.112
0.043
5.641
0.018
LDH Normal (\240 U/L)
18
Elevated (C240 U/L) NSE (n = 35)
10
Normal (\15.2 lg/L)
34
Elevated (C15.2 lg/L)
11
Neutrophil-to-lymphocyte ratio Normal (\3)
18
Elevated (C3)
11
SC/Sq combined small-cell and squamous-cell carcinoma, SC/LC combined small-cell and large-cell carcinoma, SC/A combined smallcell and adenocarcinoma, LDH lactic dehydrogenase, NSE neuronal specific enolase
Forty-three (8.6 %) of our pure SCLC patients underwent surgery, which was significantly lower than that of the C-SCLC group (v2 = 30.167, P \ 0.001). With regard to laboratory parameters, NRL in our two groups was significantly different (v2 = 5.683, P = 0.017), there was no statistical difference between pure SCLC and C-SCLC patients in terms of other 10 variables. Furthermore, survival analysis showed, in pure SCLC cohort, NRL did not show significant association with OS (v2 = 1.098, P = 0.295), which was opposite to the C-SCLC cohort (v2 = 5.641, P = 0.018) (Fig. 2). The median OS in this pure SCLC group was 16 months. The 1, 2, and 5-year survival rates were 62.7, 25.0, and 7.9 %, respectively. As shown in Fig. 1, no difference in OS was observed in patients with C-SCLC and patients with pure SCLC (P = 0.995). Factors influencing the prognosis of pure SCLC were estimated with the Cox proportional hazards regression model to adjust the effects of covariates (NSE did not enter the model). After adjusting for confounding
Combined small-cell lung cancer is an uncommon subset of SCLC, and several studies have reported discordant data on the incidence of C-SCLC. In SCLC series both surgically and non-surgically managed, low incidence ranging from 2 to 12 % has been reported [19, 22–24]. On the other hand, in SCLC patients that have undergone surgery, the incidence of C-SCLC was higher. Hage et al. [21] reported an incidence of 26 %, Nicholson et al. [20] claimed 28 % of their SCLC cases showed combinations with NSCLC, and in a more recent study, Babakoohi et al. [22] said if one simply considers their SCLC patients that have undergone surgery, 45 % had C-SCLC. It is obvious that in SCLC patients diagnosed on the basis of limited biopsy material, such as bronchial biopsy or needle aspiration, the possibility of detecting a combined histology is lower due to the limited size and number of biopsy specimens and/or presence of crush artifact. Besides, it can be also concluded that, with the development of diagnostic technology, the prevalence of C-SCLC is rising in recent years. In the present study, 18.6 % of SCLC patients presented with C-SCLC of which 11.9 % had surgical resections, and when only SCLC patients that have undergone surgery were considered, 41.9 % had C-SCLC. This result is consistent with corresponding results reported in the relevant literature. Prior studies have identified a number of prognostic markers of SCLC, however, there have not been many data specific on C-SCLC. Some clinical data on characteristics and outcome of these patients have been published [18– 20], indicating some clinical features of C-SCLC were similar with pure SCLC. However, these studies date back to more than 20 years ago. Our study using the recent data, hence a potential possibility of diagnostic error resulting from outdate methods of diagnosis has been prevented. In the present study, 5-year survival of patients with C-SCLC was 15.9 %, which is lower than a prior study [22]; reasons for this discrepancy may due to the higher ratio of extensive disease and the larger sample size in this study.
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Fig. 2 a Relationship between NLR and overall survival in patients with combined SCLC (n = 114). b Relationship between NLR and overall survival in patients with pure SCLC (n = 499)
Table 4 Multivariate survival analysis in combined and pure SCLC patients Variable
Combined SCLC (n = 114)
Pure SCLC (n = 499)
HR (95 % CI)
P value
ECOG-PS C2
2.001 (1.165–3.435)
0.012
2.132 \0.001 (1.717–2.647)
Extensive disease
3.406 \0.001 (1.981–5.856)
1.482 \0.001 (1.194–1.839)
NLR C3
1.704 (1.054–2.752)
LDH C240 U/L
HR (95 % CI)
P value
0.030 1.811 \0.001 (1.449–2.265)
HR hazard ratio, CI confidence interval, NLR neutrophil-to-lymphocyte ratio, LDH lactic dehydrogenase
Moreover, similar to our results, a previous study has found that the performance status and disease extent were associated with survival of C-SCLC [23]. It has been demonstrated that NLR has a prognostic role in NSCLC [10, 11, 16, 25, 26]. However, limited data are available at present about the prognostic value of systemic inflammatory markers in SCLC. In this study, we evaluated the usefulness of NLR and PLR in SCLC for the first time. Results show that pretreatment NLR was an independent predictor of OS in C-SCLC patients, but not an important prognostic factor in pure SCLC. Further researches should be conducted to find whether systemic inflammatory
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response plays a same important role in C-SCLC like that in NSCLC. In this study, we compared 114 patients with C-SCLC to a concurrent group of 499 patients with pure SCLC. Our data indicate that a similar prognosis of patients with C-SCLC than those with pure small-cell variety. However, the rate of surgery for C-SCLC (27.2 % of cases) was much higher compared with pure SCLC (8.6 % of cases). Among patients with extensive disease who were not given surgery, that were given equivalent chemotherapy, C-SCLC cases had a poorer OS than pure SCLC patients (median OS: 9 vs. 12 months, P \ 0.0001), whereas the prognosis of cases received surgery in the two groups was similar (median OS: 25 vs. 25 months, P = 0.757). The results indicate that, in extensive stage, C-SCLC might carry a poorer outcome, and the similar prognosis in two groups might due to the higher rate of surgery in C-SCLC group. In addition, the prognostic significance of laboratory parameters including systemic inflammatory factors derived from blood routine counts, which were seldom involved in previous studies, is also evaluated in this study. We identified a different NRL in our two groups (34.8 % elevated in C-SCLC, 17.1 % elevated in pure SCLC), and in C-SCLC cohort NRL showed significant association with OS, which was opposite to the pure SCLC cohort, which resembles the low NLR survival benefit observed in NSCLC but not described for SCLC. The higher rate of surgery as well as the role of systemic inflammatory factor
Cell Biochem Biophys
Fig. 3 a Overall survival in patients with combined SCLC and patients with pure SCLC who received surgery (n = 74). b Overall survival in patients with combined SCLC and patients with pure SCLC who are with extensive disease and not given surgery (n = 280)
in prognosis of C-SCLC suggests that C-SCLC may have some of the features of NSCLC. This conclusion is also supported by the result that, LDH, which was proved to be an independent prognostic factor in the pure SCLC cohort, did not serve as an prognostic factor in multivariant analysis for C-SCLC patients. Our study used the latest data to evaluate prognostic significance of basic laboratory parameters in one of the largest C-SCLC cohort. The clinical, laboratory comparison between pure SCLC and C-SCLC patients in our study shows that C-SCLC represents a distinct pathologic variant of small-cell carcinoma of the lung, and some of clinical characteristics of C-SCLC are similar with NSCLC, which suggests the possibility for C-SCLC patients to participate in NSCLC trials. Since the shorter survival in extensive stage than the pure SCLC subtypes, early detection and surgery in early stage should be considered at the first place in C-SCLC management. Further studies associated with the origin of C-SCLC are needed for a more flexible approach in our treatment of C-SCLC.
Conclusion Although patients with C-SCLC carry a similar prognosis than those with pure small-cell variety, they retain many of the clinical characteristics of NSCLC patients. Easily accessible pretreatment parameters such as NLR should be considered in defining the prognosis of C-SCLC patients besides disease extent and performance status.
Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (Nos. 81372517 and 81000899), the Tianjin Municipal Science and Technology Commission Key Application Research Projects (No. 11JCZDJC18900), and the Science Foundation of Tianjin Health Bureau (No. 2010KZ78) Conflict of interest
The authors declare no conflicts of interest.
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ORIGINAL PAPER
Prognostic Significance of Pretreatment Laboratory Parameters in Combined Small-Cell Lung Cancer Xinyue Wang • Richeng Jiang • Kai Li
Ó Springer Science+Business Media New York 2014
Abstract Despite the increasing incidence of combined small-cell lung cancer (C-SCLC) in recent years, there have not been many data on clinical prognostic factors predicting prognosis of C-SCLC patients. In present study, we sought pretreatment features especially basic laboratory parameters predicting survival of C-SCLC. We analyzed 613 small-cell lung cancer (SCLC) patients at our institution between January 2005 and December 2010. We identified 114 patients with C-SCLC. The pathologic and clinical characteristics of these patients were reviewed. Data of laboratory parameters obtained during regular examinations at diagnosis of these patients were examined. The Kaplan–Meier method was used to calculate the survival rate and depict the survival curves. The Cox regression model was used to analyze the independent factors affecting the overall survival (OS). These data were compared with the results obtained from our 499 pure SCLC patients who presented during the same time period. Of the 613 SCLC patients analyzed, 18.6 % of the patients presented with C-SCLC. No difference in OS was observed in patients with C-SCLC and patients with pure SCLC (P = 0.995). The Kaplan–Meier survival curves
revealed that poor ECOG-PS (P \ 0.001), extensive disease (P \ 0.001), pathologic subtype of SC/LC (P \ 0.001), not receiving surgery (P = 0.001), elevated serum lactate dehydrogenase (LDH) (P = 0.005), elevated NSE (P = 0.043), and elevated neutrophile–lymphocyte ratio (NLR) (P = 0.018) were associated with adverse prognosis of patients with C-SCLC. By multivariate analysis, OS was affected by ECOG-PS (hazard ratio 2.001, P = 0.012), disease extent (hazard ratio 3.406, P \ 0.001), and NLR (hazard ratio 1.704, P = 0.030) in C-SCLC patients, while the risk factors that influenced the prognosis of the patients with pure SCLC were ECOG-PS (hazard ratio 2.132, P \ 0.001), disease extent (hazard ratio 1.482, P \ 0.001), and LDH (hazard ratio 1.811, P \ 0.001). Patients with C-SCLC carry a similar prognosis than those with pure small-cell variety. Easily accessible pretreatment parameters such as NLR should be considered in defining the prognosis of C-SCLC patients besides disease extent and performance status. Keywords Combined small-cell lung cancer Pure small-cell lung cancer Prognosis factors Neutrophile– lymphocyte ratio Surgery
Xinyue Wang and Richeng Jiang contributed equally to this study. X. Wang R. Jiang K. Li (&) National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China e-mail: [email protected] X. Wang R. Jiang K. Li Key Laboratory of Cancer Prevention and Therapy, Tianjin, China X. Wang R. Jiang K. Li Department of Thoracic Oncology, Cancer Institute and Hospital of Tianjin Medical University, Huanhuxi Road, Hexi District, Tianjin 300060, China
Introduction Small-cell lung cancer (SCLC) represents about 13 % of overall lung cancer cases worldwide. Unfortunately, despite trends toward modest improvement in survival of SCLC over the last 30 years, the outcome remains very poor [1]. Prognostic significance of various pretreatment parameters in patients with SCLC has been assessed in a number of retrospective studies. The factors recorded have differed between studies, but generally poor performance status,
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extensive stage, and an elevated serum lactate dehydrogenase (LDH) were the prognostic factors associated with poor survival in most studies [2–5]. Other factors positive in some studies are low serum sodium [2, 5–7], elevated alkaline phosphatase (ALP) [4, 6–8], male gender [2, 7–9], older age [2, 7], and low albumin [3, 6]. Neutrophile–lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) derived from blood routine counts known as systemic inflammatory markers were proved as prognostic factors in many types of cancer [10–16]. Prognostic importance of systemic inflammatory markers in NSCLC has been determined [10, 11, 16]. However, little is known whether systemic inflammatory factors are associated with the prognostic of SCLC. Combined small-cell lung carcinoma (C-SCLC) is defined by the world health organization (WHO) as smallcell carcinoma combined with an additional component that consists of any of the histologic types of non-small-cell carcinoma, usually adenocarcinoma, squamous-cell carcinoma, or large-cell carcinoma but less commonly spindle cell or giant cell carcinoma [17]. Some studies indicated that clinical characteristics in patients with C-SCLC do not differ significantly from those in patients with pure SCLC [18–21]. However, most of the research published from the 1970s to the 1990s, i.e., during when new methods of diagnosis such as PET-CT, immunohistochemistry was not routinely applied. Although in recent years, due to advances in the diagnosis of lung cancer, the incidence of C-SCLC has been increasing, and a recent study has shown that C-SCLC may have many of the features of NSCLC [22]; the WHO still considers C-SCLC to be a subset of SCLC. To our knowledge, only limited data with relative small numbers of patients are available with regard to clinical prognostic factors of cases with C-SCLC. In this study, we focus on the pretreatment basic laboratory parameters including systemic inflammatory factors which have been indicated to be important in predicting the prognosis of pure SCLC and/or NSCLC, to evaluate their prognostic significance in C-SCLC.
Materials and Methods Patients Using electronic medical records, 652 SCLC patients presented at Cancer Institute and Hospital of Tianjin Medical University between January 2005 and December 2010 were identified. After excluding patients who were initially evaluated at other centers and cases with incomplete follow-up data, 499 pure SCLC and 114 C-SCLC patients were ultimately included in this study.
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Table 1 Main patient characteristics and laboratory parameters in combined SCLC cohort (n = 114) Variable
No. of patients
%
Gender Male
89
78.1
Female
25
21.9
Age 18–69
92
80.7
*70
22
19.3
Smoking Never
26
22.8
\400
7
6.1
C400
81
71.1
0
21
18.4
1
37
32.5
2
50
43.9
3
6
5.3
Limited disease
68
59.6
Extensive disease
46
40.4
SC/Sq
80
70.2
SC/LC
23
20.2
SC/A Othersa
6
5.3
5
4.4
None
83
72.8
Done
31
27.2
None
81
71.1
Done
33
28.9
CE
92
80.3
Non CE
22
19.7
Normal (C110 g/L)
108
94.7
Anemic (\110 g/L)
6
5.3
ECOG-PS
Disease extent
Pathology subtype
Surgery
Thoracic irradiation
Chemotherapy
Hemoglobin
ALT Normal (\40 U/L)
97
85.1
Elevated (C40 U/L) Albumin
17
14.9
Normal (C30 g/L)
107
93.9
7
6.1
110
96.5
4
3.5
Decreased (\30 g/L) ALP Normal (\132 U/L) Elevated (C132 U/L) LDH Normal (\240 U/L)
75
65.8
Elevated (C240 U/L)
39
34.2
Creatinine (n = 108)
Cell Biochem Biophys Table 1 continued Variable Normal (\80 lmol/L) Elevated (\80 lmol/L) Not assessed Urea (n = 108)
No. of patients
%
104
96.3
4
3.7
6
Normal (\7.2 mmol/L)
76
70.4
Elevated (C7.2 mmol/L)
32
29.6
Not assessed
Decreased (\135 mmol/L) Not assessed
73
91.3
7
8.8
34
NSE (n = 35) Normal (\15.2 lg/L)
9
25.7
Elevated (C15.2 lg/L)
26
74.3
Not assessed
79
Neutrophil-to-lymphocyte ratio Normal (\3) Elevated (C3) Platelet-to-lymphocyte ratio
Ethics Statement
6
Serum sodium (n = 80) Normal (C135 mmol/L)
of time were also collected and evaluated for the purposes of comparison. Follow-up information was collected directly from the outpatient clinic records or from family contact. The overall survival was calculated from the date of diagnosis to the date of death or last visit. Patients known to be alive at last contact were censored.
68
59.6
46
40.4
Normal (\150)
73
64.0
Elevated (C150)
41
36.0
SC/Sq combined small-cell and squamous-cell carcinoma, SC/LC combined small-cell and large-cell carcinoma, SC/A combined smallcell and adenocarcinoma, ALT alanine transaminase, ALP alkaline phosphatase, LDH lactate dehydrogenase, NSE neuronal specific enolase a
Others: 1 combined SCLC patient had small-cell carcinoma and carcinoid tumor, and 4 patients had a mix of more than one nonsmall-cell components
Demographic and clinical data of the 114 C-SCLC patients including age, gender, smoking history, ECOG performance status, disease extent, pathology subtype, as well as pretreatment basic laboratory parameters, therapeutic strategies, and the date of death were obtained in the present study. The two-stage system of the Veteran’s Administration Lung Group was used to classify the patients. Limited disease is defined as disease confined to the ipsilateral chest within a single radiation field, and extensive disease was defined as disease beyond the ipsilateral hemithorax including malignant pleural, pericardial effusion, or hematogenous metastasis. With regard to the combined pathology, combined small-cell and squamouscell carcinoma(SC/Sq) or combined small-cell and adenocarcinoma (SC/A) were defined as the presence of any amount of non-small-cell component, and for combined small-cell and large-cell carcinoma (SC/LC) diagnosis the presence of at least 10 % LCs were considered. In addition, the data of 499 pure SCLC patients seen in the same period
The study was approved by the Research Ethics Committee of Cancer Institute and Hospital of Tianjin Medical University, China. Informed consent was obtained either from the patients or the patient’s family before participating in the study. Statistical Analysis Seventeen pretreatment variables including 6 demographic and clinicopathological factors (age, gender, smoking history, ECOG performance status, disease extent, and pathology subtype), 8 factors measured in pretreatment basic laboratory examinations (hemoglobin, alanine transaminase (ALT), albumin, ALP, LDH, urea, creatinine, serum sodium), a serum tumor marker (neuronal specific enolase (NSE)), and 2 systemic inflammatory factors derived from blood routine counts (NLR and PLR derived from neutrophil, platelets, and lymphocyte) (Table 1) were chosen for analysis. Continuous variables were described using mean ± SD or median and range. Frequency counts and proportions were calculated for categorical data, and Chi square tests or the Fisher’s exact tests were adopted to compare between groups. The median of the overall survival was determined by the Kaplan–Meier method and compared among different groups using the log-rank test. Furthermore, we performed Cox proportional hazards regression analysis with stepwise variable selection to identify significant independent prognostic factors for the overall survival. Hazard ratios (HR) and 95 % confidence interval (CI) were generated. All P values were two sided, and P \ 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 20.
Results Patient Characteristics, Treatment and Laboratory Parameters Of the 613 SCLC patients analyzed, 114 (18.6 %) of the patients are presented with C-SCLC. C-SCLC patients characteristics including demographic, clinical, and
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Cell Biochem Biophys Table 2 Statistical description for laboratory parameters in combined SCLC cohort Variable
Mean ± SD/median (range)
Hemoglobin (g/L, n = 114) 9
137.69 ± 14.261
Neutrophil (10 /L, n = 114)
7.14 ± 3.487
Lymphocyte (109/L, n = 114)
2.07 ± 0.67
Platelets (109/L, n = 114)
260.52 ± 81.64
ALT (U/L, n = 114)
17 (4–546)
Albumin (g/L, n = 114)
43.76 ± 4.483
ALP (U/L, n = 114) LDH (U/L, n = 114)
74.35 ± 26.249 246.66 ± 139.190
Creatinine (lmol/L, n = 108)
70.19 ± 17.766
Urea (mmol/L, n = 108)
5.4 (2.0–94.0)
Serum sodium (mmol/L, n = 80)
141.15 ± 5.236
NSE (lg/L, n = 35)
19.50 (7.54–370.00)
ALT alanine transaminase, ALP alkaline phosphatase, LDH lactic dehydrogenase, NSE neuronal specific enolase
pathologic data as well as data of laboratory parameters are shown in Table 1. The mean age of the patients was 59.31 years. Of the 114 patients, including 89 males and 25 females, 68 (59.6 %) patients suffered limited disease, 46 (40.4 %) suffered extensive disease. Histologically, 80 patients (73.7 %) had SC/Sq, 23 patients (20.2 %) had SC/ LC, 6 patients (5.3 %) had SC/A, 1 (0.9 %) C-SCLC patient had small-cell carcinoma and carcinoid tumor, and other 4 patients had a mix of more than one non-small-cell components. Eleven of the SC/Sq cases had basaloid/ spindle components. The ECOG performances status score of 21 patients (18.4 %) was 0, score of 37 patients (32.5 %) was 1, score of 50 patients (43.9 %) was 2, and score of other 4 patients (5.3 %) was 3. Among all the C-SCLC patients, 31 (27.2 %) underwent surgical resection with lobectomy or pneumonectomy as the initial treatment, 27 surgery cases received adjuvant chemotherapy with EP regimen (platinum and etoposide). The 83 non-surgical patients received routine SCLC treatment. All patients in our cohort underwent at least 4 cycles of platinum-based chemotherapy with routine regimen for SCLC (adjuvant chemotherapy also included), and 33 patient received thoracic irradiation (postoperative radiotherapy also included). Refer to the normal range of the laboratory parameter values in our institute or previous studies, pretreatment laboratory parameters were categorized into normal and abnormal values (Table 1). Statistical description for laboratory parameters in C-SCLC cohort is shown in Table 2. Survival Analysis The median OS was 14 months (Fig. 1). The 1, 2, and 5-year survival rates were 51.2, 30.3, and 15.9 %, respectively. The
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Fig. 1 Overall survival in patients with combined SCLC and patients with pure SCLC (n = 613)
Kaplan–Meier estimation of OS stratified by levels of different factors is shown in Table 3. The following factors were identified as adverse prognostic features by the logrank test: a poor ECOG-PS (v2 = 23.816, P \ 0.001), extensive disease (v2 = 42.449, P \ 0.001), SC/LC (v2 = 67.271, P \ 0.001), not receiving surgery (v2 = 10.294, P = 0.001), elevated LDH (v2 = 7.806, P = 0.005), elevated NSE (v2 = 4.112, P = 0.043), and elevated NLR (v2 = 5.641, P = 0.018). After selection of these parameters for multivariate analysis using Cox’s proportional hazards model, ECOG-PS (hazard ratio 2.001, P = 0.012), disease extent (hazard ratio 3.406, P \ 0.001), and NLR (hazard ratio 1.704, P = 0.030) were independent prognostic factors for poor overall survival. NSE was not taken into account because they were determined only in 35 cases, respectively, which would limit the number of patients considered for distribution into prognostic groups. Comparison with Pure SCLC With regard to the 499 patients with SCLC (375 male and 124 female patients) presented during the same time period, the mean age was 58.53 years. In this pure SCLC group, 265 (53.1 %) patients suffered limited disease and 234 (46.9 %) suffered extensive disease. There was no statistical difference between pure SCLC and C-SCLC patients in terms of gender (v2 = 0.43, P = 0.512), age (v2 = 2.998, P = 0.083), smoking history (v2 = 2.226, P = 0.329), ECOG performance status (v2 = 0.025, P = 0.873), or disease extent (v2 = 1.601, P = 0.206).
Cell Biochem Biophys Table 3 Univariate survival analysis in combined SCLC patients, showing significant values (P \ 0.05) Variable
Median OS (months)
Chi-square value
P value
0
31
23.816
\0.001
1 2
14 11
3
6 42.449
\0.001
67.271
\0.001
ECOG-PS
Disease extent Limited disease Extensive disease
24 9
Pathology subtype SC/Sq
variables, ECOG-PS (hazard ratio 2.132, P \ 0.001), disease extent (hazard ratio 1.482, P \ 0.001), as well as LDH (hazard ratio 1.811, P \ 0.001) remained independent predictors of overall survival, which was partly different with that of C-SCLC group (Table 4). With regard to the patients who received surgery (n = 74), no significant difference in survival between two subtypes of SCLC was found (v2 = 0.096, P = 0.757). However, among patients with extensive disease who were not given surgery (n = 280), C-SCLC cases had a poorer OS (v2 = 16.466, P \ 0.0001) (Fig. 3).
Discussion 18
SC/LC
6
SC/A
14
Surgery None
11
Done
25
10.294
0.001
7.806
0.005
4.112
0.043
5.641
0.018
LDH Normal (\240 U/L)
18
Elevated (C240 U/L) NSE (n = 35)
10
Normal (\15.2 lg/L)
34
Elevated (C15.2 lg/L)
11
Neutrophil-to-lymphocyte ratio Normal (\3)
18
Elevated (C3)
11
SC/Sq combined small-cell and squamous-cell carcinoma, SC/LC combined small-cell and large-cell carcinoma, SC/A combined smallcell and adenocarcinoma, LDH lactic dehydrogenase, NSE neuronal specific enolase
Forty-three (8.6 %) of our pure SCLC patients underwent surgery, which was significantly lower than that of the C-SCLC group (v2 = 30.167, P \ 0.001). With regard to laboratory parameters, NRL in our two groups was significantly different (v2 = 5.683, P = 0.017), there was no statistical difference between pure SCLC and C-SCLC patients in terms of other 10 variables. Furthermore, survival analysis showed, in pure SCLC cohort, NRL did not show significant association with OS (v2 = 1.098, P = 0.295), which was opposite to the C-SCLC cohort (v2 = 5.641, P = 0.018) (Fig. 2). The median OS in this pure SCLC group was 16 months. The 1, 2, and 5-year survival rates were 62.7, 25.0, and 7.9 %, respectively. As shown in Fig. 1, no difference in OS was observed in patients with C-SCLC and patients with pure SCLC (P = 0.995). Factors influencing the prognosis of pure SCLC were estimated with the Cox proportional hazards regression model to adjust the effects of covariates (NSE did not enter the model). After adjusting for confounding
Combined small-cell lung cancer is an uncommon subset of SCLC, and several studies have reported discordant data on the incidence of C-SCLC. In SCLC series both surgically and non-surgically managed, low incidence ranging from 2 to 12 % has been reported [19, 22–24]. On the other hand, in SCLC patients that have undergone surgery, the incidence of C-SCLC was higher. Hage et al. [21] reported an incidence of 26 %, Nicholson et al. [20] claimed 28 % of their SCLC cases showed combinations with NSCLC, and in a more recent study, Babakoohi et al. [22] said if one simply considers their SCLC patients that have undergone surgery, 45 % had C-SCLC. It is obvious that in SCLC patients diagnosed on the basis of limited biopsy material, such as bronchial biopsy or needle aspiration, the possibility of detecting a combined histology is lower due to the limited size and number of biopsy specimens and/or presence of crush artifact. Besides, it can be also concluded that, with the development of diagnostic technology, the prevalence of C-SCLC is rising in recent years. In the present study, 18.6 % of SCLC patients presented with C-SCLC of which 11.9 % had surgical resections, and when only SCLC patients that have undergone surgery were considered, 41.9 % had C-SCLC. This result is consistent with corresponding results reported in the relevant literature. Prior studies have identified a number of prognostic markers of SCLC, however, there have not been many data specific on C-SCLC. Some clinical data on characteristics and outcome of these patients have been published [18– 20], indicating some clinical features of C-SCLC were similar with pure SCLC. However, these studies date back to more than 20 years ago. Our study using the recent data, hence a potential possibility of diagnostic error resulting from outdate methods of diagnosis has been prevented. In the present study, 5-year survival of patients with C-SCLC was 15.9 %, which is lower than a prior study [22]; reasons for this discrepancy may due to the higher ratio of extensive disease and the larger sample size in this study.
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Fig. 2 a Relationship between NLR and overall survival in patients with combined SCLC (n = 114). b Relationship between NLR and overall survival in patients with pure SCLC (n = 499)
Table 4 Multivariate survival analysis in combined and pure SCLC patients Variable
Combined SCLC (n = 114)
Pure SCLC (n = 499)
HR (95 % CI)
P value
ECOG-PS C2
2.001 (1.165–3.435)
0.012
2.132 \0.001 (1.717–2.647)
Extensive disease
3.406 \0.001 (1.981–5.856)
1.482 \0.001 (1.194–1.839)
NLR C3
1.704 (1.054–2.752)
LDH C240 U/L
HR (95 % CI)
P value
0.030 1.811 \0.001 (1.449–2.265)
HR hazard ratio, CI confidence interval, NLR neutrophil-to-lymphocyte ratio, LDH lactic dehydrogenase
Moreover, similar to our results, a previous study has found that the performance status and disease extent were associated with survival of C-SCLC [23]. It has been demonstrated that NLR has a prognostic role in NSCLC [10, 11, 16, 25, 26]. However, limited data are available at present about the prognostic value of systemic inflammatory markers in SCLC. In this study, we evaluated the usefulness of NLR and PLR in SCLC for the first time. Results show that pretreatment NLR was an independent predictor of OS in C-SCLC patients, but not an important prognostic factor in pure SCLC. Further researches should be conducted to find whether systemic inflammatory
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response plays a same important role in C-SCLC like that in NSCLC. In this study, we compared 114 patients with C-SCLC to a concurrent group of 499 patients with pure SCLC. Our data indicate that a similar prognosis of patients with C-SCLC than those with pure small-cell variety. However, the rate of surgery for C-SCLC (27.2 % of cases) was much higher compared with pure SCLC (8.6 % of cases). Among patients with extensive disease who were not given surgery, that were given equivalent chemotherapy, C-SCLC cases had a poorer OS than pure SCLC patients (median OS: 9 vs. 12 months, P \ 0.0001), whereas the prognosis of cases received surgery in the two groups was similar (median OS: 25 vs. 25 months, P = 0.757). The results indicate that, in extensive stage, C-SCLC might carry a poorer outcome, and the similar prognosis in two groups might due to the higher rate of surgery in C-SCLC group. In addition, the prognostic significance of laboratory parameters including systemic inflammatory factors derived from blood routine counts, which were seldom involved in previous studies, is also evaluated in this study. We identified a different NRL in our two groups (34.8 % elevated in C-SCLC, 17.1 % elevated in pure SCLC), and in C-SCLC cohort NRL showed significant association with OS, which was opposite to the pure SCLC cohort, which resembles the low NLR survival benefit observed in NSCLC but not described for SCLC. The higher rate of surgery as well as the role of systemic inflammatory factor
Cell Biochem Biophys
Fig. 3 a Overall survival in patients with combined SCLC and patients with pure SCLC who received surgery (n = 74). b Overall survival in patients with combined SCLC and patients with pure SCLC who are with extensive disease and not given surgery (n = 280)
in prognosis of C-SCLC suggests that C-SCLC may have some of the features of NSCLC. This conclusion is also supported by the result that, LDH, which was proved to be an independent prognostic factor in the pure SCLC cohort, did not serve as an prognostic factor in multivariant analysis for C-SCLC patients. Our study used the latest data to evaluate prognostic significance of basic laboratory parameters in one of the largest C-SCLC cohort. The clinical, laboratory comparison between pure SCLC and C-SCLC patients in our study shows that C-SCLC represents a distinct pathologic variant of small-cell carcinoma of the lung, and some of clinical characteristics of C-SCLC are similar with NSCLC, which suggests the possibility for C-SCLC patients to participate in NSCLC trials. Since the shorter survival in extensive stage than the pure SCLC subtypes, early detection and surgery in early stage should be considered at the first place in C-SCLC management. Further studies associated with the origin of C-SCLC are needed for a more flexible approach in our treatment of C-SCLC.
Conclusion Although patients with C-SCLC carry a similar prognosis than those with pure small-cell variety, they retain many of the clinical characteristics of NSCLC patients. Easily accessible pretreatment parameters such as NLR should be considered in defining the prognosis of C-SCLC patients besides disease extent and performance status.
Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (Nos. 81372517 and 81000899), the Tianjin Municipal Science and Technology Commission Key Application Research Projects (No. 11JCZDJC18900), and the Science Foundation of Tianjin Health Bureau (No. 2010KZ78) Conflict of interest
The authors declare no conflicts of interest.
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